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Evaluation of bioavailability, efficacy, and safety profile of doxorubicin-loaded solid lipid nanoparticles

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Abstract

We investigated the bioavailability, efficacy, and toxicity of doxorubicin-loaded solid lipid nanoparticles (DOX-SLNs) prepared by a simple modified double-emulsification method. A 3-factor, 3-level Box–Behnken statistical design was adopted in the optimization of DOX-SLN formulation considering dependent factors particle size and entrapment efficiency. Optimized SLN formulation composed of lipid (2 %) consisting of soya lecithin and Precirol ATO 5 (1:3) with Pluronic F68 (0.3 %) resulted in 217.36 ± 3.31 nm particle size and 59.45 ± 1.75 % entrapment efficiency. DOX-SLN exhibited significant enhancement (p < 0.05) in bioavailability as compared with free DOX in Sprague–Dawley (SD) rats. DOX-SLN exhibited higher peak plasma concentration (6.761 ± 0.08 vs. 2.412 ± 0.04 μg/ml), increased AUC (61.368 ± 3.54 vs. 5.812 ± 0.49 μg/ml h), decreased clearance (36 ± 0.01 vs. 619 ± 0.005 mL/h kg), and volume of distribution (733 ± 0.092 vs. 2,064 ± 0.061 mL/kg) when compared to free DOX. The collective results of cardiac and kidney enzyme assay, antioxidant enzyme levels, hematological parameters, effect on body weight and tumor volume, tumor necrosis factor-α level, histopathological examination, and survival analysis confirmed the improved efficacy and safety profile of DOX-SLN in 7,12-dimethyl benzanthracene-induced breast cancer in SD rats.

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References

  • Allemann E, Brasseur N, Benrezzak O, Rousseau J, Kudrevich SV, Boyle RW (1995) PEG-coated poly (lactic acid) nanoparticles for the delivery of hexadecafluoro zinc phthalocyanine to EMT-6 mouse mammary tumours. J Pharm Pharmacol 47:382–387

    Article  CAS  Google Scholar 

  • Alvarez L, Sayalero ML, Lanao JM (1999) High-performance liquid chromatographic validated assay of doxorubicin in rat plasma and tissues. J Chromatogr B 721:271–278

    Article  Google Scholar 

  • Antonella M, Roberta C, Claudia B, Ludovica G, Gasco MR (2000) Cellular uptake and cytotoxicity of solid lipid nanospheres (SLN) incorporating doxorubicin or paclitaxel. Int J Pharma 210:61–67

    Article  Google Scholar 

  • Asasutiarit R, Lorenzen SI, Sirivichayakul S, Ruxrungtham K, Ruktanonchai U, Ritthidei GC (2007) Effect of solid lipid nanoparticles formulation compositions on their size, zeta potential and potential for in vitro pHIS-HIV-hugag transfection. Pharm Res 24:1098–1107

    Article  Google Scholar 

  • Ayen WY, Kumar N (2012) In vivo evaluation of doxorubicin-loaded (PEG)3-PLA nanopolymersomes (PolyDoxSome) using DMBA-induced mammary carcinoma rat model and comparison with marketed LipoDox™. Pharm Res 29:2522–2533

    Article  CAS  Google Scholar 

  • Barratt G (2003) Colloidal drug carriers: achievements and perspectives. Cell Mol Life Sci 60:21–37

    Article  CAS  Google Scholar 

  • Barraud L, Merle P, Soma E, Lefranc L, Guerret S, Chevallier M, Dubernet C, Couvreur P, Trepo C, Vitvitski L (2005) Increase of doxorubicin sensitivity by doxorubicin-loading into nanoparticles for hepatocellular carcinoma cells in vitro and in vivo. J Hepatol 42:736–743

    Article  CAS  Google Scholar 

  • Bhardwaj V, Ankola DD, Gupta SC, Schneider M (2009) PLGA nanoparticles stabilized with cationic surfactant: safety studies and application in oral delivery of paclitaxel to treat chemical-induced breast cancer in rat. Pharm Res 26:2495–2503

    Article  CAS  Google Scholar 

  • Bocca O, Cavalli CR, Gabriel L, Miglietta A, Gasco MR (1998) Phagocytic uptake of fluorescent stealth and non-stealth solid lipid nanoparticles. Int J Pharm 175:185–193

    Article  CAS  Google Scholar 

  • Brigger I, Dubernet C, Couvreur P (2002) Nanoparticles in cancer therapy and diagnosis. Adv Drug Deliv Rev 54:631–651

    Article  CAS  Google Scholar 

  • Chattopadhyay N, Zastre J, Wong HL, Wu XY, Bendayan R (2008) Solid lipid nanoparticles enhance the delivery of the HIV protease inhibitor, Atazanavir, by a human brain endothelial cell line. Pharma Res 25:2262–2271

    Article  CAS  Google Scholar 

  • Chaudhary H, Kohli K, Amin S, Rathee P, Kumar V (2011) Optimization and formulation design of gels of Diclofenac and Curcumin for transdermal drug delivery by Box–Behnken statistical design. J Pharm Sci 100:580–593

    Article  CAS  Google Scholar 

  • Claiborne A (1985) Catalase activity. In: Greenwald RA (ed) CRC handbook of oxygen radical research. CRC Press, Boca Raton, pp 283–284

    Google Scholar 

  • Deres P, Halmosi R, Toth A, Kovacs K, Palfi A, Habon T, Czopf L, Kalai T, Hideg K, Sumegi B, Toth K (2005) Prevention of doxorubicin-induced acute cardiotoxicity by an experimental antioxidant compound. J Cardiovasc Pharmacol 45:36–43

    Article  CAS  Google Scholar 

  • Dong X, Mattingly CA, Tseng MT, Cho MJ, Liu Y, Adams VR, Mumper RJ (2009) Doxorubicin and paclitaxel-loaded lipid-based nanoparticles overcome multidrug resistance by inhibiting P-glycoprotein and depleting ATP. Cancer Res 69:3918–3926

    Article  CAS  Google Scholar 

  • Duncan R (1999) Polymer conjugates for tumour targeting and intracytoplasmic delivery. The EPR effect as a common gateway? Pharm Sci Tech Today 2:441–449

    Article  CAS  Google Scholar 

  • EI-Shitany NA, EI-Haggar S, EI-desoky K (2008) Silymarin prevents adriamycin-induced cardiotoxicity and nephrotoxicity in rats. Food Chem Toxicol 46:2422–2428

    Article  Google Scholar 

  • Ellman GL, Fiches FT (1959) Quantitative determination of peptides by sulfhydryl groups. Arch Biochem Biophys 82:70–72

    Article  CAS  Google Scholar 

  • Fundaro A, Cavalli R, Bargoni A, Vighetto D, Zara GP, Gasco (2000) Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin: pharmacokinetics and tissue distribution after i.v. administration to rats. Pharmacol Res 42:337–343

    Article  CAS  Google Scholar 

  • Gabizon AS (2001) Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of chemotherapy. Cancer Invest 19:424–436

    Article  CAS  Google Scholar 

  • Gabizon A, Catane R, Uziely B, Kaufman B, Safra T (1994) Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 54:987–992

    CAS  Google Scholar 

  • Harivardhan RL, Murthy RSR (2003) Polymerization of n-butyl cyanoacrylate in presence of surfactant: study of influence of polymerization factors on particle properties, drug loading and evaluation of its drug release kinetics. ARS Pharmaceutica 44:351–369

    Google Scholar 

  • Hu L, Tang X, Cui F (2004) Solid lipid nanoparticles (SLNs) to improve oral bioavailability of poorly soluble drugs. J Pharm Pharmacol 56:1527–1535

    Article  CAS  Google Scholar 

  • Jacquet P, Averbach A, Stuart OA, Chang D, Sugarbaker PH (1998) Hyperthermic intraperitoneal doxorubicin: pharmacokinetics, metabolism, and tissue distribution in a rat model. Cancer Chemother Pharmacol 41:147–154

    Article  CAS  Google Scholar 

  • Kabanov AV, Batrakova EV, Alakhov VY (2002) Pluronic block copolymers for overcoming drug resistance in cancer. Adv Drug Deliv Rev 54:759–779

    Article  CAS  Google Scholar 

  • Kakkar V, Singh S, Singla D, Kaur IP (2011) Exploring solid lipid nanoparticles to enhance the oral bioavailability of curcumin. Mol Nutr Food Res 55:495–503

    Article  CAS  Google Scholar 

  • Kang KW, Chun MK, Kim O, Subedi RK, Ahn SG, Choi HK (2010) Doxorubicin-loaded solid lipid nanoparticles to overcome multidrug resistance in cancer therapy. Nanomedicine 6:210–213

    CAS  Google Scholar 

  • Kilbanov AL, Maruyama K, Torchilin VP, Huang L (1990) Amphipatic polyethylene glycols effectively prolong the circulation time of liposomes. FEBS Lett 268:235–239

    Article  Google Scholar 

  • Kim D, Lee ES, Oh KT, Gao ZG, Bae YH (2008) Doxorubicin-loaded polymeric micelle overcomes multidrug resistance of cancer by double-targeting folate receptor and early endosomal pH. Small 4:2043–2050

    Article  CAS  Google Scholar 

  • Li J, Jiang Y, Wen J, Fan G, Wu Y, Zhang C (2009) A rapid and simple HPLC method for the determination of curcumin in rat plasma: assay development, validation and application to a pharmacokinetic study of curcumin liposome. Biomed Chromatogr 23:1201–1207

    Article  CAS  Google Scholar 

  • Liu LL, Li QX, Xia L, Shao L (2007) Differential effects of dihydropyridine calcium antagonists on doxorubicin-induced nephrotoxicity in rats. Toxicology 231:81–90

    Article  CAS  Google Scholar 

  • Mady MM, Shafaa MW, Abbase ER, Fahium AH (2011) Interaction of doxorubicin and dipalmitoylphosphatidylcholine liposomes. Cell Biochem Biophys 62:481–486

    Article  Google Scholar 

  • Mattheolabakis G, Rigas B, Constantinides PP (2012) Nanodelivery strategies in cancer chemotherapy: biological rationale and pharmaceutical perspectives. Nanomedicine 10:1577–1590

    Article  Google Scholar 

  • Maurya DP, Sultana Y, Aqil M, Ali A (2011) Formulation and optimization of rifampicin microparticles by Box–Behnken statistical design. Pharm Dev Technol 17:1–10

    Google Scholar 

  • Menak KB, Ramesh A, Thomas B, Kumari NS (2009) Estimation of NO as an inflammatory marker in periodonitis. J Ind Soc Periodontol 13:75–78

    Article  Google Scholar 

  • Menna P, Paz OG, Chello M, Covino E, Salvatorelli E, Minotti G (2012) Anthracycline cardiotoxicity. Expert Opin Drug Saf 11:S21–S36

    Article  CAS  Google Scholar 

  • Mishra HP, Fredivich I (1972) The role of superoxide in the auto oxidation of epinephrine and a simple assay for SOD. J Biol Chem 247:3170–3175

    Google Scholar 

  • Momparler RL, Karon M, Siegel SE, Avila F (1976) Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. Cancer Res 36:2891–2895

    CAS  Google Scholar 

  • Murray DR, Freeman GL (1996) Tumor necrosis factor-alpha induces a biphasic effect on myocardial contractility in conscious dogs. Circ Res 78:154–160

    Article  CAS  Google Scholar 

  • Niu G, Cogburn B, Hughes J (2010) Preparation and characterization of doxorubicin liposomes. Methods Mol Biol 624:211–219

    Article  CAS  Google Scholar 

  • Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  CAS  Google Scholar 

  • Oktem F, Ozguner F, Sulak O, Olgar S, Akturk O, Yilmaz HR (2005) Lithium-induced renal toxicity in rats: protection by a novel antioxidant caffeic acid phenethyl ester. Mol Cell Biochem 277:109–115

    Article  CAS  Google Scholar 

  • Ozen S, Akyol O, Iraz M, Sogut S, Ozugurlu F, Ozyurt H, Odaci EZ, Yildirim Z (2004) Role of caffeic acid phenethyl ester, an active component of propolis, against cisplatin-induced nephrotoxicity in rats. J Appl Toxicol 24:27–35

    Article  Google Scholar 

  • Recknagel RO, Glende EA, Glende JA, Dolak JA, Waller RL (1989) Mechanisms of carbon tetrachloride toxicity. Pharmacol Therapeut 43:139–154

    Article  CAS  Google Scholar 

  • Sanyog J, Meghal AM, Nitin KS (2011) Enhanced dermal delivery of acyclovir using solid lipid nanoparticles. Drug Deliv Trans Res 1:395–406

    Article  Google Scholar 

  • Schwarz C, Mehnert W, Lucks JS, Muller RH (1994) Solid lipid nanoparticles (SLN) for controlled drug delivery: I. Production, characterization and sterilization. J Control Release 30:83–96

    Article  CAS  Google Scholar 

  • Shuhendler AJ, Cheung RY, Manias J, Connor A, Rauth AM, Wu XY (2010) A novel doxorubicin-mitomycin C co-encapsulated nanoparticle formulation exhibits anti-cancer synergy in multidrug resistant human breast cancer cells. Breast Cancer Res Treat 119:255–269

    Article  CAS  Google Scholar 

  • Singh B, Kapil R, Nandi M, Ahuja N (2011) Developing oral drug delivery systems using formulation by design: vital precepts retrospect and prospects. Expert Opin Drug Deliv 8:1160–1341

    Google Scholar 

  • Subedi RK, Kang KW, Choi HK (2009) Preparation and characterization of solid lipid nanoparticles loaded with doxorubicin. Eur J Pharm Sci 37:508–513

    Article  CAS  Google Scholar 

  • Sutananta W, Craig DQ, Newton JM (1995) An investigation into the effects of preparation conditions and storage on the rate of drug release from pharmaceutical glyceride bases. J Pharm Pharmacol 47:355–359

    Article  CAS  Google Scholar 

  • Sze A, Erickson D, Ren L, Li D (2003) Zeta-potential measurement using the Smoluchowski equation and the slope of the current-time relationship in electro osmotic flow. J Colloid Interface Sci 261:402–410

    Article  CAS  Google Scholar 

  • Tikoo K, Sane MS, Gupta C (2011) Tannic acid ameliorates doxorubicin-induced cardiotoxicity and potentiates its anti-cancer activity: potential role of tannins in cancer chemotherapy. Toxicol Appl Pharmacol 251:191–200

    Article  CAS  Google Scholar 

  • Upadhyay KK, Bhatt AN, Mishra AK, Dwarakanath BS, Jain S, Schatz C et al (2010) The intracellular drug delivery and antitumor activity of doxorubicin loaded poly(g-benzyl l-glutamate)-b-hyaluronan polymersomes. Biomaterials 31:2882–2892

    Article  CAS  Google Scholar 

  • Venkateswarlu V, Manjunath K (2004) Preparation, characterization and in vitro release kinetics of clozapine solid lipid nanoparticles. J Control Rel 95:627–638

    Article  CAS  Google Scholar 

  • Wang H, Zhao Y, Wu Y, Hu Y, Nan K, Nie G et al (2011) Enhanced anti-tumor efficacy by co-delivery of doxorubicin and paclitaxel with amphiphilic methoxy PEG-PLGA copolymer nanoparticles. Biomaterials 32:8281–8290

    Article  CAS  Google Scholar 

  • Wissing SA, Kayser O, Muller RH (2004) Solid lipid nanoparticles for parenteral drug delivery. Adv Drug Deliv Rev 56:1257–1272

    Article  CAS  Google Scholar 

  • Wong HL, Bendayan R, Rauth AM, Wu XY (2004) Development of solid lipid nanoparticles containing ionically complexed chemotherapeutic drugs and chemosensitizers. J Pharm Sci 93:1993–2008

    Article  CAS  Google Scholar 

  • Yagmurca M, Erdogan H, Iraz M, Songur A, Ucar M, Fadillioglu E (2004) Caffeic acid phenethyl ester as a protective agent against doxorubicin nephrotoxicity in rats. Clin Chim Acta 348:27–34

    Article  CAS  Google Scholar 

  • Yan F, Zhang C, Zheng Y, Mei L, Tang L, Song C, Sun H, Huang L (2010) The effect of poloxamer 188 on nanoparticle morphology, size, cancer cell uptake, and cytotoxicity. Nanomedicine 6:170–178

    CAS  Google Scholar 

  • Yilmaz S, Atessahin A, Sahna E, Karahan I, Ozer S (2006) Protective effect of lycopene on adriamycin-induced cardiotoxicity and nephrotoxicity. Toxicology 218:164–171

    Article  CAS  Google Scholar 

  • Yoo SH, Oh JE, Lee KH, Park TG (1999) Biodegradable nanoparticles containing doxorubicin-PLGA conjugate for sustained release. Pharm Res 16:1114–1118

    Article  CAS  Google Scholar 

  • Yuan H, Jiang SP, Du YZ, Miao J, Zhang XG, Hu FQ (2009) Strategic approaches for improving entrapment of hydrophilic peptide drugs by lipid nanoparticles. Colloids Surf B Biointerfaces 70:248–253

    Article  CAS  Google Scholar 

  • Zhang Y, Shi J, Li Y, Wei L (2009) Cardiomyocyte death in doxorubicin-induced cardiotoxicity. Arch Immunol Ther Exp 57:438–445

    Google Scholar 

  • Zhiwei X, Shiqing L, Weikang W, Hongmei T, Zhi W, Chao C, Lihe L, Xuanhong Z (2008) Ghrelin prevents doxorubicin-induced cardiotoxicity through TNF-alpha/NF-kB pathways and mitochondrial protective mechanisms. Toxicology 247:133–138

    Article  Google Scholar 

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Acknowledgments

Authors would wholeheartedly thank Prof. B.G. Shivananda, Principal, Al-Ameen College of Pharmacy for his kind support and encouragement to carry out this project. Authors are also thankful to University Grant Commission (UGC) for awarding fellowship to Mr. Nagaraju M Patro (10-01/2008 SA-I). The Authors thank Dr. Girish Kunte, Technology Manager, Micro- and Nano-Characterization Facility (MNCF), Centre for Nano-Science and Engineering (CeNSE), Indian Institute of Sciences, Bangalore, for his assistance in XRD and SEM study and Dr. Manjunatha Reddy G.B., Scientist, Project Directorate on Animal Disease Monitoring and Surveillance (PD-ADMAS), Indian Council of Agriculture Research, Bangalore, for his support in histopathological study.

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Authors and Affiliations

  1. Department of Pharmaceutics, Al-Ameen College of Pharmacy, Hosur Road, Bangalore, 560 027, India

    Nagaraju M. Patro, Roopa S. Pai & Sarasija Suresh

  2. Department of CEQIC, Al-Ameen College of Pharmacy, Hosur Road, Bangalore, 560 027, India

    Kshama Devi

  3. Department of Pharmaceutical Technology (Formulation), National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, 160062, Punjab, India

    Sarasija Suresh

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  1. Nagaraju M. Patro
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Correspondence to Sarasija Suresh.

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Patro, N.M., Devi, K., Pai, R.S. et al. Evaluation of bioavailability, efficacy, and safety profile of doxorubicin-loaded solid lipid nanoparticles. J Nanopart Res 15, 2124 (2013). https://doi.org/10.1007/s11051-013-2124-1

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