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Formulation and Pharmacokinetics of HSA-core and PLGA-shell Nanoparticles for Delivering Gemcitabine

AAPS PharmSciTech volume 19, pages 812–819 (2018)Cite this article

Abstract

Gemcitabine-loaded core-shell nanoparticles (CSNPs), comprised of a cross-linked HSA-core and PLGA-shell, were prepared through a modified double emulsification method, and the processing parameters were systematically investigated. The optimized CSNPs had a particle size of 241 ± 36.2 nm and an encapsulation efficiency of 41.52%. The core-shell structure was characterized by optical microscope (OM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The amorphous nature of the encapsulated drug was confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). An in vitro release study demonstrated that the CSNPs had an improved sustained release profile controlled by erosion of materials in combination with drug diffusion. In vivo pharmacokinetics of CSNPs obtained a bigger area under concentration-time curve (AUC), t 1/2, and C max compared to free drug solution. The results suggest that HSA-PLGA-based CSNPs can be a promising carrier for the sustained release of gemcitabine.

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References

  1. Boeck S, Hausmann A, Reibke R, Schulz C, Heinemann V. Severe lung and skin toxicity during treatment with gemcitabine and erlotinib for metastatic pancreatic cancer. Anti-Cancer Drugs. 2007;18(18):1109–11.

    CAS  Article  PubMed  Google Scholar 

  2. Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403–13.

    CAS  Article  PubMed  Google Scholar 

  3. Crinò L, Scagliotti GV, Ricci S, De MF, Rinaldi M, Gridelli C, et al. Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: a randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol. 1999;17(11):3522–30.

    Article  PubMed  Google Scholar 

  4. Carmichael J, Possinger K, Phillip P, Beykirch M, Kerr H, Walling J, et al. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol. 1995;13(11):2731–6.

    CAS  Article  PubMed  Google Scholar 

  5. Von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18(18):3068–77.

    Article  PubMed  Google Scholar 

  6. Lorusso D, Stefano AD, Fanfani F, Scambia G. Role of gemcitabine in ovarian cancer treatment. Ann Oncol. 2006;17 Suppl 5(suppl_5):v188–94.

    CAS  Article  PubMed  Google Scholar 

  7. Wong A, Soo RA, Yong WP, Innocenti F. Clinical pharmacology and pharmacogenetics of gemcitabine. Drug Metab Rev. 2009;41(2):77–88. https://doi.org/10.1080/03602530902741828.

    CAS  Article  PubMed  Google Scholar 

  8. Le UM. Advancement in gemcitabine delivery for cancer treatment: Springer International Publishing; 2015.

    Book  Google Scholar 

  9. Toschi L, Finocchiaro G, Bartolini S, Gioia V, Cappuzzo F. Role of gemcitabine in cancer therapy. Future Oncol. 2005;1(1):7–17.

    CAS  Article  PubMed  Google Scholar 

  10. Turco C, Jary M, Kim S, Moltenis M, Degano B, Manzoni P, et al. Gemcitabine-induced pulmonary toxicity: a case report of pulmonary veno-occlusive disease. Clin Med Insights Oncol. 2015;9:75–9. https://doi.org/10.4137/CMO.S26537.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Barlesi F, Villani PC, Gimenez C, Kleisbauer JP. Gemcitabine-induced severe pulmonary toxicity. Fundam Clin Pharmacol. 2004;18(1):85–91.

    CAS  Article  PubMed  Google Scholar 

  12. Mini E, Nobili S, Caciagli B, Landini I, Mazzei T. Cellular pharmacology of gemcitabine. Ann Oncol. 2006;17 Suppl 5(suppl_5):v7.

    CAS  Article  PubMed  Google Scholar 

  13. Daman Z, Ostad S, Amini M, Gilani K. Preparation, optimization and in vitro characterization of stearoyl-gemcitabine polymeric micelles: a comparison with its self-assembled nanoparticles. Int J Pharm. 2014;468(1–2):142–51. https://doi.org/10.1016/j.ijpharm.2014.04.021.

    CAS  Article  PubMed  Google Scholar 

  14. Domenicoantonio R, Franco A, Donatella P, Stefania B, Maria C, Marilena C, et al. Cytotoxic effects of gemcitabine-loaded liposomes in human anaplastic thyroid carcinoma cells. BMC Cancer. 2004;4(1):63.

    Article  Google Scholar 

  15. Wang Y, Fan W, Dai X, Katragadda U, McKinley D, Teng Q, et al. Enhanced tumor delivery of gemcitabine via PEG-DSPE/TPGS mixed micelles. Mol Pharm. 2014;11(4):1140–50. https://doi.org/10.1021/mp4005904.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Chen Y, Chen H, Zeng D, Tian Y, Chen F, Feng J, et al. Core/shell structured hollow mesoporous nanocapsules: a potential platform for simultaneous cell imaging and anticancer drug delivery. ACS Nano. 2010;4(10):6001.

    CAS  Article  PubMed  Google Scholar 

  17. Jang MK, Jeong YI, Nah JW. Characterization and preparation of core–shell type nanoparticle for encapsulation of anticancer drug. Colloids Surf B Biointerfaces. 2010;81(2):530.

    CAS  Article  PubMed  Google Scholar 

  18. Vrignaud S, Benoit JP, Saulnier P. Strategies for the nanoencapsulation of hydrophilic molecules in polymer-based nanoparticles. Biomaterials. 2011;32(33):8593–604.

    CAS  Article  PubMed  Google Scholar 

  19. Hu SH, Chen SY, Gao X. Multifunctional nanocapsules for simultaneous encapsulation of hydrophilic and hydrophobic compounds and on-demand release. ACS Nano. 2012;6(3):2558.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Chitkara D, Kumar N. BSA-PLGA-based core-shell nanoparticles as carrier system for water-soluble drugs. Pharm Res. 2013;30(9):2396–409. https://doi.org/10.1007/s11095-013-1084-6.

    CAS  Article  PubMed  Google Scholar 

  21. Sinn H, Schrenk HH, Friedrich EA, Schilling U, Maier-Borst W. Design of compounds having an enhanced tumour uptake, using serum albumin as a carrier. Part I. Int J Rad Appl Instrum B Nucl Med Biol. 1990;17(8):819–25.

    CAS  Article  Google Scholar 

  22. Kratz F. Albumin, a versatile carrier in oncology. Int J Clin Pharmacol Ther. 2010;48(7):453.

    CAS  Article  PubMed  Google Scholar 

  23. Santhi K, Dhanaraj SA, Koshy M, Ponnusankar S, Suresh B. Study of biodistribution of methotrexate-loaded bovine serum albumin nanospheres in mice. Drug Dev Ind Pharm. 2000;26(12):1293–6.

    CAS  Article  PubMed  Google Scholar 

  24. Panyam J, Labhasetwar V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv Drug Deliv Rev. 2003;55(3):329.

    CAS  Article  PubMed  Google Scholar 

  25. Zheng W, Li J, Zheng YF. Preparation of poly(L-lactide) and its application in bioelectrochemistry. J Electroanal Chem. 2008;621(1):69–74.

    CAS  Article  Google Scholar 

  26. Wu XS. Synthesis, characterization, biodegradation, and drug delivery application of biodegradable lactic/glycolic acid polymers: Part III. Drug delivery application. Artif Cells Blood Substit Immobil Biotechnol. 2004;32(4):575.

    CAS  Article  PubMed  Google Scholar 

  27. Song CX, Cui XM, Underwood T, Levy RJ, Labhasetwar V. Arterial uptake of biodegradable nanoparticles for intravascular local drug delivery: results with an acute dog model. J Control Release. 1998;54(2):201.

    CAS  Article  PubMed  Google Scholar 

  28. García MC, Muñoz J, Alfaro MC, Franco JM. Physical characterization of multiple emulsions formulated with a green solvent and different HLB block copolymers. Colloids Surf A Physicochem Eng Asp. 2014;458(1):40–7.

    Article  Google Scholar 

  29. Shen S, Yang L, Lu Y, Chen JG, Song S, Hu D, et al. A new route to liposil formation by an interfacial sol-gel process confined by lipid bilayer. ACS Appl Mater Interfaces. 2015;7(45):25039.

    CAS  Article  PubMed  Google Scholar 

  30. Dubey RD, Alam N, Saneja A, Khare V, Kumar A, Vaidh S, et al. Development and evaluation of folate functionalized albumin nanoparticles for targeted delivery of gemcitabine. Int J Pharm. 2015;492(1–2):80.

    CAS  Article  PubMed  Google Scholar 

  31. Dan P, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol. 2007;2(12):751–60.

    Article  Google Scholar 

  32. Wicki A, Witzigmann D, Balasubramanian V, Huwyler J. Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications. J Control Release. 2015;200:138–57.

    CAS  Article  PubMed  Google Scholar 

  33. Kandagal PB, Ashoka S, Seetharamappa J, Shaikh SM, Jadegoud Y, Ijare OB. Study of the interaction of an anticancer drug with human and bovine serum albumin: spectroscopic approach. J Pharm Biomed Anal. 2006;41(2):393–9. https://doi.org/10.1016/j.jpba.2005.11.037.

    CAS  Article  PubMed  Google Scholar 

  34. Bercea M, Darie RN, Niţă LE, Morariu S. Temperature responsive gels based on pluronic F127 and poly(vinyl alcohol). Ind Eng Chem Res. 2011;50(7):4199–206. https://doi.org/10.1021/ie1024408.

    CAS  Article  Google Scholar 

  35. Xie S, Wang S, Zhao B, Han C, Wang M, Zhou W. Effect of PLGA as a polymeric emulsifier on preparation of hydrophilic protein-loaded solid lipid nanoparticles. Colloids Surf B Biointerfaces. 2008;67(2):199–204.

    CAS  Article  PubMed  Google Scholar 

  36. Benichou A, Aserin A, Garti N. Double emulsions stabilized by new molecular recognition hybrids of natural polymers. Polym Adv Technol. 2002;13(13):1019–31.

    CAS  Article  Google Scholar 

  37. Trentin A, Ferrando M, López F, Güell C. Premix membrane O/W emulsification: effect of fouling when using BSA as emulsifier. Desalination. 2009;245(1):388–95.

    CAS  Article  Google Scholar 

  38. Huang J, Yuan Y, Liang H. Binding equilibrium study of phosphotungstic acid and HSA or BSA with UV spectrum, fluorescence spectrum and equilibrium dialysis. SCIENCE CHINA Chem. 2002;45(2):200–7.

    CAS  Article  Google Scholar 

  39. Kuznetsova NP, Mishaeva RN, Gudkin LR, Panarin EF. Reactions of glutaraldehyde with dipolar ions of amino acids and proteins 2013.

  40. Haswani DK, Nettey H, Oettinger C, D'Souza MJ. Formulation, characterization and pharmacokinetic evaluation of gentamicin sulphate loaded albumin microspheres. J Microencapsul. 2006;23(8):875–86.

    CAS  Article  PubMed  Google Scholar 

  41. Zweers ML, Engbers GH, Grijpma DW, Feijen J. In vitro degradation of nanoparticles prepared from polymers based on DL-lactide, glycolide and poly(ethylene oxide). J Control Release. 2004;100(3):347–56.

    CAS  Article  PubMed  Google Scholar 

  42. Kim SY, Ha JC, Lee YM. Poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide)/poly(ϵ-caprolactone) (PCL) amphiphilic block copolymeric nanospheres: II. Thermo-responsive drug release behaviors. J Control Release. 2000;65(3):345–58.

    CAS  Article  PubMed  Google Scholar 

  43. Ritger PL, Peppas NA. A simple equation for solute release. Part 1. Fickian and non-Fickian release from nonswellable devices in the form of slabs, spheres, cylinders or disks. 1987.

    Google Scholar 

  44. Raval A, Parikh J, Engineer C. Mechanism and in vitro release kinetic study of sirolimus from a biodegradable polymeric matrix coated cardiovascular stent. Ind Eng Chem Res. 2011;50(16):9539–49.

    CAS  Article  Google Scholar 

  45. Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanisms of potassium chloride release from compressed, hydrophilic, polymeric matrices: effect of entrapped air. J Pharm Sci. 1983;72(10):1189–91.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

We sincerely thank Amanda Pearce for the linguistic assistance during the revision of this manuscript.

Funding

This investigation was supported by the National Natural Science Foundation of China (No. 81673378) and 2016 Annual Youth Teachers’ Career Development Support Program of Shenyang Pharmaceutical University (grant number ZQN2016008).

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  1. Department of Pharmaceutics, Shenyang Pharmaceutical University, Wen Hua Road No. 103, Shenyang, China

    Xinlong Wang, Yuheng Liang, Siyang Fei, Haibing He, Yu Zhang, Tian Yin & Xing Tang

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  1. Xinlong Wang
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  2. Yuheng Liang
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Correspondence to Xing Tang.

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Wang, X., Liang, Y., Fei, S. et al. Formulation and Pharmacokinetics of HSA-core and PLGA-shell Nanoparticles for Delivering Gemcitabine. AAPS PharmSciTech 19, 812–819 (2018). https://doi.org/10.1208/s12249-017-0888-9

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  • DOI: https://doi.org/10.1208/s12249-017-0888-9

Key words

  • core-shell nanoparticles
  • gemcitabine
  • formulation
  • pharmacokinetics