Advances in polymeric and non-polymeric nanocarriers for the magnified delivery of levofloxacin against bacterial infection

Abstract

This review examines the latest developments in nanoscopic antibiotic formulations used to treat infections caused by bacteria. A wide range of nanocarrier platforms are discussed, including polymer-based nanoparticles (NPs), lipid-based vesicles, mesoporous silica, and other inorganic materials. The antibiotic levofloxacin (LVF) is predominantly used as a model drug given its broad-spectrum activity. Studies in this regard have evaluated drug loading and encapsulation efficiency (EE) using analytical techniques such as FTIR, DLS, and TEM. In vitro release kinetics was characterized through dialysis and fluorescence-based assays. Zone of inhibition and viability studies provided insights into antibacterial efficacy. Some approaches incorporated stimuli-responsive polymers or targeting ligands to facilitate controlled or targeted drug release. Overall, the nanocarriers demonstrated potential for sustained antibiotic levels, reduced dosing, and improved treatment of biofilms and intracellular infections compared to free drug administration. The review offers a comprehensive analysis of this promising field with implications for combating antibiotic resistance.

Introduction

Bacterial infections have a profound impact on the population of well-being. Pathology can manifest in any anatomical location and may arise either from the organism itself or the immune response of the body to its presence. Bacteria can be transmitted to individuals through various methods, including inhalation of air, ingestion of contaminated water or food, or by living organisms acting as carriers [1]. Nanotechnology is the discipline focused on creating materials at the atomic and molecular levels. As outlined by the National Nanotechnology Initiative, it concentrates on structures with dimensions falling within the range of 1 to 100 nm. In practical terms, nanoscience commonly includes structures that extend to several hundred nanometers. The fabrication of these structures involves the design of individual parts. Notably, despite their size limitations, nanoparticles show substantial capability as an exceptionally efficient method of delivering drugs [2, 3]. In recent decades, researchers have identified the potential of polymer-based NPs as effective vehicles for delivering biologically active substances, like drugs, proteins, and genes. These nanoparticles may be specifically designed to react to particular stimuli, either occurring naturally or externally induced. This modification capability enables precise control over drug or gene release at targeted locations. Various types of nanoparticles, such as metallic nanoparticles, dendrimers, polymeric NPs, quantum dots, and liposomes, have been functionalized and employed as templates for imaging systems [4, 5]. Lipid nanocarriers represent a rapidly advancing and highly promising technology for delivering medications with limited solubility, bioavailability, and stability, a challenge observed in around 40% of recently developed drugs. Originally, the term “lipid carrier” included liposomes and other vesicular systems; however, it is currently categorized as colloidal nanolipid-based carriers. In order to tackle problems associated with the breakdown of traditional nanocarriers due to pH and enzyme activity, particularly in the context of oral administration and stability, recent lipid nanocarriers, including solid lipid nanoparticles (SLNs), lipid drug conjugates (LDCs), nanostructured lipid carriers (NLCs), and pharmacosomes, have proven their efficacy. These developments provide the benefits of reduced toxicity, improved ability to be absorbed by the body, strong compatibility with biological systems, high capacity to carry drugs, and protection against degradation in the gastrointestinal tract. Lipid nanocarriers have the potential to encapsulate and convey medications that are soluble in both water and fat. Lipophilic drugs belonging to Biopharmaceutics Classification System (BCS) Class II and IV are usually hindered in their absorption rate due to their restricted solubility. However, this constraint may be effectively circumvented by developing lipid nanocarriers. Furthermore, lipid nanocarriers have the capacity to enhance the penetration of water-soluble drugs in BCS I and III categories, therefore addressing the process that limits the rate of drug absorption in this particular situation. Moreover, these carriers exhibit efficient controlled and site-specific drug delivery systems, continually attracting the attention of researchers [6, 7]. Mesoporous silica nanoparticles (MSNs) are often employed as vehicles due to the advantageous chemical characteristics, thermal resilience, and biocompatibility of silica. The distinctive mesoporous configuration of silica enables effective drug encapsulation and precise release at the targeted location. The attributes of mesoporous materials, including porosity, medication loading capacity, porosity, and surface characteristics, may be adjusted by incorporating additives during the MSN preparation process [8]. Antibacterial drugs are classified based on their mechanism of action, such as inhibiting cell wall synthesis, altering cell membrane permeability, or interfering with various cellular processes. Additionally, they can be classified according to their molecular structure. Researchers have published numerous reviews and study papers in recent decades, investigating the effectiveness of various nanopharmaceutical systems, including flutamide [9], cabazitaxel [4], mitomycin C [5], carmustine [10], and fludarabine [11] among others. Levofloxacin is the l-isomer of ofloxacin, which is a racemate consisting of both d and l isomers [12]. It is an antibiotic utilized for treatment of bacterial infections and is considered as reliable and efficient medication listed among the essential drugs identified by the World Health Organization. It is accessible in oral and intravenous forms, both of which exhibit comparable bioavailability and has been authorized for the management of various infections. Originally patented in 1985 and approved for clinical utilization in the United States in 1996, levofloxacin (CAS 100986–85-4) exhibits a wide-ranging antibacterial efficacy, targeting a diverse array of Gram-positive and Gram-negative aerobic bacteria, as well as atypical bacterial strains such as Streptococcus pneumoniae [13, 14]. It offers several advantages compared to previous quinolones, showcasing improved antibacterial effectiveness, particularly against Streptococci. The common adverse effects associated with levofloxacin include nausea and diarrhea, with a lower propensity for photosensitivity issues relative to certain other quinolones. Additionally, notable cardiac and hepatic adverse events are rarely seen with levofloxacin in clinical practice. Additionally, notable cardiac and hepatic adverse events are infrequently reported in clinical settings [15]. Within this context, the discussion will focus on recommended uses, pathways, side effects, contraindications, treatment protocols, safety considerations, and related drug combinations. This information holds paramount importance for healthcare professionals engaged in the care of patients with bacterial infections [16, 17]. This review examined the possibility of utilizing LVF in conjunction with specific NPs for the treatment of bacterial infections. Throughout our conversation, we examined various medication delivery systems that possess a broad spectrum of unique functionalities. Multiple researchers have investigated the application of polymer-based and lipidic NPs, as well as an array of organic, inorganic, and combined delivery systems, for delivering LVF.

Levofloxacin: a drug of choice for the treatment of bacterial infection

Levofloxacin (LEVAQUIN®), a chiral fluorinated carboxyquinolone, is the pure (-)-(S)-enantiomer of the racemic drug substance ofloxacin. The chemical name is (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hemihydrate. The empirical formula is C₁₈H₂₀FN₃O₄ · ½ H₂O, and its molecular weight is 370.38. Levofloxacin is a light yellowish-white to yellow-white crystal or crystalline powder. In pH 6 to 5.8, the solubility of levofloxacin is constant, but at pH = 6.7, the solubility is at maximum and above that, it decreases [18]. Figure 1 displays LVF’s molecular structure [19].

Fig. 1

Chemical structure of levofloxacin [19]

The type of the participating bacteria will determine the degree of bacterial infections, which vary greatly. Targeting particular body parts, bacterial organisms often have for instance germs including syphilis, Chlamydia trachomatis, and Neisseria gonorrhoeae can all cause sexually transmitted diseases (STIs). Mostly affecting the vaginal area, these diseases in Table 1 give a thorough summary of typical bacterial infections.

Table 1 Common bacterial infections

In Table 2, the most popular antibacterial agents approved by the United States Food and Drug Administration (US FDA) are highlighted.

Table 2 Main features of antibacterial medications developed in last decade

Applications of levofloxacin

Infectious Diseases Society of America (IDSA) recommends levofloxacin in the treatment of community-acquired pneumonia (CAP). Levofloxacin 750 mg once daily has shown efficacy in treating various infections, such as complicated skin and skin structure infections (CSSSIs), due to its ability to reach higher concentrations in wound tissue compared to blood levels. Additionally, levofloxacin is employed as a bactericidal agent in the treatment of urinary tract infections and acute uncomplicated pyelonephritis due to its high concentration in the urinary tract and renal clearance [39, 40]. Furthermore, levofloxacin is a recommended treatment option for tuberculosis (TB) at a daily dose of 750–1000 mg, according to WHO guidelines. In addition, levofloxacin’s ophthalmic solution is effective in treating ophthalmic infections like conjunctivitis [23]. A daily oral dose of 500 mg of levofloxacin is a safe and effective antibiotic therapy for bone and joint infections (BJIs). Levofloxacin is well-tolerated by patients and shows efficacy in treating these types of infections [41].

Mechanism of actions

The mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair, and recombination. Levofloxacin is active against a range of gram-positive bacteria like Staphylococcus aureus, S. pyogenes, S. pneumoniae, and viridans and β-hemolytic streptococci. Levofloxacin tended to be more active than ciprofloxacin against Gram-positive organisms, but less active compared with moxifloxacin and gatifloxacin against Gram-positive organisms. although some strains may show only moderate susceptibility (Providencia rettgeri and Pseudomonas aeruginosa) or resistance (Serratia marcescens). Levofloxacin tended to have higher minimum inhibitory concentration MIC90 on Gram-positive bacteria and lower effect against anaerobes [12]. Furthermore, it has been shown that levofloxacin is active against aerobic Gram-negative bacteria like H. pylori, Haemophilus influenzae, Moraxella catarrhalis, Acinetobacter spp., and Stenotrophomonas maltophilia. Levofloxacin, like several other fluoroquinolones, was active in vitro against strains of Helicobacter pylori. MIC90 values for levofloxacin, ciprofloxacin, and moxifloxacin were all 0.5 m/L [42].

Drug resistance

Drug resistance refers to the various ways in which microorganisms, such as bacteria or viruses, develop the ability to withstand the effects of drugs meant to kill or inhibit their growth. These mechanisms can include changes in the target of the drug, activation of alternative pathways, increased efflux of the drug from the cell, and others. Understanding these mechanisms is important in the development of new drugs and treatment strategies to combat drug-resistant microorganisms. Antibiotic resistance mechanisms involve mutations in target enzymes like DNA gyrase and topoisomerase IV, leading to reduced drug binding and the accumulation of highly resistant bacterial strains. Additionally, mutations in regulatory genes can result in overexpression of efflux pumps, decreasing drug accumulation within bacterial cells. Acquired resistance-conferring genes, found on plasmids, can encode protective proteins that impede the action of antibiotics on target enzymes. This understanding of resistance mechanisms is crucial for developing strategies to combat antibiotic-resistant pathogens, such as exploring alternative treatments like bacteriophage therapy [43]. There is evidence suggesting that prior use of antibiotics within 3 months may lead to reduced effectiveness of levofloxacin. To prevent potential resistance and preserve their effectiveness for when they are truly needed, we have to limit unnecessary prescriptions of levofloxacin [44].

Addressing drug resistance

To combat antibiotic resistance, various strategies can be implemented. Some approaches to tackle this issue are developing new antibiotics and emphasizing the need for a comprehensive approach [45].

Using quorum quenchers

The second method of overcoming is using quorum quenchers or quorum sensing inhibitors as an alternative to antibiotics to disrupt a process called quorum sensing in bacteria. Quorum sensing is a way bacteria communicate with each other to coordinate their activities like spreading infections. By disrupting quorum sensing, we can potentially stop bacterial activities without relying on antibiotics. One particular quorum inhibitor, FS3, was tested in rats and showed good results, but its use in clinical settings is still uncertain [45].

Biologic methods

The third method is using antimicrobial peptides (AMPs). They work by damaging bacterial cell membranes, inhibiting cell wall synthesis, forming pores in membranes, and disrupting membrane structures. Some FDA-approved AMPs are bacitracin, colistin, and polymyxin B [46]. Furthermore, Bacteriophages also have shown effectiveness against both gram-negative and gram-positive bacteria. Bacteriophages are viruses that are specialized to infect bacteria by recognizing specific receptors on the bacterial cell surface [47].

Dual drugs

Relying solely on one type of antibiotic for clinical treatment may not be effective due to the potential for the bacteria to develop resistance to that particular antibiotic. To address this challenge, dual-drug delivery can be effective [48].

Levofloxacin drug delivery systems

Recent advancements have led to the suggestion of diverse delivery systems for encapsulating drug and bioactive compounds using nanoparticles. These systems are classified into polymeric, non-polymeric, lipid-based, and nanocrystalline categories, each offering unique characteristics for effective encapsulation and delivery of drug. Figure 2 shows primary categories of nanoparticles (NPs) [49].

Fig. 2

Primary categories of nanoparticles (NPs), such as polymeric, non-polymeric, lipid-based, and nanocrystalline materials are utilized for encapsulating nutrients and bioactive compounds from food sources [49]

Polymer-based NPs for levofloxacin delivery

Polymeric NPs exhibit their practicality in delivering therapeutic agents by effectively integrating large molecular chains physically or chemically linked to drug molecules. This approach enhances drug stability, water solubility, and therapeutic effectiveness while reducing dosing frequency and minimizing adverse effects. It achieves this through the controlled release of drugs, managing site, duration, and rate effectively. These nanoparticles maintain their structural integrity due to the rigid polymer matrix [50, 51]. Additionally, they enable precise drug control and sustained release, ultimately improving therapeutic efficacy by reducing the need for frequent dosing. Furthermore, stimuli-sensitive polymers have been gaining recognition in academic and industrial settings. Notably, elevated pH levels in wounds serve as diagnostic signals for clinical conditions [52]. Monitoring significant temperature changes in wound areas is an established method for detecting bacterial infections [53]. Utilizing stimuli-responsive polymers shows promise in enhancing control in these specific applications. These nanoparticles possess the ability to increase the solubility kinetics of weakly dissolvable or hydrophobic components. Moreover, their surface modification capabilities allow precise drug targeting and immune system avoidance, extending the in vivo therapeutic duration [54]. Polymeric nanoparticles are excellent options for both oral and intravenous delivery and can seamlessly integrate into various aspects of drug delivery–related endeavors [55]. Figure 3 shows different forms of polymer-based nanoparticles used in pharmaceutical formulation systems [56].

Fig. 3

The diverse types of polymer-based nanoparticles serve as carriers for medication delivery [56]

Non-responsive polymer-based NPs

Jalvandi et al. [57] in 2016 developed a system in which drug-conjugated chitosan (CS) was integrated into nanofibers made of polyvinyl alcohol (PVA). Their findings demonstrated the feasibility of achieving controlled release of LVF which were connected with an amino linkage to CS. Subsequently, the modified CS was blended with polyvinyl alcohol nanofibers before electrospinning. The primary focus of their research involved creating a regulated medication delivery formulation. The study also examined the structure and diameter of the electrospun fibers, noting that the inclusion of CS led to a reduction in fiber diameter. Specifically, the mean nanofiber size decreased from 200–300 to 100–200 nm. In terms of drug delivery patterns, there was a substantial reduction in the initial rapid discharge, declining from 90% in the electrospun fibers made from a PVA combined with LVF to 27% in the mats composed of polyvinyl alcohol linked with CS modified with LVF after an 8-h incubation in a buffer solution containing phosphate ions at 37 °C. Furthermore, roughly 50% of the drug was transported over a 72-h duration. Drug-eluting meshes have the potential to act as the main barrier against bacterial infections. In 2021, Corduas et al. [58]-manufactured meshes have been filled with polycaprolactone (PCL) and LVF. In their study, PCL was utilized to create resorbable meshes loaded with LVF, designed in two variations (at 90° and 45°). The meshes underwent comprehensive characterization, including assessments of their physical structure, strength characteristics, drug release rates, and antibacterial effectiveness. Tensile testing revealed that the 45° drug-loaded meshes exhibited mechanical properties similar to vaginal tissue and had an average fiber diameter close to 400 μm. In their study, meshes demonstrated the capability to provide constant release of LVF for a minimum of 3 days; over the course of this period, nearly 80% of the initially enclosed drug was discharged. Approximately 90% of the LVF was released in 4 weeks. Additionally, they assessed the antibacterial effectiveness of these meshes employing the inhibition zone technique. In other research, Agha et al. [59] in 2023 proposed a novel strategy to the ocular delivery of LVF, involving the creation of a Spanlastic-laden in situ gel. In their study, they entrapped the antimicrobial agent LVF hemihydrate within a matrix of Spanlastics (SLs). This method was designed to facilitate sustained drug release, enhance antimicrobial activity, and improve the penetration of LVF across the cornea. To formulate the Spanlastics, the experiment utilized a blend of span 60 used in gradient along with tweens as edge activator. Thirty-two factorials were used to examine the impact of formulation variables. In the optimal formulation, it exhibited an encapsulation EE% of 59.7 ± 4.2%, a particle size of 177.6 ± 1.8 nm, and a zeta potential (ZP) of − 40.6 ± 0.68 mV. The release kinetics of LVF from the prepared formulations followed the Higuchi model, with the optimal formulation (Span 60: Tween 60 at 80: 20) displaying a high R-squared (R²) value of 0.9947. Moreover, only 39.37 ± 0.72% of LVF was released during a 4-h interval, in stark contrast to the complete release observed with the LVF solution. An assessment for ocular irritation was executed, revealing the absence of any indications of irritation or congestion subsequent to the application of the formulations. In laboratory-based investigations, a substantial 200% enhancement in antibacterial effectiveness against Pseudomonas aeruginosa and a notable 100% increase against Staphylococcus aureus were ascertained. Researchers chose an in vivo model over ex-vivo methods to validate in vitro corneal permeability. This confirmed the formulation’s safety for applying to the eyes without any adverse effects. In a separate study, Kırımlıoğlu et al. [60] successfully integrated LVF hemihydrate into Eudragit® RL 100 (ERL) nanoparticles, with the 2016 aim of facilitating oral administration.

Various ratios of ERL and LVF were utilized to formulate Eudragit® RL 100-LVF1, Eudragit® RL 100 -LVF2, Eudragit® RL 100-LVF3 formulations, respectively. The LVF-loaded nanoparticles demonstrated an average particle size spanning from 232 to 427 nm across all formulations, and a decrease in the LVF quantity led to reduction in the mean particle size. The measured ZPs were 39.23 ± 0.18 mV, 38.43 ± 0.15 mV, and 41.33 ± 0.47 mV for the respective formulations mentioned above. The study also assessed drug loading and encapsulation effectiveness. EE% was discovered to be 11.33%, 9.07%, and 7.73 ± 0.86%, while drug loading was 8.70 ± 0.48%, 4.69 ± 0.51%, and 2.71 ± 0.07% for the respective formulations. Among the prepared formulations, ERL-LVF1 exhibited a smaller particle size, a restricted size variation, comparatively robust encapsulation efficiency, and a sustained release pattern. The released results revealed that LVF nanoparticles showed first rapid discharge within the first 30 min after application, subsequently leading to prolonged discharge followed by constant release over a 24-h period. In new research, CS-NPs were used to entrap the antibacterial drug LVF for treating eye infections. Ameeduzzafar and colleagues [61] in 2017 produced these CS nanoparticles, combining CS and sodium tripolyphosphate (TPP) to optimize their delivery to the eyes. The selected optimized CS nanoparticles had particle sizes of 161.90 ± 3.32 to 283.97 ± 4.21 nm and ZPs of + 30.43 ± 1.08 to + 21.87 ± 1.87 mV. By increasing the level of CS and TPP, the particle size significantly increased, and higher ZP values indicated stronger electrostatic repulsion between the particles. The pharmaceutical content and entrapment effectiveness were 3.13 ± 0.67 to 4.23 ± 1.11% and 56.87 ± 1.54 to 73.63 ± 1.54%, respectively. Irritation potential was assessed, concluding that the in situ gel system containing LVF-loaded CS nanoparticle is gentle on the eyes and is well-received for ocular use. Furthermore, the histological examination of goat corneal tissue displayed no alterations following the application of the optimized system containing LVF-loaded CS nanoparticles. Additionally, antimicrobial assessments showcased the potent antibacterial properties of the formulation against P. aeruginosa and S. aureus.

In another study, Cheow and coworkers in 2010 [62] explored ways to enhance the effectiveness of encapsulating LVF, known for its high solubility in water and solvents, within PLGA nanoparticles. In the scholarly investigation, three distinct nanoparticle preparation techniques were employed called nanoprecipitation (NPC), single emulsification-solvent evaporation (ESE), and double ESE (DESE). Nanoparticles produced through the NPC method showed a notably reduced size (approximately 100 nm) compared to those created using the ESE and DESE methods around 200 nm. Despite their small dimensions, the NPC technique had less productivity rates of about 65% compared to the ESE and DESE techniques, which had approximately 90%. The ZPs of all the NPs fell between the boundaries of − 10 to − 30 mV, indicating their colloidal stability. The percentage of LVF encapsulated in nanoparticles using the standard methods was predictably less than or equal to 16% w/w. The medication content in nanoparticles was also less than or equal to 1.1% w/w. More specifically, the NPC approach yielded the most minimal medication content, registering at 0.70% w/w. For nanoparticles produced through the NPC procedure, approximately 80% of the drug released in initial hour, with the entirety of the loaded drug being fully discharged within a span of 3 h. In contrast, nanoparticles formulated via the ESE and DESE techniques showed early rapid discharge of around 40–50% in the first hour and 80–90% over a duration of 24 h. Consequently, nanoparticles developed using the ESE and DESE methods were adjudged to be more effective than those generated using the NPC method. Furthermore, the dry-powder nanoparticles displayed comparable antibacterial activity to their aqueous suspension counterparts when tested against biofilm cells of P. aeruginosa. Patients with cystic fibrosis (CF) often confront persistent bacterial infections that develop resistance if not addressed early in the disease. Derbali and colleagues [63] conducted a study comparing liposomes with polymeric nanoparticles made from polylactic acid (PLA)–polyethylene glycol (PEG). LVF-loaded liposomes displayed favorable characteristics for treating P. aeruginosa in CF patients’ lungs. Although PLA–PEG nanoparticles exhibited suitable physical and chemical feature, their encapsulation efficiency was low. For PLA-g-PEG nanoparticles, medication content and entrapment effectiveness measured 1.42% and 6.15%, in the order given, while for liposomes, these values were 5.72% and 11.92%, respectively. Additionally, all formulations had particle sizes below 200 nm. The ZP for PLA-g-PEG ranged from − 6.3 ± 1.2 to − 1.2 ± 1.0 mV, while for liposomes, it was − 8.8 ± 0.8 to − 7.9 ± 0.6 mV. In terms of the efficacy of the nanocarriers, liposomes exhibited a gradual release of LVF, amounting to 34% over a span of 72 h, while maintaining the drug’s antibacterial effectiveness against five P. aeruginosa strains. Conversely, polymeric nanoparticles released their entire drug payload rapidly, resulting in an elevation of the minimum inhibitory concentration required for LVF. Consequently, LVF-loaded liposomes displayed promising attributes for combating P. aeruginosa infections in the lungs. The study evaluated liposome cytotoxicity on lung epithelial cells and found that they were biocompatible compared to minimum inhibitory concentration (MIC).

Efficiently managing various ocular infections with LVF eye drops remains a challenge due to limited drug absorption in the eyes. Gevariya and colleagues [64] in 2011 investigated nanospheres containing LVF as a prospective method for delivering ophthalmic drugs. These nanospheres were created by combining LVF with CS nanoparticles using spatial technique with tripolyphosphate anions (STPP). Their study aimed to illustrate how varying STPP and CS concentrations affect the physical and chemical characteristics and release behavior of the NPs. The NP dimensions ranged from 501 ± 15 nm at the maximum to 317 ± 06 nm at the minimum. ZP levels were from + 37.2 to + 43.5 mV, with the level decreasing as the STPP content rose. The encapsulation efficiency varied from 65 to 83%. On the other hand, the drug-loading capacity increased with higher drug concentrations, ranging from 15 to 25%. Moreover, for nanoparticles with a size of 317 ± 06 nm, LVF was initially released quickly, with subsequent gradual release occurring over 20 h. The discharge pattern of LVF from the NPs seemed to best correspond with the Higuchi model, displaying zero-order kinetics and non-Fickian diffusion. In 2019, Siafaka and colleagues [65] employed three different nanomaterials, namely, amorphous mesoporous silica (AMS), halloysite nanotubes (HNTs), and multiwalled carbon nanotubes (MCNTs), to load the fluoroquinolone LVF for antimicrobial purposes. These tubes had an average diameter of 99.18 ± 26.31 nm. The results from the LVF-loaded nanomaterials showed that AMS exhibited the highest drug loading at 23.64%, while MCNTs had a drug loading of 10.1%, and HNTs absorbed only 2.6% of the drug. They observed a low initial burst release for all the nanocarriers. After this primary release, AMS exhibited a more rapid release rate, with 100% of the drug being released in 12 h. Specifically, within the first hour, 37% of LVF dissolved, and after 2 h, AMS had released almost 70% of LVF. Complete dissolution was observed after 12 h. In contrast, carbon nanotubes showed a more sustained release profile. HNTs exhibited a significantly different dissolution profile, e.g., 40% of the medication was discharged in 2 h and the entire discharge was achieved in 24 h. In the initial 2 h, only 7% of the drug was delivered, with the release rate reaching 30% after 24 h. MCNTs emerged as the most promising candidates for delivering LVF. Danilo Antonini Alves and his colleagues in 2016 [66] conducted a study to analyze the properties of poloxamers in relation to LVF-regulated delivery. The study also explored the treatment options of poloxamers in addressing bacterial infections resistant to multiple drugs. Colloidal dispersions prompted the creation of micelles, self-assembled formations emerging from amphiphilic molecules in defined conditions, including concentration and temperature. These micelles typically ranged in diameter from 5 to 100 nm. The incorporation of LVF into nanospheres demonstrated increased efficacy and improved antibacterial activity against Escherichia coli, P. aeruginosa, and Klebsiella pneumoniae compared to LVF alone. Moreover, none of the formulations exhibited cytotoxicity towards the NIH/3T3 cell lineage. The combination of poloxamers and LVF exhibited promising outcomes, surpassing the effects of individual components by reducing the minimal inhibitory concentration against multi-antibiotic-resistant bacterial strains. The study focused on micelle production in colloidal dispersions using poloxamers, with these sub-100-nm micelles demonstrating notable penetration across various tissues. The single-type loading of LVF using PL 407 and PL 338 and binary hydrogels (PL 407/PL L-81, PL 338/PL L-81, PL 108/PL 403, PL 108/PL L-81) loading LVF was demonstrated. The research underscores the significance of this approach in treating antibiotic-resistant infections, particularly those affecting the skin or exposed tissues. Particle sizes ranged from 35 to 380 nm, and temperature influenced some formulation sizes. The encapsulation within smart nano- and microbiopolymeric devices represents an innovative technology with the potential for precise and regulated pharmaceutical release. Gaspar and their team [67] in 2015 developed an innovative approach involving swellable microspheres loaded with LVF for the dry aerosol treatment of a kind of bacteria in cystic fibrosis disease. They created LVF-loaded CS microspheres using the spray drying method. In their study, they examined four different crosslinkers. The size of the microspheres was 4.70 ± 0.45 to 12.65 ± 2.82 µm and the drug loading was 48.4 ± 5.8 to 50.8 ± 0.9%, while the encapsulation efficiency was 99 ± 12 to 107 ± 1% for these crosslinkers, respectively. However, due to the highly soluble nature of the drug LVF and the substantial drug content, attaining a regulated release pattern through the utilization of CS has been crosslinked. Cytotoxicity assessments on cells revealed that cytotoxicity significantly became lower by using theses crosslinkers. Overall, the efficacy of these microspheres against P. aeruginosa isolates was similar to those of free LVF. In another study, nanoparticles composed of a kind of polymer were used to encapsulate LVF. Gupta and colleagues’ [68] study in 2010 aimed to create LVF-polymer nanoparticles for applications in field of aphtalogy and assess various factors, including lab-based discharge, ex vivo, ocular tolerance, and in vivo optical retention. The data indicated that the best formula had a drug-to-polymer ratio of 1:20. The EE% was 86.13%, and nanoparticle recovery was 71%. The developed nanoparticles had a ZP of approximately − 25 mV, which is crucial for long-term stability. The average particle size varies from 190 to 195 nm. Drug entrapment efficiency was nearly 85%. The lab-based discharge pattern revealed a first rapid discharge accompanied by a prolonged, sustained release over 24 h. The most appropriate kinetic model was the Peppas model. Additionally, in the HET-CAM assay, the developed nanosuspension demonstrated non-irritating efficacy with an average score of 0.33 over 24 h. Fatahi et al. [69] in 2021 encapsulated LVF within various nanofiber matrices, including HNT combined with sodium alginate (SA) and polyethylene oxide (PEO) and studied the formulation and LVF effect. The nanofibers exhibited different diameters of 251 ± 28 nm for poly ethylene oxide combined with sodium alginate, 165 ± 19 nm for combination of drug poly ethylene oxide and sodium alginate, and 330 ± 17 nm for composition of LVF, polyethylene oxide, sodium alginate, and halloysite nanotube. A 1:1 ratio of HNT to LVF resulted in the highest drug loading efficiency, achieving a content of 27.1% w/w LVF. In vitro drug release experiments conducted and demonstrated that the combination of drug and halloysite nanotube nanohybrids released approximately 90% of LVF within 3 days, while LVF and polyethylene oxide combined with sodium alginate mats achieved a similar release rate within 2 days. In contrast, the nanocomposite consisting of halloysite nanotube loaded with LVF and encapsulated within a matrix of sodium alginate and polyethylene oxide mats sustained drug release over 7 days. Biocompatibility tests demonstrated that LVF, polyethylene oxide, sodium alginate, and halloysite nanotube mats were non-toxic, with over 90% cell viability. Additionally, halloysite nanotubes loaded with LVF and encapsulated within a matrix of sodium alginate and polyethylene oxide nanocomposite mats exhibited superior antibacterial activity compared to matrix of drug sodium alginate and polyethylene oxide mats, extending the release period to 7 days. Kumar et al. [70] in 2011 developed a new formulation of LVF, using PLGA, to address multidrug-resistant tuberculosis, aiming for a prolonged release in the bloodstream. To enhance drug encapsulation, they adjusted the ratio of drug to polymer which ranged from 1:1 to 1:10 while keeping other factors constant. As polymer concentrations increased, there was a gradual improvement in encapsulation efficiency, with the highest reaching 36.9 ± 6.1% at the smallest drug-polymer ratio, resulting in a drug loading of 4.1 ± 0.7 mg/100 mg nanopowder. The nanoparticle size remained in the submicron range, around 280–350 nm, even after drug loading, with no significant increase, measuring 312 ± 26 nm. These nanoparticles displayed a negative ZP of − 10.2 ± 1.5 mV.

In vitro drug release pattern exposed first rapid discharge of the medication, with 60%, 56%, and 44% released in phosphate-buffered saline, simulated gastric fluid, and simulated intestinal fluid, respectively, within 24 h. Afterward, there was a gradual and sustained release of LVF from the nanoparticles, with 85% of the contained medication released in phosphate-buffered saline, 69% in simulated gastric fluid, and 70% in simulated intestinal fluid within a 5-day period of LVF. In contrast, free LVF was rapidly eliminated from the system within 24 h. Importantly, this innovative formulation showed no significant adverse effects on body weight. In another report by Kumar and coworkers [71], graft copolymers were synthesized. To confer amphiphilic properties, they were crosslinked with sodium alginate; it was observed that the system effectively administered the highly water-soluble LVF dug at a precisely regulated rate. The drug entrapment efficiency for drug-loaded graft copolymers was measured at 62%. Approximately 80% of the drug was released over 36 h under inert conditions at 45 °C in phosphate-buffered saline with a pH of 7.4. Li et al. [72] in 2023 developed nanoparticles loaded with LVF using two polymer and conjugated them with an aptamer on the particle surface. For the blank nanoparticle, LVF, and nanoparticles containing LVF under the aptamer formulation, the average diameters were 235 ± 6.9 nm, 238 ± 8.4 nm, and 274 ± 1.1 nm, correspondingly. Additionally, the average ZPs for nanoparticles containing LVF under the aptamer, LVF in nanoparticles, and free nanoparticle were − 18.3 ± 0.4 mV, − 16.8 ± 0.3 mV, and − 14.6 ± 0.8 mV, in the given order. Significant differences in release efficiency were observed between LVF and nanoparticle and nanoparticles containing LVF before and after ultrasound treatment. LVF released significantly faster when triggered by ultrasound compared to without ultrasound. The inherent drug release rate from nanoparticles containing LVF within 72 h was roughly 45%, signifying an extended and gradual release mechanism. Nevertheless, when subjected to ultrasound for the same timeframe, the overall release rate elevated to 72% compared to free LVF. The cell viability percentage in the nanoparticles containing LVF group was significantly high, suggesting that these nano-biomaterials reduced the cytotoxicity of LVF. Cell cytotoxicity was assessed with an MTT assay, and only nanoparticles containing LVF with 16 μg/mL LVF showed an effect on cell viability. Wang and colleagues [73] successfully created zwitterionic nanogels through a polymerization process. They then encapsulated the LVF within these nanogels. Subsequently, they incorporated these drug-loaded nanogels into contact lenses using a cast molding method. A range of nanogels was synthesized, designated 1 to 4. The particle size of nanogels ranged from 294.7 to 219.9 nm.

The scanning electron microscopy (SEM) image of nanogel is shown in Fig. 3. Moreover, the ZP was from − 4 to − 14 mV. Notably, one of the nanogel formulations demonstrated excellent colloidal stability, primarily due to their small and compact particle size. The drug loading–capacity and encapsulation efficiency were determined to be 13% and 77%, in order. The dimension of the nanogels carrying the drug increased from 219.9 to 267.6 nm, while the ZP exhibited a decrease from − 14.2 to − 20.0 mV. In investigations involving the release of LVF within these nanogels, an initial rapid release of roughly 16% was observed during the first 4 h followed by 74% after 96 h. When considering both drug-loaded nanogels and drug-soaked contact lenses, by the 10th day, roughly 55% of LVF had been discharged from the contact lenses. The prepared contact lenses demonstrated compatibility with living cells. In 2022, İMAMOĞLU and their team [74] focused on developing drug delivery systems for administering LVF via pulmonary routes.

They created LVF-loaded microparticles and utilized PLGA as the carrier. Four types of Tween® for polymer preparation and four types of Span® were used. The smallest microparticles were observed with a diameter of 5.6 ± 0.5 µm, while the largest microparticles were 10.6 ± 0.1 µm. Moreover, increasing the one type of Span® concentration can lead to a decrease in particle size from 76.19 ± 2.20 to 9.57 ± 1.87 µm. The study achieved high encapsulation efficiency values, reaching up to 90% and a production yield ranging from 64.81 to 98.73%. In terms of medication discharge, LVF release by the PLGA-based microparticles was monitored over 24 h. The experimental medication discharge pattern indicated that 4.2 to 36.1% of LVF was released within the first hour. Finally, after analysis, the researchers selected optimum formulation which had a NP size of 5.59 ± 0.54 µm, a ZP of ± 30 mV, an EE% of 82.51%, and a production yield of 81.71%. The antimicrobial efficacy of these PLGA-based microparticles against certain bacteria causing lung infections was investigated. Significant increases in zone sizes were observed as the incubation time increased for E. coli at all analyzed time intervals. In their research, López-López and coworkers [75] in 2019 synthesized nanoparticles using PLGA and CS to encapsulate LVF. A comprehensive study was conducted to enhance the production of polymeric nanoparticles loaded with LVF for potential parenteral administration. This comprehensive examination encompassed alterations in the manufacturing technique, the selection of organic solvents, the pH levels of the aqueous phase, and the preparation temperature. For PLGA nanoparticle, the desired size was smaller than 400 nm to ensure suitability for their intended purpose. Two methods were found to be effective for preparing PLGA nanoparticle. In the first method, the ZP, size, and encapsulation efficiency ranged from − 4.3 to − 52 mV, from 222 to 1000 nm, and from 16 to 27%, respectively. In contrast, the second method yielded results of − 33 mV, 221 to 424 nm, and 13 to 30%, respectively. For CS nanoparticles, their ZP, size, and encapsulation efficiency ranged from + 18 to + 28 mV, from 108 to 218 nm, and from 2 to 25%, respectively. For PLGA nanoparticles, approximately 90% of the drug was released within 60 h as shown in Fig. 4. The antibacterial activity of these NPs was fewer than what is exhibited by pure LVF against all the tested microorganisms. Gaetano and colleagues [76] in 2021 have formulated CS nanoparticles based on a polyanion for delivering LVF to the eyes. CS nanoparticles were prepared through IG method using either a polyanion or TPP as gelling agents. The yield percentage for both CS/polyanion nanoparticles and CS/TPP nanoparticles fell within the range of 72–83%. Encapsulation efficiency and drug content ranged from 21.53 to 47.83% and from 3.47 to 8.65%, respectively. Additionally, the hydrodynamic radius (R_H) and ZP of CS nanoparticles loaded with LVF were in the ranges of 85 to 160 nm and 20 to + 21 mV to + 28 mV, respectively. The results showed initial burst effect of roughly 60% for LVF–CS/TPP₃ nanoparticles while it reduced to about 20% for LVF–CS/polyanion nanoparticles, and the total release of drug was approximately 72 h. In vitro antibacterial test bacteria indicated that LVF–CS/polyanion nanoparticles loaded with LVF exhibited higher activity compared to the free drug. So, CS nanoparticles based on polyanion are valuable for treating ocular infections. The objective of other research was to create an additively manufactured scaffold loaded with LVF, serving as a method for an antimicrobial fluoroquinolone. To achieve the purpose, Puppi and colleagues [77] in 2016 employed a technique to functionalize scaffolds (Fig. 7).

Fig. 4

SEM images of the PSBMA-4 nanogel, images (a, b). The images also depict the surface of a freeze-dried nanogel-embedded contact lens, namely, images c and d. The scale bars for a–d are 2 μm, 500 nm, 50 μm, and 4 μm, respectively [73]

They explain a formulation for combining scaffold and LVF, resulting in fibers with diameters ranging from 200 to 300 µm. Two types of scaffolds were produced: scaffold/LVF-B with a high drug concentration and scaffold/LVF-A with a lower drug concentration. They also assessed loading content and encapsulation efficiency for these scaffolds. For scaffold/LVF-A, L, EE% was 5.5%, while for scaffold/LVF-B, the value increased to 16.43%. When using scaffold /LVF-B, there was an initial rapid release of approximately 50% of the LVF released during the first 4 days. Afterward, the release rate gradually decreased, ultimately achieving stabilization within a 30-day period, during which approximately 90% of the initially loaded medication was released. The computer-assisted wet-spinning method introduced in this context appears to be highly appropriate for the fabrication of anatomical scaffolds. Cheow and colleagues [78] in 2010 encapsulated LVF within nanoparticles made of PCL and PLGA using NPC and ESE methods. Encapsulation efficiency and drug loading, ranged between 4 and 7 and 5%, respectively. In the NPC method, particle size was 100 nm, but the ESE method had sizes around 200 nm, for PCL and PLGA. The PCL and PLGA nanoparticles obtained through NPC exhibited approximately 80% drug release in the initial hour, and the complete medication was discharged after 6 h. However, for PLGA ESE nanoparticles, about 80% of the encapsulated medication was released the following day, while for PCL ESE nanoparticles, approximately three-quarters of the medicine was delivered after 144 h. The other research was to investigate the bactericidal effects and low-intensity ultrasound (LFLIU) mixed with LVF-loaded polymer NPs against Mycobacterium tuberculosis. Xie and colleagues [79] in 2020 prepared LVF NPs that had mean diameter of 229.8 ± 12.1 nm, and the nanoparticles had a negatively charged surface with a ZP of approximately − 28.8 ± 3.78 mV. The pharmacological content was 8.36 ± 0.74, and the entrapment effectiveness was 84.74 ± 1.28. When LVF nanoparticles were subjected to ultrasonic treatment, around 74% and 78% of the LVF were discharged after 72 h and 120 h, respectively. In contrast, for LVF nanoparticles lacking ultrasound, roughly 40% and 44% of LVF were discharged after 72 h and 120 h, respectively. The MTT assay was performed on both LVF and LVF nanoparticle. The results showed that LVF nanoparticle alone did not exhibit cytotoxicity. However, when the LVF nanoparticle was combined with ultrasound treatment, a decrease in cell survival was observed which led to cell viability. The study of Maharini et al. [80] in 2023 aimed to create and optimize CS-alginate nanoparticles containing LVF. They employed a D-Optimum Mixture Design for optimization. For the ideal formulation, which resulted in nanoparticles with uniform particle size and a ZP of 24.45 mV, the particle size was 300 nm. These nanoparticles exhibited a spherical shape, with an encapsulation efficiency of 35.65 ± 0.612% and a drug loading of 2.3 ± 0.038%. Regarding drug release, the cumulative release percentage of LVF nanoparticle reached 54.72 ± 2.606% within 6 h. The release profile displayed an initial burst release, with approximately 22.67% of the drug delivered within the first 15 min. This was accompanied by continuous discharge over time. The experimental results were examined to identify the most appropriate kinetics model, with the Korsmeyer-Peppas model, including a lag time (R² = 0.991), identified as the most effective model. In another research project led by Agnoletti [81] in 2020, microspheres were created and loaded with LVF. These microspheres exhibited an average diameter of 12 μm. By introducing lauric acid into the organic phase, the researchers achieved a further increase in LVF loading (reaching 18.4%) and encapsulation efficiency (reaching 44.4%). LVF was released from these vesicles in two stages: the first one is quick release of 10–20% of the encapsulation drug near the surface succeeded by a sustained and steady release as the drug permeates the pores within a polymer-based matrix. After 5 days, up to 85% of the LVF was discharged. To assess cytotoxicity, the microspheres were tested using the MTT assay. They exhibited IC₅₀ values ranging from 1.4 to 2 mg/mL for endothelial cells, 2.5 to 3.5 mg/mL for alveolar lung epithelial cells, and 0.7 to 1.5 mg/mL for human lung epithelial cells. In general, the microspheres demonstrated minimal harm to endothelial and alveolar epithelial cell lines and did not induce the breakdown of red blood cells. In a separate investigation, Zhang and colleagues [82] in 2018 introduced a novel approach for creating liquid crystalline molecularly imprinted polymers (LC-MIPs) with LVF serving as the model substance. The imprinted polymer possessed a mean layer thickness of 140 nm. The release patterns exhibited a distinct zero-order release of LVF from imprinted polymer. Significantly, imprinted polymer exhibited a remarkable release duration of over 21 h and released nearly 90% of loaded LVF. It is important to note that an LVF concentration of 100 μg/mL in soaking solution was found to be optimal for imprinted polymer. Furthermore, in vivo pharmacokinetic analysis revealed that the gastro-floating imprinted polymer exhibited a remarkable relative bioavailability of 578.9%. Furthermore, in vivo pharmacokinetic analysis revealed that the gastro-floating MWCNT@LC-MIP exhibited a remarkable relative bioavailability of 578.9%, whereas MWCNT@MIP achieved only 58.0%, and bare MWCNT managed a mere 11.7%. Table 3 presents nanostructures based on non-responsive polymers for controlled release of LVF.

Table 3 NPs based on polymers that are non-responsive to LVF delivery

Stimuli-responsive polymer-based NPs

In this section, the studies using stimuli responsive polymeric NPs were reviewed. Figure 5 shows various types of stimuli responsive polymer [83]. In biomedical research, a strategy encompasses the application of a thermo-responsive polymer for the controlled release of LVF from porous silicon (pSi) membranes. Müller et al. [55] in 2016 aimed to demonstrate the feasibility of this approach by employing thermo-responsive polymer brushes, specifically designed to respond to increased wound temperatures resulting from infection. In this process, LVF is loaded into bottle-shaped nanopores at a temperature above the lower critical temperature of thermo-responsive polymer (LCST).

Fig. 5

The cumulative release from PLGA and CS nanoparticles that were synthesized using various ways [75]

The encapsulation is achieved by cooling the sample to room temperature while rinsing it. The quicker release at 45 °C compared to 20 °C was due to enhanced LVF diffusion caused by lower solvent viscosity and higher temperature. Crucially, the release from poly (diethylene glycol methylether methacrylate) (PDEGMA)-coated pSi membranes follows a burst release pattern, with no notable concentration increase after 60 min. This suggests that the faster release at temperatures above the LCST is mainly due to the collapse of polymer brushes rather than just temperature-induced diffusion. Their study validated the temperature-triggered release potential of PDEGMA-functionalized pSi, confirming the proof of concept. Imran and colleagues [84] in 2016 synthesized a new niosomal vesicles, with the goal of encapsulating LVF to improve its oral bioavailability. The researchers examined the structure of vesicles containing medication. The average diameter of the free vesicles was 222 ± 7.7, while that of the drug-loaded vesicles was 190.3 ± 4.5 nm. The ZPs were measured as 36.24 ± 1.36 mV for the drug-loaded vesicles and 32.71 ± 2.45 mV for the empty vesicles. The encapsulation efficiency results indicated that niosomal vesicles encapsulated 68.3 ± 3.5% of the compound. Maximum drug release was achieved at an acidity of 7.4, with 84.23% of the medication delivered over 9 h, while the lowest release occurred at pH 1.2, with 59.76% of the drug released over the same duration. The cytotoxicity of niosomal vesicles was evaluated, using the MTT assay. Additionally, acute toxicity studies of niosomal vesicles were led in vivo using mice and showed that niosomal vesicles can enhance the oral bioavailability of LVF. In another research, Bhalerao et al. [85] in 2019 designed and assessed a solution containing LVF using an ion-sensitive polymer. In LVF 1.6% w/v solutions, elevating the ion-sensitive polymer concentration from 0.10 to 0.50% w/v led to a notable viscosity increase and a significant reduction in the in vitro gelling time. Different LVF solutions, with varying concentrations and the inclusion of gellan gum, underwent testing to assess medication discharge rates. Without gellan gum, the medication was released quickly, taking between 0.35 and 0.41 h to reach 50%, and complete release was within 4.71–5.06 h. Conversely, when gellan gum was added, the release of the medicine was considerably slowed; 50% of the discharge reached in 9.6 to 13.7 h, with complete release taking between 48.5 and 58.5 h. Studies conducted on eye tolerance yielded positive results. Additionally, the LVF in situ gel formulation demonstrated an enhancement in drug bioavailability when compared to the commercially available version. Hassani and colleagues [86] in 2022 created a novel nano-antibiotic through the attachment of a drug to carbon nanotubes. The research marks the initial exploration of the drug’s impact on cell survival and its ability to combat bacteria both in laboratory settings and in living organisms using a burn wound model. The study achieved impressive drug entrapment and loading rates of 90 and 80%, respectively, for drug to carbon nanotubes. Also, drug to carbon nanotubes exhibited sustained-release capabilities at pH 5.5, maintaining a constant rate. However, at pH 7.4, they observed a first gradual discharge accompanied by a rapid one, suggesting that pH 7.4 is less effective for medication discharge than pH 5.5. At pH 10.5, effective drug delivery did not occur. Drug to carbon nanotubes was highly effective against S. aureus in acidic conditions, unlike alkaline and acidic carbon nanotubes. In vivo experiments also showed drug to carbon nanotubes prevent S. aureus growth in burn infections. Abdelbar and colleagues [87] in 2020 aimed to develop a system involving mesoporous nanoparticles embellished with acid PLA-nanoflower (NF). LVF was encapsulated within three different types of nanoparticles (mesoporous nanoparticles, amino group decorated mesoporous nanoparticles, and mesoporous nanoparticles with amino group and polylactic acid, with the latter featuring pores measuring 5.4 nm). The entrapment efficiency and loading capacities were determined for mesoporous nanoparticles, amino group decorated mesoporous nanoparticles, and mesoporous nanoparticles modified with amino groups, loaded with LVF and incorporated into polylactic acid, resulting in values of 95.71% with 478.55%, 93.18% with 465.90%, and 98.32% with 491.60%, respectively. The release of LVF from these materials exhibited distinct kinetic profiles, namely, zero-order, first-order, and Hixson kinetics. Specifically, for amino group decorated mesoporous nanoparticles, a first-order release pattern was observed, leading to approximately 87% drug release within a 300-min timeframe, across varying pH levels (2.01, 4.5, and 7.01). Conversely, mesoporous nanoparticles modified with amino groups, loaded with LVF, and incorporated into polylactic acid exhibited Hixson kinetics, with release percentages of 90%, 70%, and 5% at pH levels 2.01, 4.5, and 7.01, respectively, after 280 min. Shin and colleagues [88] in 2018 blended cross-linked CS networks with nanogels and fabricated a hydrogel responsive to temperature fluctuations then they incorporated LVF into the hydrogel. The investigation involved the assessment of LVF release kinetics from nanogels under controlled temperatures of 37 °C and 25 °C. Irrespective of the temperature, an initial rapid release phase, spanning 13 to 44%, was observed within the initial 30 min. At temperatures exceeding the LCST of nanogels, which was 32 °C, LVF exhibited an accelerated release in the first hour, subsequently leading to gradual deceleration until reaching a state of equilibrium within a span of 6 h. Conversely, below the LCST, approximately 27% of the LVF was discharged over a 1 day. Vasani and colleagues [89] in 2017 have detailed the creation of a pH-sensitive drug delivery structure designed for potential use in wound decontamination, offering on-demand drug release triggered by an increase in wound pH. This innovative device utilizes a porous silicon film as a carrier for antibiotics, which are sealed within it using dual pH-responsive polymer made of poly1,7-octadiene (POct) and polyacrylic acid (PAAc). Their study reveals that at a pH of 5, antibiotic release is inhibited, while raising the pH to 8 enables sustained and controlled release. Significantly, the released antibiotic effectively inhibits the P. aeruginosa wound pathogen and exhibits bacteriostatic properties. The LVF amount loaded into the porous silicon measured 182 ± 19 ng/mm² before plasma polymer deposition. They investigated the LVF release from silicon-poly1,7-octadiene-polyacrylic acid when exposed to pH 5 and pH 8 buffers. Initially, there is a rapid LVF discharge in pH 5 buffer, accompanied by a controlled but slower discharge. After pH 5 incubation, the surface appears smooth and LVF-resistant, but after pH 8 incubation, it becomes wrinkled with visible pores. Table 4 summarizes the characteristics of the nanocarriers reported in this part.

Table 4 Summary of stimuli responsive polymer used as LVF nanocarrier

Lipid-based NPs

In this part, we review the papers using LVF with lipid-based NPs. Figure 6 shows classification of lipid-based NPs used in drug delivery systems [91].

Fig. 6

Various types of stimuli responsive polymer [83]

Fig. 7

Lipid-based nanocarriers sorted depending on formulation and shape [91]

Non-sensitive NPs based on lipids

Hybrid NPs, blending polymer-based particles embedded in lipid-based layers, amalgamate the strong biocompatibility of lipids with the structural robustness provided by polymer-based NPs. In 2011, in a study conducted by Wean Sin Cheow et al. [54], antibiotics enclosed in hybrid nanoparticles were investigated for their efficient drug delivery capabilities. Hybrid nanoparticles, a combination of lipids and polymeric nanoparticles, face instability in salt solutions, but the addition of tocopherol polyethylene glycol succinate (TPGS) to the formulation enhances their stability. The positively charged nature of TPGS results in a reduction in the negative ZP of phosphatidylcholine (PC) NPs, aligning them more closely with PLGA-PVA NPs in terms of ZP.

Specifically, the ZP of PLGA–PC/SA/TPGS NPs containing CIP experiences a decrease in magnitude from + 26 to + 10 mV. Particle traversal through the mucus barrier demonstrates a size-dependent pattern, with greater efficacy observed for particles below 300 nm. Despite their larger size and increased ZPs compared to their non-hybrid counterparts, hybrid NPs present advantages for anti-biofilm therapy. This is ascribed to the interaction of liposomes with bacterial cells through membrane fusion and the sustained discharge of antibiotics from polymer-based NPs, effectively managing biofilm cell growth. Wean Sin Cheow and collaborators assessed the medication discharge rate from the NPs applying the dialysis-bag technique. The test occurred at 37 ºC with constant agitation. The presence of a lipid coat in hybrid NPs did not impact the discharge of OFX, showing a release pattern similar to non-hybrid nanoparticles. In both cases, OFX encapsulated in the nanoparticles was entirely released after 15 h, with a burst release of 90% within 5 h. Conversely, the release of LVF from hybrid nanoparticles differed significantly from non-hybrid counterparts. While LVF was discharged from PLGA-PVA NPs in around 5 h, reaching nearly total release, only 70% of entrapped LVF was discharged through PLGA-PC/TPGS NPs in the identical timeframe. Subsequently, LVF was consistently discharged over the following 20 h, resulting in approximately 90% of total LVF release. In 2012, Yajie Wang and colleagues [92] carried out a comparative investigation into the application of spray drying (SD) and spray freeze drying (SFD) methods for generating inhalable dry-form drug-loaded lipid-polymer hybrid NPs. The research employed poly(lactic-co-glycolic acid) as the polymer, lecithin as the lipid, and LVF as the pharmacological model. Hybrid NPs underwent conversion into larger micro-scale aggregates, referred to as nano-aggregates, through two approaches, SD and SFD. The investigation assessed the impact of various excipients (mannitol, PVA, and leucine) and the ratio of nanoparticles to excipients on nano-aggregate properties, including size, flow ability, reconstitution ability in water, and aerosolization efficiency. Both approaches, employing PVA, demonstrated similar efficacy in generating nano-aggregates with optimal characteristics for inhalation delivery, such as size, density, flowability, yield, and reconstitutibility. Nano-aggregates created through SFD showed superior aerosol performance compared to SD, with higher emitted doses and a greater proportion of fine particles, along with a smaller average particle size. Lipid-polymer hybrid NPs emerge as a novel and maybe superior substitute to conventional polymer-based NPs. These hybrid carriers combine the benefits of liposomes (cell compatibility and targeting) with the structural and functional advantages of polymeric NPs (stability, controlled release, and customization), resulting in improved stability in the bloodstream. The average size of the PLGA–LC nanoparticles, accounting for volume, was approximately 420 ± 30 nm, and their ZP ranged from − 25 to − 30 mV, indicating strong colloidal stability. Efficient drug encapsulation within the hybrid nanoparticles was achieved, with an encapsulation effectiveness of around 19% and a drug loading of approximately 2.0% (w/w). In 2016, Muhammad Faizan Nazarand and his team [63] developed a biocompatible microemulsion (μE) formulation to encapsulate LVF. The formulation consisted of clove oil, Tween 20, 2-propanol, and water, with a cosurfactant/surfactant ratio of 2:1. The μEs’ microstructure was investigated using various characterization methods. LVF showed significant solubility in an ideal μE formulation, reaching 5.0 wt% at a pH of 6.9. The μE composition containing LVF showed exceptional endurance and durability during half a year of preservation. FTIR test indicated LVF stability within the formulation, indicating no potential aggregation. Dynamic light scattering (DLS) analysis exhibited LVF accumulates in the interfacial layers of micelles. In 2016, Germán A. Islan and collaborators[93] produced SLN of myristyl myristate using ultrasonication with Pluronic®F68. Thorough analysis assessed their potential as LVF carriers, emphasizing size and morphology. NLCs were also studied, improving LVF encapsulation and preservation, with a comparison to solid lipid nanoparticles. The SLNs demonstrated an EE% of 20.1 ± 1.4% for LVF, while the NLCs achieved a significantly higher encapsulation efficiency of 55.9 ± 1.6% for LVF. The controlled release profile of the NLC formulation surpassed that of the SLN formulation. Nevertheless, both formulations showed a biphasic pattern of drug release, marked by an initial burst release within the initial 5 h, followed by controlled discharge thereafter. These observations were validated through in vitro experimentation. The NLCs exhibited a hydrodynamic average diameter of 182.6 ± 3.2 nm and a ZP of − 10.2 ± 0.2 mV, maintaining stability for a minimum of 3 months. Generally, the ZP varied between − 8.65 and − 10.3 mV. During the in vitro test, the SLN3 formulation released almost 80% of LVF during the initial 4 h, whereas the NLCs released less than 60% within the identical period. The rapid initial discharge seen in both instances was ascribed to the presence of unenclosed LVF dissolved by surfactant micelles. Adjusting the pH of the water-based surroundings, altering the pace at which the antibiotic dissolves in the lipid phase, or structuring the matrix by including oil were discovered as viable methods to tailor nanoparticle formation. This approach led to different amounts of encapsulation, ranging from 5 to 56%. The correlation analysis between DLS outcomes and transmission electron microscopy (TEM) pictures demonstrated that both SLNs and NLCs exhibited a spherical shape, with a mean dimension of 200 nm. The lipid nanoparticles demonstrated a regulated discharge of LVF for a minimum duration of 2 days, providing the benefit of diminishing antibiotic concentrations and allowing for a decreased dose to enhance patient comfort. In 2020, a research was undertaken by Mayssa Abdel Hady and her colleagues [94] to investigate the feasibility of administering an innovative mixture of LVF and doxycycline (LVF/DOX) to the brain via the intranasal route. The goal was to get a substantial drug concentration in the brain and develop a direct route from the nasal cavity to the brain. SLNs were used as carriers for drug administration, and a Box-Behnken design was used to improve LVF/DOX-SLN. The objective was to reduce NP dimensions and enhance EE%. In order to improve the capacity of LVF-DOX to cross the blood–brain barrier and in indirect ways reach the brain, LVF-DOX-loaded SLNs were developed. SLNs are a kind of biodegradable dispersion system that has a roughly spherical shape. The average diameter of SLNs typically falls within the range of 800 to 1000 nm. The enhanced LVF/DOX-SLN (LD-SLN) formulation displayed nanoparticles characterized by a uniform, symmetrical spherical morphology, sleek surfaces, and absence of particle aggregation. The TEM investigation showed that the NPs had an average diameter of about 50 nm. This aligns with previous research that suggests NPs having a size smaller than 100 nm have a stronger ability to distribute efficiently to the brain. Within the LD-SLN samples, LD11-SLN had the most diminutive particle size measuring 14.46 nm, whilst LD1-SLN demonstrated the highest particle size of 53.32 nm. The percentages of LVF and DOX released from the three LD-SLN samples (LD-SLN1, LD-SLN2, and LD-SLN3) were 33.37%, 55.07%, and 100% for LVF and 30%, 59.99%, and 99.998% for DOX, respectively. In fixing breathing problems resulting from newly acquired infections, new NLCs were developed. These carriers exhibited antioxidant and antibacterial properties originating from α-tocopherol (αT) and LVF, respectively. The hybrid NLCs consisted of solid lipid esters with liquid αT forming the central core, with CS and poloxamer 188 as surface stabilizers. The study conducted by Germán A. Islan and his colleagues [94] in 2020 examined the properties and long-lasting nature of the nanoformulations using DLS, considering the influence of homogenization time, surfactant concentration, and initial lipid content on the average size, and ZP of the NPs. SLNs containing different lipids encapsulated LVF at varying concentrations. NLC formulations achieved higher LVF encapsulation (80–90%) and facilitated controlled drug release. Surfactant concentrations exceeding 2.0% resulted in increased foam generation, potentially reducing the availability of poloxamer 188 molecules to stabilize SLN structure. The ZP of SLNs exhibited more negative values as poloxamer 188 concentration decreased, indicating increased formulation stability within the biologically acceptable range of approximately − 10 to − 30 mV. DY200-SLNs had an average diameter of approximately 440 nm, with an observed rise in the PDI value over 0.5. ZP values of SLN/CS were positive, indicating the presence of biopolymer on the surface of SLNs. Carbon monoxide (CO) and dysprosium (DY) ZP values ranged from + 16 to + 21 mV. The addition of chitosan to cetyl ester increased ZP values to over + 45 mV, potentially posing harm to mammalian cells. The inclusion of 20% α-tocopherol consistently decreased the average size of nanoparticles by 50–100 nm. The release kinetics of LVF from NLCs were investigated, revealing nearly complete release in its active form across various NLCs. An initial rapid release within the first 4 h was attributed to drug desorption from the NLC surface. Subsequently, a gradual and continuous release occurred until 24 h, with the majority of encapsulated LVF being released (80–90%). In 2022, a research was undertaken by Viviane Lucia Beraldo-Araújo and colleagues [95] to investigate the crucial process parameters and their impact on achieving an efficient system with an excellent capture of drugs. The researchers used a design of experiment to create NLCs for the delivery of the antibiotic LVF. This method entailed optimizing the process parameters in order to generate nanoparticles that are smaller than 200 nm in size, possess a ZP between − 21 and − 24 mV, exhibit a high EE% surpassing 71%, and fall within a suitable range of product degradation (0.37–1.13%). The criteria for establishing the best formulation comprised a z-average below 250 nm and the maximum EE% value. Around 85% of the medication included in NLC-LVF was discharged following 15 min, whereas the rest of the medication was kept inside the nanoparticles for the whole 24-h experiment. The medication’s discharge from NLC-LVF in the Franz cell approach exhibited a delayed pattern relative to the free medication in the same setup, with roughly 50% of the drug being released after 5 h. Upon completion of the test, about 10% of the drug remained intact inside the NLC. Table 5 summarizes the characteristics of the nanocarriers reported in this part.

Table 5 Summary of non-responsive lipid used as LVF nanocarrier

Non-polymer base NPs

Non-responsive non-polymer-based NPs

In 2012, Cicuéndez et al. [97] conducted a study on mesoporous matrices, focusing on impregnation (IP) and surfactant-assisted drug loading (one-pot, OP). The study assessed the physicochemical properties, cellular response, drug release profiles, and antibacterial efficacy of these matrices. The study found that neither calcined nor calcined matrices showed any cytotoxic effects on osteoblasts. However, matrices without calcination showed a significant retardation in fibroblast proliferation and changes in morphology. These matrices also showed a dose-dependent increase in fibroblast size, internal complexity, and intracellular calcium levels without cell lysis or death. The study successfully loaded LVF into both IP and OP matrices, demonstrating comparable in vitro LVF release characteristics. The data obtained demonstrate a rapid release during the first 24-h period, with OPSiLVF-1 and IPSiLVF matrices achieving 60% and 30% of the loaded LVF quantity, respectively. Subsequently, a gradual and continuous release is seen in both instances throughout the subsequent hours. The intraperiosteal and osseous periosteal matrices show promise as targeted medication delivery methods for the treatment of osteomyelitis and other bone infections. In 2015, Bernardo Bayon and colleagues [98] created spherical mesoporous Ag₃PO₄ microspheres by combining pectin with a nucleation agent. The hybrid microspheres underwent characterization by a range of biophysical methods, including optical microscopy, SEM, and X-ray diffraction. The SEM study showed that the silver phosphate microspheres without pectin exhibited a surface with diverse features. Additionally, the microspheres demonstrated a bimodal size distribution, with sizes ranging between 0.9 and 1.0 μm and between 1.5 and 1.8 μm. The population yield for the smaller microspheres was around 20%, while the larger microspheres had a yield of approximately 25%. Furthermore, a significant quantity of salt detritus was seen in the samples. The SEM microphotographs revealed a significant alteration in the morphology of the particles, exhibiting a uniform surface and a narrow size distribution within the range of 1.3 to 1.5 μm. Moreover, the synthesis process yielded a population of microspheres with a 90% success rate. Additionally, an increase in pore size of around 20 to 30% was seen, and no debris was detected. The X-ray diffraction study of silver phosphate microspheres indicated that the crystal profile remained consistent regardless of the presence or absence of pectin. This suggests that the addition of the biopolymer did not induce any alterations in the crystalline structure of Ag₃PO₄. The bactericidal action of silver phosphate hybrid microspheres loaded with LVF was shown to be much stronger when tested against E. coli and S. aureus, in comparison to the bacteriostatic effect seen with free LVF. The findings indicate that the incorporation of LVF into hybrid Ag₃PO₄-pectin microspheres yields potent antibacterial properties against various microbes. Consequently, these microspheres have promise for a variety of medical uses such as the development of antimicrobial control systems and the enhancement of medical equipment. The Ag₃PO₄-pectin hybrid microspheres possess many notable advantages. Firstly, they are synthesized using a green chemistry approach, which aligns with environmentally friendly principles. Moreover, the synthesis process can be carried out under conventional laboratory settings, eliminating the need for complex or specialized equipment. Additionally, these microspheres do not need purification processes, simplifying the manufacturing process. Furthermore, the technology used for their synthesis exhibits a high level of reproducibility, ensuring consistent results. Lastly, these microspheres provide the capability for drug loading and may be tailored to particular targets, enhancing their potential applications. One of the primary benefits of Ag₃PO₄-pectin microspheres lies in their ability to exhibit synergistic antimicrobial activity via the combined action of silver ions and antibiotics inside a single microdevice. This microdevice serves as both a biocide matrix and a carrier for LVF. In 2015, Javid Jalvandi et al. [99] created composite nanofibrous mats to ensure continuous release of a medication by using LVF as a model. The research used two techniques, introducing LVF into MSN and integrating MSN into the central areas of PCL nanofibers using core–shell electrospinning. The loading ratio of LVF to MSN was found to be 100 mg/g. Electron microscopy investigation revealed successful localization of MSN into the center of the nanofibers. The medication discharge kinetics demonstrated that about 70% of the administered therapeutic substance was discharged during the first 20-min interval. The release rate reached a plateau after 60 min, with not much additional progress in the following hour. The MSN exhibited the ability to transiently store the drug within the framework. After being submerged in a phosphate buffer at 37 °C for 1 day, the rapid discharge of PCL/LVF electrospun mats decreased from 59 to 39% in the core–shell PCL/LVF-MSN mats. The mixture of electrospun mats has shown remarkable effectiveness in eliminating E. coli, even after being incubated in a phosphate solution for a period of 14 days. In 2017, Qi Wang et al. [100] created a composite scaffold using mesoporous silica microspheres, nano-hydroxyapatite, and polyurethane loaded with LVF. The researchers tested its therapeutic efficacy in addressing chronic osteomyelitis with bone defects in a rabbit model. Using X-ray, micro-CT, gross pathology, and immunohistochemistry staining, they found that the composite scaffolds with a 5-mg LVF loading showed significantly superior efficacy in treating bone defects compared to other experimental groups. The use of this unique synthetic scaffold exhibits potential as a viable therapeutic approach for addressing the challenges associated with chronic osteomyelitis management. In 2016, Yao Wang and colleagues [101] conducted a research that showed the efficacy of a nanoplatform composed of mesoporous silica nanovehicles containing silver cores and loaded with LVF, as a potent antibacterial agent against drug-resistant diseases. The nanoplatform, consisting of a silver core and antibiotic medicines enclosed inside mesopores, exhibited superior antibacterial effectiveness in comparison to LVF-loaded MSNs and MSNs with a silver core. The release profiles demonstrated fast release during the first 12-h period, with MSNs@LVF and Ag@MSNs@LVF attaining 58.5% and 61.3% of the initially loaded LVF amount, respectively. The nanoparticles produced at this stage have more distinct pore architectures, indicating that the process of drug release is still in progress. During the subsequent phase, it is noted that both MSNs@LVF and Ag@MSNs@LVF exhibit extended-release profiles exceeding 3 days. The total percentage of discharged substance reaches 95.9% for MSNs@LVF and 83.8% for Ag@MSNs@LVF after 96 h. In the experimental model of acute peritonitis conducted in live organisms, the presence of drug-resistant E. coli GN102 in the peritoneal cavity of mice is significantly decreased by about three orders of magnitude. Additionally, the administration of Ag@MSNs@LVF effectively eliminates the abnormal pathological characteristics seen in the spleen and peritoneum. Significantly, the nanoplatform showed no apparent hazardous side effects in the mice during the duration of the experiment. The work provides compelling evidence that Ag@MSNs@LVF has significant promise as a synergistic and safe therapeutic approach for clinical drug-resistant infections. In 2018, Blanca González [102] proposed a unique and efficacious approach for addressing infections via the use of nanovehicles loaded with antibiotics. This innovative strategy enables the penetration of bacterial walls, hence augmenting the antimicrobial efficacy. The nanosystems, referred to as “nanoantibiotics,” were composed of MSNs that served as nanocarriers for the targeted delivery of LVF inside the mesopores. In order to enhance the nanosystem’s capacity to interact with bacterial membranes, a third-generation poly(propyleneimine) dendrimer (G3) was chemically attached to the outer surface of the LVF loaded MSNs. The hydrodynamic size distribution of the materials floating in water ranges from 140 to 190 nm, suggesting that the grafting procedure has little impact on the size of the nanoparticles. The results of the study suggest that there is a significant alteration in the ZP values, shifting from − 36.4 mV in the unmodified MSN to around + 35 mV in the hybrid materials. The samples were loaded with LVF at concentrations of 3.2%, 5.0%, and 7.8% (wt.) for MSN-LVF, MSN-DAMO-LVF, and MSN-G3-LVF, respectively. Following the physicochemical characterization of the nanoantibiotic, an assessment was conducted to determine the release kinetics of LVF and the antibacterial effectiveness of each dose released. Furthermore, investigations were conducted on the internalization of MSNs functionalized with the G3 dendrimer. These findings have shown a significant capacity of the MSNs to penetrate the membranes of Gram-negative bacteria. Their study demonstrates that the combined use of polycationic dendrimers as agents to permeabilize bacterial membranes, together with LVF-loaded MSNs, effectively induces antibacterial activity against Gram-negative bacterial biofilms. The favorable outcomes of the study provide very encouraging prospects for the possible use of these findings in novel infection treatment modalities. In 2018, Daniel Pedraza et al. [103] devised an innovative method for addressing bone infections by the production of an antibiotic nanocarrier. The nanoantibiotic, consisting of MSNs containing LVF and externally modified with N-(2-aminoethyl)-3 aminopropyltrimethoxysilane (DAMO), successfully penetrates bacterial biofilms, hence improving the effectiveness of antimicrobial treatment. The TEM pictures revealed the nanocarrier’s spherical form and hexagonal symmetry. The ZP of the hybrid nanocarrier was determined to be + 35.1 mV. The features of the nanoantibiotic were investigated using a range of characterization methods, including as X-ray diffraction, TEM, N2 adsorption porosimetry, elemental chemical analysis, DLS, ZP measurement, and solid-state nuclear magnetic resonance (NMR). The research examined the patterns of LVF release from vials and analyzed the effectiveness of various doses in killing germs in a laboratory environment. The findings indicated that the discharge of LVF from MSN occurs at a slower rate compared to MSN-DAMO. Furthermore, the use of MSN-DAMO resulted in the partial retention of the drug in the former. In contrast, the drug release profile from MSN-DAMO exhibits characteristics consistent with a conventional diffusion model, whereby almost the whole quantity of loaded LVF is released within a 72-h timeframe of the experiment. The effectiveness of the nanoantibiotic against a biofilm formed by S. aureus was also assessed, revealing a near-complete eradication of the biofilm owing to the exceptional penetrating capabilities of the created nanosystem. The outcomes of their research offer encouraging prospects in the realm of bone infection therapy. In 2017, Javid Jalvandi et al. [104] used electrospinning to produce composite LVF/nanofibers. The drug release profiles exhibited a reduction in the first rapid discharge from 59% in homogeneous PCL/LVF electrospun mats to 20% in PCL/immingled LVF–MSN mats after 1 day in a phosphate buffer at 37 °C. The process of controlled discharge occurred during 13 days as a result of the hydrolysis of the connection between LVF and MSN. The discharge of the drug from immingled LVF–MSN was much greater in an alkaline medium, with 90% of the drug being released after 120 min. In contrast, at pH 7.4, only 74% of LVF was discharged. The profile of the elimination of the drug from LVF–MSN (control) at pH 9.0 closely paralleled the elimination pattern at pH 7.4, suggesting that the pH level does not have a significant effect on the persistence interactions between drug and MSN. Encapsulating drug-conjugated MSN into nanofibers seems to be a successful approach for reducing the rapid release of the medication. In 2017, Magda Ferreira and her colleagues [105] conducted a study to assess the fundamental biological characteristics of a new carrier system. This system consisted of acrylic bone cement that was combined with a discharge modulator (lactose) and LVF. The antibacterial properties of LVF-loaded bone cement (BC) were assessed against both planktonic and biofilm types of S. aureus using a flow chamber technique. The unique BC formulation exhibited potent antibacterial activity inside osteoblasts, indicating that LVF, released from BC matrices, may effectively permeate osteoblast cell walls and exert its antimicrobial effects against S. aureus strains within the intracellular milieu. In addition, the LVF-BC formulations had no noteworthy cytotoxicity when tested in vitro, and no allergenic potential was seen when examined using the in vivo chorioallantoic membrane assay. The findings suggest that LVF-loaded bioactive ceramic has promise as a localized antibiotic delivery device for the treatment of bone infections caused by S. aureus. In 2019, Noemí Encinas et al. [106] conducted surface modifications on MSNs using two silane molecules. The modified MSNs were assessed for surface characteristics, low-fouling capabilities, and cell uptake. The study found that both mixed-charge pseudo-zwitterionic MSNs (ZMSN) and PEG-MSN showed a significant decrease in serum protein adhesion and macrophage uptake compared to pristine MSNs. Protein adsorption was reduced by 70–90%, while cellular absorption was reduced by approximately 60%. The primary objective of this pseudo-zwitterionic alteration is to target bacterial infections locally using the combined antibacterial properties of a mixed-charge system and the controlled release profile of the LVF antibiotic. The drug release rate of ZMSN-1.5 is quicker than pristine MSNs, with an effective release of around 40%. Marina Martínez-Carmona et al. [106] developed a nanosystem in 2019 using MSN loaded with LVF and lectin concanavalin A (ConA). This nanosystem enhances the antibacterial effectiveness of antibiotics contained within mesopores. TEM analysis revealed NPs with a mean diameter of 150 nm, exhibiting a mesoporous structure. The potential measurements in aqueous colloidal suspensions showed significant variations in surface charge. Specifically, the values obtained for MSN, MSN-3-(triethoxysilyl)propylsuccinic anhydride, and MSNConA were − 21.5 mV, − 33.5 mV, and − 25.3 mV, respectively. The drug release experiments for various samples were conducted in phosphate-buffered saline (PBS) at a temperature of 37 °C with orbital motion. The findings suggest that the release profiles of both curves may be modified to conform to first-order kinetics. Notably, the release rate is shown to be quicker and much greater after ConA grafting. Furthermore, the MSN@LVF system exhibits a partial retention of the loaded medication, with a maximum drug release of around 30% observed after a 48-h period. The nanodevice was conceptualized as a potentially advantageous substitute for traditional infection treatments, since it aims to enhance antimicrobial effectiveness while minimizing adverse reactions. In 2020, a research team led by Hajin Kim [107] developed oxidized porous silicon (OPS) nanoparticles that were covalently linked with LVF inside a hydrogel polymer. These nanoparticles were used to assess the effectiveness of controlled-release medication delivery. The process of catalytic condensation facilitates the covalent bonding of LVF to the Si–OH surface of OPS NPs. The mean diameter of the NPs was around 100 nm. The fluorescence feature of LVF has been used to quantify its release via the use of a fluorescence spectrometer. The LVF release profile indicated that both LVF-lens and LVF-OPS nanoparticles had a rapid initial release within a time frame of 1 h. The LVF-OPS nanoparticle lens demonstrated a release mechanism characterized by two distinct steps, an initial rapid release lasting for a duration of 5 h followed by a subsequent gradual release. The total amount of medication released from the LVF-OPS nanoparticle lens over a period of 200 h was measured to be 9.0 μg. The examination of the release profile indicates that the covalent bonding of LVF with OPS (LVF-OPS) shows significant promise as a controlled release agent. The pace at which the medicine is released is contingent upon the hydrolysis of the silyl ester located on the surface of OPS nanoparticles. In 2020, Ioanna Koumentakou and her team [108] created novel hemostatic products using CS as a base material, enhanced with inorganic additives like aluminum chloride, aluminum sulfate hydrate, or iron(III) sulfate, and the antibiotic LVF. The study explored their potential application, revealing that the interaction between CS and additives altered pore size, resulting in a 2500% increase in swelling. Additionally, the incorporation of additives enhanced the durability of the wound dressings. In order to prevent infections, it is essential that wound dressings promptly provide antibacterial agents upon application to an open wound. Hence, there is a preference for rapid liberation of low-emission vehicles from the materials under investigation. The drug loading values of the composites including CS and inorganic additives exhibited comparable results (CS-LVF 30.84%, CS-AS-LVF 29.17%, CS-FS-LVF (iron(III) sulfate, FS) 33.28%, CS-ACl-LVF (aluminum chloride, ACl) 30.57%). The dissolution investigations indicated that all of the formulations exhibited a rapid release of 70–95% of LVF. The release of LVF exhibited a uniphasic pattern, which was distinguished by a rapid and pronounced drug release. The degree of crystallinity has shown a decrease in LVF, resulting in an instantaneous release of the compound. The materials exhibited biocompatibility when in contact with cultivated keratinocytes and has shown hemocompatibility and hemostatic efficiency both in vitro and in vivo. Table 6 summarizes the characteristics of the nanocarriers reported in this part.

Table 6 NPs based on some other materials that are non-responsive to LVF delivery

Stimuli-responsive non-polymer-based NPs

In 2019, researchers Hayley B. Schultz and colleagues [109] explored the use of stimulus-sensitive plasma polymers in creating antibiotic formulation that are responsive to adjustments in pH and temperature. They incorporated antibiotic LVF into porous silicon films coated with plasma polymer layers, including poly(1,7-octadiene) (pOCT) for stability and poly N,N-diethylacrylamide (pDEA) and poly 2-(diethylamino)ethyl methacrylate (pDEAEMA), which were responsive to changes in pH. The delivery devices underwent comprehensive chemical and physical characterization, followed by in vitro testing. The pDEA system showed a 3.2 times higher release rate at 45 °C than 22 °C and 2.2 times higher release rate when exposed to pH 8.5 medium compared to pH 6.2 media. In 2021, Ana García et al. [110] successfully fabricated MSNs that exhibit light sensitivity and possess integrated photothermal (PTT) and antibacterial functionalities. The therapeutic potential of these nanosystems is considerable in terms of their ability to impact the architectural structure of bacterial biofilms and therefore impede their development. The process of gold nanorod nucleation, followed by the subsequent development of a silica shell, results in the formation of a core@shell structure known as AuNR@MSN. This particular design exhibits PTT capabilities. The introduction of nitrosothiol groups (–SNO) via a thermally sensitive linker allows for an increased production of nitric oxide when exposed to near-infrared light during photothermal stimulation. The additional administration of LVF antibiotic results in the formation of a distinct nanoassembly, which exhibits promising therapeutic effectiveness in combating bacterial biofilms caused by S. aureus. The study validated the sample’s monodispersity and the rod-like morphology of AuNR NPs. The mean dimensions of the nanoparticles were found to be 52.4 ± 4.9 nm and 14.4 ± 3.4 nm, respectively. The dimensions of AuNR@MSN-SNO were around 106 nm, with a ZP of − 12.6 mV. The application of light stimuli revealed a dispersal rate of the bacterial biofilm, which was reduced by approximately 30%. However, when illuminated with near-infrared (NIR) irradiation, a significantly higher reduction of approximately 90% was observed. This suggests that localized antimicrobial exposure and PTT enhance therapeutic efficiency. The results propose the development of nanoparticle carriers that can be activated by NIR light, which can deliver a combination therapy involving photothermal therapy and the release of LVF and nitric oxide. This combined therapy aims to break down bacterial biofilms and effectively combat microbial infections. The potent antimicrobial activity of this substance can be explained by its threefold impact on photothermal treatment, which successfully disrupts the integrity of S. aureus biofilm. Additionally, the substance enhances the release of nitric oxide agents and exhibits bactericidal activity when combined with LVF.

Conclusion

In summary, this review presents compelling evidence that nanotechnology can play a transformative role in solving the problem of antibiotic resistance via improved formulation approaches. A wide array of nanocarrier platforms was shown to enhance the pharmacokinetic and pharmacodynamic properties of LVF compared to conventional administration. Polymer-based nanoparticles, lipid-based vesicles, mesoporous silica, and other inorganic nanomaterials demonstrated versatility in drug encapsulation while facilitating controlled, sustained-release profiles. Some formulations incorporated additional functionalities like stimuli-responsiveness, targeting ligands, or photothermal capabilities to facilitate on-demand drug release in response to physiological cues. This represents significant progress towards personalized treatment paradigms. Moving forward, further optimization is still needed to translate many of these proof-of-concept studies into clinical applications. More rigorous in vivo and human trials are required to validate safety, efficacy, and therapeutic advantages. Large-scale, cost-effective manufacturing processes must also be developed to ensure commercial viability. Beyond LVF, expanding this work to additional classes of antibiotics will broaden the potential impact on resistance. Combination therapies employing multiple drugs or with other treatment modalities may offer synergistic benefits worth exploring. Functionalizing carriers with multiple targeting moieties could further enhance intracellular delivery and biofilm penetration. Understanding host immunomodulatory responses to various nanomaterials is also important from a translational perspective. While many formulations showed good biocompatibility, long-term effects must be established. More research is also warranted to elucidate molecular mechanisms of drug release and carrier clearance. This includes elucidating the interplay between carrier properties and drug pharmacokinetics. Overall, continued multidisciplinary collaboration between nanotechnology, pharmaceutical science, microbiology, and medicine holds tremendous promise to revolutionize infectious disease management through personalized, precision-guided antibiotic therapies. With ongoing advances, these strategies may help stem the growing crisis of antimicrobial resistance.