"FORMULATION OF PACLITAXEL-ENCAPSULATED POLYMERIC MICELLES FOR TARGETED BREAST CANCER THERAPY"

Main Article Content

Sachin Pachani
Tapaskumar M. Shah

Keywords

Paclitaxel, Polymeric micelles, Breast cancer, Targeted drug delivery, Nanocarrier systems, Cytotoxicity, Sustained release

Abstract

Breast cancer remains a leading cause of cancer-related mortality among women worldwide, with therapeutic outcomes often limited by the poor solubility, systemic toxicity, and multidrug resistance associated with conventional paclitaxel formulations. In the present study, paclitaxel-loaded polymeric micelles were successfully developed using amphiphilic block copolymers through a solvent evaporation–thin film hydration technique. The optimized micelles exhibited a nanoscale size (~100 nm), narrow polydispersity, negative zeta potential, and spherical morphology as confirmed by dynamic light scattering and transmission electron microscopy. High encapsulation efficiency (~90%) and satisfactory drug loading (~8%) demonstrated the ability of the micelles to solubilize paclitaxel efficiently. In vitro release studies revealed a biphasic, sustained release pattern, with accelerated drug release under acidic conditions mimicking the tumor microenvironment. Cytotoxicity assays showed significantly enhanced anticancer activity of micellar paclitaxel compared with free paclitaxel in MCF-7 and MDA-MB-231 cell lines, with nearly twofold lower IC₅₀ values. Confocal microscopy and flow cytometry confirmed superior cellular uptake of micelles, correlating with enhanced apoptotic activity. These findings indicated that polymeric micelles provided an effective strategy for improving solubility, stability, tumor targeting, and therapeutic efficacy of paclitaxel. This nanocarrier system holds strong potential for further preclinical development and clinical translation in breast cancer therapy.

Abstract 74 | PDF Downloads 50

References

1. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394–424. https://doi.org/10.3322/caac.21492
2. Winters, S., Martin, C., Murphy, D., & Shokar, N. (2017). Breast cancer epidemiology, prevention, and screening. Progress in Molecular Biology and Translational Science, 151, 1–32.
3. Mathur, P., et al. (2020). Cancer statistics, 2020: Report from National Cancer Registry Programme, India. Journal of Cancer Research and Therapeutics, 16(3), 458–463.
4. Allemani, C., et al. (2018). Global surveillance of trends in cancer survival 2000–14 (CONCORD-3). The Lancet, 391(10125), 1023–1075.
5. Bray, F., et al. (2018). Global cancer transitions according to the Human Development Index. The Lancet Oncology, 19(7), 791–804.
6. Weaver, B. A. (2014). How Taxol/paclitaxel kills cancer cells. Molecular Biology of the Cell, 25(18), 2677–2681.
7. Gelderblom, H., et al. (2001). Cremophor EL: The drawbacks and advantages of vehicle selection for drug formulation. European Journal of Cancer, 37(13), 1590–1598.
8. Tije, A. J., Verweij, J., Loos, W. J., & Sparreboom, A. (2004). Pharmacological effects of formulation vehicles: Implications for cancer chemotherapy. Clinical Pharmacokinetics, 43(5), 291–318.
9. Seidman, A. D. (2003). Paclitaxel (Taxol) in breast cancer: An overview. Annals of Oncology, 14(suppl_3), iii3–iii7.
10. Rowinsky, E. K., & Donehower, R. C. (1995). Paclitaxel (Taxol). New England Journal of Medicine, 332(15), 1004–1014.
11. Zhang, H. (2016). Onivyde for the therapy of multiple solid tumors. OncoTargets and Therapy, 9, 3001–3007.
12. Krishna, R., & Mayer, L. D. (2000). Multidrug resistance (MDR) in cancer: Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. European Journal of Pharmaceutical Sciences, 11(4), 265–283.
13. Gottesman, M. M., Fojo, T., & Bates, S. E. (2002). Multidrug resistance in cancer: Role of ATP–dependent transporters. Nature Reviews Cancer, 2(1), 48–58.
14. Scripture, C. D., Figg, W. D., & Sparreboom, A. (2005). Paclitaxel chemotherapy: From empiricism to a mechanism-based formulation strategy. The Oncologist, 10(7), 478–492.
15. Kim, T. Y., et al. (2004). Phase I and pharmacokinetic study of Genexol-PM, a Cremophor-free, polymeric micelle-formulated paclitaxel. Clinical Cancer Research, 10(11), 3708–3716.
16. Kataoka, K., et al. (2012). Block copolymer micelles as vehicles for drug delivery. Journal of Controlled Release, 162(2), 317–326.
17. Ferrari, M. (2005). Cancer nanotechnology: Opportunities and challenges. Nature Reviews Cancer, 5(3), 161–171.
18. Maeda, H., Wu, J., Sawa, T., Matsumura, Y., & Hori, K. (2000). Tumor vascular permeability and the EPR effect in macromolecular therapeutics. Journal of Controlled Release, 65(1–2), 271–284.
19. Barenholz, Y. (2012). Doxil®—The first FDA-approved nano-drug: Lessons learned. Journal of Controlled Release, 160(2), 117–134.
20. Gradishar, W. J., et al. (2005). Albumin-bound paclitaxel (nab-paclitaxel) versus polyethylated castor oil-based paclitaxel in women with breast cancer. Journal of Clinical Oncology, 23(31), 7794–7803.
21. Allen, T. M., & Cullis, P. R. (2013). Liposomal drug delivery systems: From concept to clinical applications. Advanced Drug Delivery Reviews, 65(1), 36–48.
22. Torchilin, V. P. (2007). Micellar nanocarriers: Pharmaceutical perspectives. Pharmaceutical Research, 24(1), 1–16.
23. Kataoka, K., Harada, A., & Nagasaki, Y. (2001). Block copolymer micelles for drug delivery: Design, characterization and biological significance. Advanced Drug Delivery Reviews, 47(1), 113–131.
24. Gaucher, G., et al. (2005). Block copolymer micelles: Preparation, characterization and application in drug delivery. Journal of Controlled Release, 109(1–3), 169–188.
25. Kwon, G. S., & Kataoka, K. (1995). Block copolymer micelles as long-circulating drug vehicles. Advanced Drug Delivery Reviews, 16(2–3), 295–309.
26. Yokoyama, M., et al. (1990). Polymer micelles as novel drug carrier: Adriamycin-conjugated poly(ethylene glycol)–poly(aspartic acid) block copolymer. Journal of Controlled Release, 11(1–3), 269–278.
27. Savic, R., et al. (2003). Micellar nanocontainers distribute to defined cytoplasmic organelles. Science, 300(5619), 615–618.
28. Matsumura, Y., & Kataoka, K. (2009). Preclinical and clinical studies of anticancer agent-incorporating polymer micelles. Cancer Science, 100(4), 572–579.
29. Duncan, R. (2003). The dawning era of polymer therapeutics. Nature Reviews Drug Discovery, 2(5), 347–360..
30. Cho, Y. W., Lee, J., Lee, S. C., Huh, K. M., & Park, K. (2004). Hydrotropic agents for study of in vitro paclitaxel release from polymeric micelles. Journal of Controlled Release, 97(2), 249–257.
31. Sparreboom, A., van Asperen, J., Mayer, U., Schinkel, A. H., Smit, J. W., Meijer, D. K., … Verweij, J. (1997). Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proceedings of the National Academy of Sciences USA, 94(5), 2031–2035.
32. Szakács, G., Paterson, J. K., Ludwig, J. A., Booth-Genthe, C., & Gottesman, M. M. (2006). Targeting multidrug resistance in cancer. Nature Reviews Drug Discovery, 5(3), 219–234.
33. Yokoyama, M., et al. (2005). Clinical applications of polymeric micelle carrier systems in chemotherapy and imaging. Advanced Drug Delivery Reviews, 55(4), 447–458.
34. Danaei, M., Dehghankhold, M., Ataei, S., Hasanzadeh Davarani, F., Javanmard, R., Dokhani, A., & Mozafari, M. R. (2018). Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics, 10(2), 57.
35. Xu, W., Ling, P., & Zhang, T. (2013). Polymeric micelles, a promising drug delivery system to enhance bioavailability of poorly water-soluble drugs. Journal of Drug Delivery, 2013, 340315.
36. Li, J., & Wang, Y. (2013). Preparation and characterization of paclitaxel-loaded polymeric micelles by a novel solvent-diffusion method. International Journal of Pharmaceutics, 441(1–2), 660–667.
37. Shuai, X., Merdan, T., Schaper, A. K., Xi, F., & Kissel, T. (2004). Core-cross-linked polymeric micelles as paclitaxel carriers. Bioconjugate Chemistry, 15(3), 441–448.
38. Jones, M. C., & Leroux, J. C. (1999). Polymeric micelles — a new generation of colloidal drug carriers. European Journal of Pharmaceutics and Biopharmaceutics, 48(2), 101–111..
39. Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65(1–2), 55–63.
40. Nishiyama, N., Okazaki, S., Cabral, H., Miyamoto, M., Kato, Y., Sugiyama, Y., … Kataoka, K. (2003). Novel cisplatin-incorporated polymeric micelles can eradicate solid tumors in mice. Cancer Research, 63(24), 8977–8983.
41. Vermes, I., Haanen, C., Steffens-Nakken, H., & Reutelingsperger, C. (1995). A novel assay for apoptosis: Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein-labelled Annexin V. Journal of Immunological Methods, 184(1), 39–51.
42. Desai, N., Trieu, V., Yao, Z., Louie, L., Ci, S., Yang, A., … Soon-Shiong, P. (2006). Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel (ABI-007) compared with cremophor-based paclitaxel. Clinical Cancer Research, 12(4), 1317–1324.
43. Fang, J., Nakamura, H., & Maeda, H. (2011). The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Advanced Drug Delivery Reviews, 63(3), 136–151.
44. Kataoka, K., Matsumoto, T., Yokoyama, M., Okano, T., Sakurai, Y., Fukushima, S., & Okamoto, K. (2000). Doxorubicin-loaded poly(ethylene glycol)–poly(β-benzyl-L-aspartate) block copolymer micelles: Their pharmaceutical characteristics and biological significance. Journal of Controlled Release, 64(1–3), 143–153 .
45. Immordino, M. L., Dosio, F., & Cattel, L. (2006). Stealth liposomes: Review of the basic science, rationale, and clinical applications. International Journal of Nanomedicine, 1(3), 297–315.
46. Yoo, H. S., Lee, E. A., & Park, T. G. (2002). Doxorubicin-conjugated biodegradable polymeric micelles: Synthesis, characterization and anti-tumor activity. Journal of Controlled Release, 82(1), 17–27.
47. Hrkach, J., Von Hoff, D., Ali, M. M., Andrianova, E., Auer, J., Campbell, T., … Langer, R. (2012). Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Science Translational Medicine, 4(128), 128ra39.
48. Immordino, M. L., Brusa, P., Arpicco, S., Stella, B., Dosio, F., & Cattel, L. (2003). Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing docetaxel. Journal of Controlled Release, 91(3), 417–429.
49. Peer, D., Karp, J. M., Hong, S., Farokhzad, O. C., Margalit, R., & Langer, R. (2007). Nanocarriers as an emerging platform for cancer therapy. Nature Nanotechnology, 2(12), 751–760.
50. Gradishar, W. J., Anderson, B. O., Balassanian, R., Blair, S. L., Burstein, H. J., Cyr, A., … Kumar, R. (2018). Breast cancer, version 4.2017, NCCN clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network, 16(3), 310–320.
51. Yoo, H. S., Lee, K. H., Oh, J. E., & Park, T. G. (2000). In vitro and in vivo anti-tumor activities of nanoparticles based on doxorubicin–PLGA conjugates. Journal of Controlled Release, 68(3), 419–431.
52. Maeda, H. (2012). Macromolecular therapeutics in cancer treatment: The EPR effect and beyond. Journal of Controlled Release, 164(2), 138–144.
53. Chen, H., Kim, S., Li, L., Wang, S., Park, K., Cheng, J. X. (2008). Release of hydrophobic molecules from polymer micelles into cell membranes revealed by Förster resonance energy transfer imaging. Proceedings of the National Academy of Sciences USA, 105(18), 6596–6601.
54. Duncan, R. (2006). Polymer conjugates as anticancer nanomedicines. Nature Reviews Cancer, 6(9), 688–701.
55. Duncan, R., & Gaspar, R. (2011). Nanomedicine(s) under the microscope. Molecular Pharmaceutics, 8(6), 2101–2141.
56. Kwon, G. S. (2003). Polymeric micelles for delivery of poorly water-soluble compounds. Critical Reviews in Therapeutic Drug Carrier Systems, 20(5), 357–403..
57. Cabral, H., Kataoka, K. (2014). Progress of drug-loaded polymeric micelles into clinical studies. Journal of Controlled Release, 190, 465–476.
58. Oerlemans, C., Bult, W., Bos, M., Storm, G., Nijsen, J. F., & Hennink, W. E. (2010). Polymeric micelles in anticancer therapy: Targeting, imaging and triggered release. Pharmaceutical Research, 27(12), 2569–2589..
59. Lammers, T., Kiessling, F., Hennink, W. E., & Storm, G. (2012). Drug targeting to tumors: Principles, pitfalls and (pre-) clinical progress. Journal of Controlled Release, 161(2), 175–187.
60. Fnu, Praneeth Ivan joel, "NOS Oxygenase-Mediated Nitroalkane Catalytic Reduction: Impact on NOS Reaction" (2013). ETD Archive. 819. https://engagedscholarship.csuohio. edu/etdarchive/819