Introduction

In the past decades, a variety of nanoparticle drug carriers such as nanocapsules, liposomes, nanogels, and polymeric micelles have been utilized in delivering anticancer agents [1–4]. Nanocapsules have attracted great attention as the carrier of various drugs, therapeutic agents, and gene with promising outlook [5, 6]. Recently, nanocapsules that are responsive to environmental stimuli (such as pH, temperature) are attracting significant interest for controlled release of drugs. The thermally responsive nanocapsules are of particular interest to many researchers because the drug can be encapsulated in the empty core of nanocapsules and controlled release by heating and cold shock treatment [7–9]. Besides, nanocapsules of less than 150 nm have been demonstrated to be easily internalized by mammalian cells via endocytosis, a natural means of cell self-feeding [10, 11].

Pluronic F127 (an amphiphilic, triblock copolymer) has been authenticated by the Food and Drug Administration (FDA) for use as food additives and pharmaceutical ingredients [12, 13]. It has been used for preparing thermally responsive micelles, hydrogels, and nanocapsules [14–16] due to its temperature-sensitive amphiphilicity and excellent biocompatibility. A distinctive feature of Pluronic block copolymers is their ability to self-assemble in aqueous solution into multimolecular aggregates such as spherical, rodlike, or lamellar structures above the lower critical solution temperature (LCST) by hydrophobic interaction of the propylene oxide (PPO) middle block in the macromolecular chain [17, 18]. Park’s group have recently synthesized a series of nanocapsules based on Pluronic that can expand and shrink rapidly in response to temperature change and used them to deliver anticancer drugs and gene [3, 6, 10]. These nanocapsules were produced by shell cross-linking of polyethylene oxide (PEO)–PPO–PEO copolymers with heparin and polyethylenimine (PEI) at an organic/aqueous interface. The shell-cross-linked Pluronic F127 micelles were prepared using gold nanoparticle (Au-NP) as cross-linker. Using glutathione as an effective trigger, the Pluronic F127 micelles spontaneously evolve and reassemble into large nanocapsules. Beside their thermal responsiveness in size, they demonstrated that the controlled release properties of the Pluronic F127–chitosan nanocapsules are thermally responsive as well [19].

The natural polymers, such as poly(ε-lysine) (ε-PL) and hyaluronic acid (HA), were used as another composition of the nanocapsules in this work. ε-PL is composed of 25∼30 lysine residues which are connected via peptide bonds between α-carboxyl and ε-amino groups. It has recently received interest in several applications in medicine, food, environment, and electronics [20, 21]. As a highly positively charged polyelectrolyte, ε-PL can be explored for DNA complex agents with potential applications for gene delivery [22]. Hyaluronic acid (HA) is a biodegradable, biocompatible, polyanionic, and non-immunogenic glycosaminoglycan [23]. HA plays a role in cellular processes including inflammation, morphogenesis, cell proliferation, and wound repair. In addition, HA could be readily chemically modified through both its hydroxyl and carboxyl groups [24]. It has been used for preparing hydrogels and nanoparticles for controlled release drugs or tissue engineering due to its good features [25].

In the present study, thermosensitive polymeric Pluronic F127-based nanocapsules having a diameter of dozens of nanometers at body temperature were produced and used as the delivery vehicle of DOX·HCl. PL and HA were used as shell cross-linkers of the nanocapsules. The size and morphological characters of the nanocapsules were demonstrated by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Besides its size and surface charge, the wall permeability of the nanocapsule is temperature dependent. The thermally responsive properties of the nanocapsules were utilized to physically encapsulate DOX·HCl for controlled release. This study proposes a novel delivery carrier for controlled release drugs with temperature responsiveness.

Experimental

Materials

PEO–PPO–PEO triblock copolymer ((PEO)100(PPO)65(PEO)100, Pluronic F127, M W = 12,600) was obtained from Sigma-Aldrich. Poly(ε-lysine) (ε-PL, Mn = 3,600–4,200) was kindly supplied from Zhengzhou Bainafo Bioengineering Co., Ltd. Hyaluronic acid (Mn = 3,200 Da) was provided by Freda Biochem Co., Ltd. (Shandong, China). 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC·HCl) and p-nitrophenyl chloroformate (p-NPC) were purchased from Energy Chemical. Ethylene diamine was obtained from Alfa Aesar. DOX·HCl was supplied from Zhejiang Hisun Pharmaceutical Co. Ltd. Dichloromethane and triethylamine were obtained from Sinopharm Chemical Reagent Co. Ltd. Highly pure water with resistance of 18 × 106 Ωcm was obtained through deionization and filtration with a Milli-Q purification system.

Preparation of activated Pluronic F127

The activated Pluronic F127 was synthesized according to the previous reference [26]. Briefly, Pluronic F127 (6.3 g, 0.5 mmol) was dissolved in 50 mL of anhydrous dichloromethane. TEA (0.15 mL) and NPC (0.605 g, 3 mmol) were slowly added to the solution in a dropwise manner. The reaction mixture was stirred overnight at room temperature and then the solution was concentrated. The active NPC–Pluronic–NPC was obtained by precipitating three times in ice-cold diethyl ether and dried under vacuum.

For synthesizing of the amine end-capped Pluronic F127 (NH2–Pluronic–NH2), NPC–Pluronic–NPC (0.65 g, 0.05 mmol) was reacted with excess ethylene diamine (16 μL, 0.25 mmol) in 20 mL of anhydrous dichloromethane. The NH2–Pluronic–NH2 was recovered by precipitating three times in ice-cold diethyl ether and dried under vacuum.

Synthesis of nanocapsules based on Pluronic F127

The thermally responsive nanocapsules based on Pluronic F127 were prepared using an emulsification/solvent evaporation method [6, 18, 27–29] with slight modifications. Briefly, the activated Pluronic F127 was dissolved in dichloromethane at a concentration of 30 % (w/v) and added dropwise into the aqueous solution of 0.75 % (w/v) ε-PL or HA (including 96 mg of EDC), and the oil-in-water mixture was emulsified for 4 min. The emulsion was further stirred gently for 20 h to allow cross-link formation between the activated Pluronic F127 and PL or HA on the aqueous side of the oil–water interface. The organic solvent (dichloromethane) in the emulsion was then removed by rotary evaporation until the emulsion became clear. The samples were further dialyzed against deionized (DI) water with a dialysis tube (MWCO = 50 KD) to remove non-cross-linked Pluronic F127, PL, HA, and residual organic solvents. Water in the sample was then removed by freeze-drying, and the resultant dry nanocapsules were either used immediately or kept at −20 °C for future use.

Encapsulation and controlled release of doxorubicin hydrochloride (DOX·HCl)

To encapsulate DOX·HCl into the Pluronic F127-based nanocapsules, the nanocapsules (60 mg) with DOX·HCl (5 mg) were incubated in 20 mL of DI water overnight at 4 °C when the nanocapsules were swollen and their wall permeability was high. The water both inside and outside the nanocapsules was removed by freeze-drying. The heating–cooling process was conducted in order to obtain clean drug-loaded nanocapsules without any free (non-encapsulated) DOX·HCl outside the nanocapsules: the freeze-dried mixture of free and encapsulated DOX·HCl was heated at 55 °C to shrink the nanocapsules, dissolved in DI water at 37 °C in a dialysis tube (MWCO = 50 KD), and dialyzed against DI water at 37 °C for 24 h with the dialysis water being changed every 2 h. The sample was then freeze-dried for future use.

In order to measure the drug loading contents (DLC) and drug loading efficiency (DLE), 5 mg of lyophilized drug-loaded nanocapsules were dispersed in 5 mL of dimethylformamide and then were diluted with an equal volume of DI water. The mixed solution was used to determine the drug concentration by a UV/vis spectrometer at 480 nm. The DLC and DLE were calculated according to the following formulas:

$$ \mathrm{DLC}\left(\mathrm{wt}\%\right)=\left(\mathrm{weight}\kern0.5em \mathrm{of}\kern0.5em \mathrm{loaded}\kern0.5em \mathrm{drug}/\mathrm{weight}\kern0.5em \mathrm{of}\kern0.5em \mathrm{drug}\hbox{-} \mathrm{loaded}\kern0.5em \mathrm{nanocapsules}\right)\times 100\% $$
$$ \mathrm{DLE}\left(\mathrm{wt}\%\right)=\left(\mathrm{weight}\kern0.5em \mathrm{of}\kern0.5em \mathrm{loaded}\kern0.5em \mathrm{drug}/\mathrm{weight}\kern0.5em \mathrm{of}\kern0.5em \mathrm{feeding}\kern0.5em \mathrm{drug}\right)\times 100\% $$

For controlled release study, the nanocapsules which dispersed in 5 mL of phosphate-buffered solution (PBS, 100 mM, pH 7.4) was further dialyzed against 50 mL of PBS at 37 °C with constant stirring in a beaker. A total of 0.5 mL of the dialysate outside the dialysis tube in the beaker was collected at various times to determine the drug concentration in the dialysate. The total volume of the dialysate outside the dialysis tube was kept at 50 mL by replenishing it with 0.5 mL of PBS at each sampling time.

Characterization

The 1H NMR of activated Pluronic F127 and nanocapsules was performed on a Bruker ARX 600 NMR spectrometer at ambient temperature. D2O was used as solvent. The hydrodynamic diameter (D h) and size distribution of nanocapsules were determined using dynamic light scattering (DLS). Measurements were carried out at different temperatures using a PAS (NANO2590) from Malvern Instruments. Morphology of nanocapsules was analyzed using transmission electron microscopy (TEM) (JEOL-2100F) at 150 kV. Samples for TEM were prepared by directly depositing nanocapsule solution onto carbon-coated copper grids. The ultraviolet (UV)–visible spectra of the samples were recorded on a Perkin Elmer Lambda 750 spectrophotometer.

Results and discussion

Synthesis and characterization of nanocapsules based on Pluronic F127

The synthetic route of nanocapsules based on Pluronic F127 is shown in Scheme 1, and the schematic illustration of nanocapsule synthesis is depicted in Scheme 2. For synthesis of Pluronic F127/PL nanocapsules, the Pluronic F127 was first preactivated by the reaction between p-NPC and two terminal hydroxyl groups of Pluronic F127. The mixture solution of active NPC–Pluronic–NPC in dichloromethane and PL in aqueous formed a stable oil-in-water emulsion through ultrasonic treatment. The terminal p-NPC groups of the Pluronic F127 were conjugated with primary amine groups in PL at the oil/water interface, resulting in shell cross-linking of the Pluronic F127/PL nanocapsules. Furthermore, in the process of synthesis of Pluronic F127/HA nanocapsules, NPC–Pluronic–NPC was chemically modified by ethylene diamine to obtain NH2–Pluronic–NH2 with two terminal amine groups. During the cross-linking reaction, EDC was used as a catalyst to accelerate the conjugation reaction between the carboxyl groups of HA and the amine group of NH2–Pluronic–NH2 to form shell-cross-linked nanocapsules [26, 30].

Scheme 1
scheme 1

Synthetic route of the Pluronic F127/HA and Pluronic F127/PL nanocapsules

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Scheme 2
scheme 2

Illustration of the procedures to synthesize the Pluronic F127/HA and Pluronic F127/PL nanocapsules. The oil used is dichloromethane. HA hyaluronic acid, PL poly(ε-lysine), PPO polypropylene oxide, PEO polyethylene oxide, US ultrasound

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The 1H NMR spectra of the activated Pluronic F127 and cross-linked nanocapsules based on Pluronic F127 are shown in Fig. 1. The 1H NMR spectrum of NPC–Pluronic–NPC shows peaks at δ∼8.4 and δ∼7.5 ppm corresponding to the aromatic protons of p-NPC groups at both ends of Pluronic (Fig. 1a) [31]. The 1H NMR spectrum of the NH2–Pluronic–NH2 shows a prominent resonance peak at δ∼3.15 ppm which was assigned to the methylene protons (–CH2–CH2–) of the ethylene diamine added to the terminals of Pluronic F127 along with the major resonance peaks of Pluronic F127 (Fig. 1b) [19]. In the 1H NMR spectrum of the Pluronic F127/HA nanocapsules, a new peak at δ∼2.0 ppm was attributed to an acetyl group of HA (Fig. 1c) [32]. The methylene resonance peak (δ∼3.15 ppm) splits into two peaks at δ∼3.15 ppm and δ∼2.9 ppm, which confirmed the cross-linking reaction between the terminal amine groups of NH2–Pluronic–NH2 and the carboxyl groups of hyaluronic acid through an amide bond [19]. In the 1H NMR spectrum of the Pluronic F127/PL nanocapsules, peaks of the aromatic protons of p-NPC disappeared and new peaks at δ∼3.25, 3.15, 1.5, 1.36, and 1.25 ppm were attributed to alkyl chain of PL (Fig. 1d) [33]. By integrating the proton resonance peaks of PL (at ∼1.5 ppm), HA (at ∼2.0 ppm), and Pluronic F127 (at ∼1.05 ppm), PL and HA were found to take up ∼17 and ∼37 % (by weight) of the nanocapsules, respectively.

Fig. 1
figure 1

1H NMR spectra of NPC–Pluronic–NPC (a), NH2–Pluronic–NH2 (b), Pluronic F127/HA nanocapsules (c), and Pluronic F127/PL nanocapsules (d)

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The morphological characteristics of Pluronic F127-based nanocapsules were evaluated by transmission electron microscopy (TEM). Figure 2 presents the TEM image of the Pluronic F127/PL nanocapsules (a, b, c) and Pluronic F127/HA nanocapsules (d, e, f) taken after preequilibrating at room temperature. It can be seen that the nanocapsules were well dispersed and separated from each other from the TEM image. By allowing a short time of the cross-linking reaction (15 min) for Pluronic F127/PL (Fig. 2a) and Pluronic F127/HA (Fig. 2d) nanocapsules, the typical empty core–shell structure with a lighter contrast inner cavity and a deeper contrast polymer shell was obviously observed. However, after 20 h of cross-linking reaction, the core–shell structure became invisible as shown in Fig. 2b, e. The darker contrast in these images compared with that of the nanocapsules with observable empty core–shell structure may be attributed to denser shell structure. The empty core–shell structure was not observable in Pluronic F127–chitosan nanocapsules and Pluronic F127–PEI nanocapsules which were prepared using the same emulsification/solvent evaporation method [9, 19]. Zhang and his coworkers investigated the effect of EDC catalysis time on the Pluronic F127–chitosan nanocapsule synthesis and morphology by TEM; they found that the empty core–shell structure was clearly visible for the nanocapsules synthesized in short EDC catalysis (without EDC or 10-min catalysis), but the empty core–shell structure became invisible after a 20-h catalysis [19]. As shown in Fig. 2a, for the Pluronic F127/PL nanocapsules, the diameter of the inner cavity was determined to be about 75 nm and the PL shell was estimated to be almost 5 nm. The short cross-linking reaction time led to the formation of nanocapsules with thin and low-cross-linked PL shell because the cross-linking reaction between the –NPC groups and –NH2 groups was slow. The difference of the contrast between the PL shell and the hollow core resulted in the typical empty core–shell structure which can be found in the TEM images. After reacting for 20 h, the diameter of the nanocapsules increased to about 200 nm as shown in Fig. 2b. Assuming that the size change of the inner cavity was negligible, the thickness of the PL shell can be estimated to be more than 60 nm. The denser and tighter (with high cross-linking density for long reaction time) PL shell resulted in the empty core–shell structure invisible in the TEM image even though the hollow inner cavity was still there [19]. For the Pluronic F127/HA nanocapsules as shown in Fig. 2d, the smaller and instable nanocapsules were formed because of the slower reaction rate between –COOH groups and –NH2 groups. After reacting for 20 h, the diameter of the Pluronic F127/HA nanocapsules was determined to be about 220 nm. The size of the Pluronic F127/HA nanocapsules was larger than the Pluronic F127/PL nanocapsules because the content of HA was more than PL taken up by the nanocapsules. The average size was consistent with those determined from DLS results.

Fig. 2
figure 2

Typical TEM images of Pluronic F127/PL nanocapsules prepared by 15-min cross-linking reaction (a) and 20-h cross-linking reaction at different resolutions (b, c). TEM images of Pluronic F127/HA nanocapsules by 15-min cross-linking reaction (d) and 20-h cross-linking reaction at different resolutions (e, f)

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The temperature-sensitive size change of the Pluronic F127/HA and Pluronic F127/PL nanocapsules in aqueous solution was further studied quantitatively by DLS at different temperatures from 4 to 37 °C, and the results are shown in Fig. 3. A broad thermal responsiveness of the nanocapsules can be observed over the temperature range. For the Pluronic F127/PL nanocapsules, they are about 72 ± 4 nm at 37 °C (with narrow size distribution, polydispersity index [PDI] = 0.08), whereas they are about 226 ± 23 nm at 4 °C (with broad size distribution, PDI = 0.34). The Pluronic F127/PL nanocapsules exhibit a change in diameter (D h) and volume (V ∝ D 3h ) of more than 3 and 31 times (\( \mathrm{volume}\kern0.5em \mathrm{change}={\left(\frac{\mathrm{diameter}\kern0.5em \mathrm{at}\kern0.5em 4\kern0.5em {}^{\circ}\mathrm{C}}{\mathrm{diameter}\kern0.5em \mathrm{at}\kern0.5em 37\kern0.5em {}^{\circ}\mathrm{C}}\right)}^3 \)) between 4 and 37 °C, respectively. The average diameter of the Pluronic F127/HA nanocapsule was decreased from 206 ± 20 to 69 ± 5 nm with increasing temperature from 4 to 37 °C, which indicates that the volume of nanocapsules is reduced by about 26 times. A solid monolithic Pluronic F127 micelle in aqueous solution (about 30 nm [18]) is much smaller than this Pluronic-based nanocapsule (about 70 nm in this study) at 37 °C. As a result of the balance between the hydrophobic interactions (leading to dehydration in the PPO blocks and volume contraction) and the repulsion between the positive charges in the cross-linked PL or HA molecules (resisting volume contraction or collapse), the nanocapsule was proposed to have an empty core [9]. The change of size was attributed to the hollow morphology and the hydrophobic interactions between the middle propylene oxide (PPO) blocks in Pluronic F127 copolymers that were grafted or cross-linked within nanocapsules in response to temperature variation [6, 27]. In the current study, the volume contraction of the Pluronic F127/PL and Pluronic F127/HA nanocapsules was relatively smaller than that of Pluronic F127/heparin nanocapsules (1,000-fold volume transition) and Pluronic F127–chitosan nanocapsules (more than 200 times contraction), but compared with that of Pluronic F127/PEI nanocapsules (20–40 times volume contraction) [18]. The difference in the extent of volume transition was possibly caused by the different shell cross-linking density and the highly charged nature of HA and PL chains within the shell layer. As with PEI, which is a cationic polymer with a highly charged density, PL is a highly charged cationic polymer and HA is an anionic polyelectrolyte with highly negatively charged density.

Fig. 3
figure 3

Size change of Pluronic F127/PL and Pluronic F127/HA nanocapsules measured by DLS over a temperature range of 4–37 °C (A). DLS profiles of Pluronic F127/PL nanocapsules at 4 (B1) and 37 °C (B2), and Pluronic F127/HA nanocapsules at 4 (C1) and 37 °C (C2)

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Encapsulation and controlled release of DOX·HCl

A schematic illustration of the procedure for encapsulating DOX·HCl in the Pluronic F127/PL and Pluronic F127/HA nanocapsules is given as steps a–e in Scheme 3. In this study, DOX·HCl was used as a model drug to investigate the potential application of the thermally responsive nanocapsules. In brief, DOX·HCl was loaded into the nanocapsules by soaking (a) the drug (5 mg) and nanocapsules (60 mg) in water (20 mL) at 4 °C for 24 h when the nanocapsules are swollen with a high wall permeability. After soaking, the sample was freeze-dried (a, b) to remove water both inside and outside the nanocapsules. The dried mixture of free and encapsulated DOX·HCl was then heated (b, c) to shrink the nanocapsules. The sample was then dissolved (c, d) in 37 °C DI water and dialyzed (d, e) against DI water to remove any non-encapsulated drug. The DLC and DLE of are summarized in Table 1. The higher encapsulation capability of the Pluronic F127/HA nanocapsules compared to that of the Pluronic F127/PL nanocapsules may be attributed to the anionic polyelectrolyte nature of HA. HA can adsorb DOX·HCl by electrostatic interactions between carboxyl of HA and amine of DOX·HCl. Moreover, the content of HA in the shell of the Pluronic F127/HA nanocapsules is more than that of PL in the Pluronic F127/PL nanocapsules.

Scheme 3
scheme 3

Schematic illustration of the process of DOX·HCl encapsulation (a–e) and temperature-controlled release (e–g)

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Table 1 The drug loading contents (DLC) and drug loading efficiency (DLE) of two nanocapsules
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The release profiles of DOX·HCl from the DOX·HCl-loaded nanocapsules at physiological temperature and pH are presented in Fig. 4. It was found that the Pluronic F127-based nanocapsules could mediate efficiently DOX·HCl release; the release of DOX·HCl from these nanocapsules showed two phases. An initial rapid-release phase in which about 50 % of the entrapped DOX·HCl was released during 3 h, which was considered to be due to the near-surface location of DOX·HCl to diffuse rapidly out of the nanocapsules for the drug concentration gradient inside and outside of the nanocapsules. After the rapid release, a sequential slow-release period in which more than 12 % of DOX·HCl was released in a continuous way during 32 h. The release of DOX·HCl from the Pluronic F127/HA nanocapsules exhibited a slightly rapid release at the initial rapid-release phase compared with that from the Pluronic F127/PL nanocapsules, which was likely due to the DOX·HCl concentration gradient shell and hollow core of the nanocapsules. Compared with the distribution of DOX·HCl in the Pluronic F127/PL nanocapsules, more DOX·HCl was loaded in the shell of the Pluronic F127/HA nanocapsules as a result of the electrostatic interactions between carboxyl of HA and amine of DOX·HCl, which caused the DOX·HCl near the shell to diffuse rapidly out of the nanocapsules.

Fig. 4
figure 4

In vitro release of DOX·HCl from Pluronic F127/HA and Pluronic F127/PL nanocapsules in PBS (pH 7.4, 100 mM) at 37 °C

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To investigate the mechanism of drug release from the nanocapsules, the release data was analyzed using Higuchi model and Korsmeyer–Peppas model. The Higuchi model described the cumulative percentage drug release from insoluble matrix as a square root of time-dependent process based on Fickian diffusion Eq. (1) [34, 35]. Korsmeyer–Peppas described the drug release from a polymeric system using Eq. (2) [36].

$$ \raisebox{1ex}{${M}_{\mathrm{t}}$}\!\left/ \!\raisebox{-1ex}{${M}_{\infty }$}\right.={k}_{\mathrm{H}}{t}^{\frac{1}{2}} $$
(1)
$$ \ln \left(\raisebox{1ex}{${M}_{\mathrm{t}}$}\!\left/ \!\raisebox{-1ex}{${M}_{\infty }$}\right.\right)=\operatorname{l}\mathrm{n}k+n\operatorname{l}\mathrm{n}t $$
(2)

where M t and M ∞ are the total amount of drug release at time t and equilibrium time, respectively; k H is the Higuchi dissolution constant; k is a kinetic constant that measures the drug release rate; and n represents an exponent characteristic of the release mechanism. The values of n are less than or equal to 0.5 for Fickian diffusion, between 0.5 and 1.0 for non-Fickian diffusion, and 1 for zero-order release. The model is valid only for M t / M ∞ < 0.6.

The data obtained from Fig. 4 were plotted as cumulative percentage drug release versus square root of time and are shown in Fig. 5. For the release of DOX·HCl from the Pluronic F127/PL nanocapsules, a linear plot was obtained which indicated a typical Fickian diffusion control mechanism. The inconformity to the Higuchi model was observed for the release of DOX·HCl from the Pluronic F127/HA nanocapsules which revealed that the drug release deviates from the Fickian diffusion mechanism. The cumulative release data from Fig. 4 also were analyzed according to Eq.2 and the relevant formulas of the regression relation as shown in Table 2. The n value in the Pluronic F127/PL nanocapsule release system is 0.4908, implying that the drug release is primarily controlled by the Fickian diffusion mechanism. The n value (0.5475) in the Pluronic F127/HA nanocapsule release system is slightly larger than 0.5, indicating that the drug transport mechanism appears to be anomalous and the diffusion is the predominant mechanism. The electrostatic interactions between HA and DOX·HCl hindered the Fickian diffusion. Hence, diffusion coupled with electrostatic binding might be the mechanism for the DOX·HCl release from the Pluronic F127/HA nanocapsules.

Fig. 5
figure 5

The cumulative release as a function of the square root of time according to the Higuchi model

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Table 2 Regression equations and kinetic parameters obtained from fitting drug release data to Korsmeyer–Peppas model
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Conclusions

In this study, the thermally responsive Pluronic F127/PL and Pluronic F127/HA nanocapsules were successfully synthesized and exhibited a larger volume transition over a temperature range of 4–37 °C. The size of nanocapsule was about 70 nm with low wall permeability at 37 °C, while that expanded to about 220 nm with high permeability at 4 °C. Encapsulation of DOX·HCl can be done by simply incubating the nanocapsules in aqueous solution at low temperature, followed by freeze-drying to remove water. The electrostatic interactions between HA and DOX·HCl in the Pluronic F127/HA nanocapsules resulted in a slightly higher encapsulation capability and more rapid release rate compared to those in the Pluronic F127/PL nanocapsules. The drug release kinetic of the Pluronic F127/HA nanocapsules confirmed that the drug release is controlled by the Fickian diffusion mechanism. The DOX·HCl release from the Pluronic F127/HA nanocapsules is controlled by diffusion coupled with electrostatic binding. The temperature-sensitive Pluronic-based nanocapsules could be utilized as an effective drug delivery vehicle for specific biomedical applications.