Recent Advances in Paclitaxel Drug Delivery: Challenges, Innovations, and Future Directions

Balisa Mosisa Ejeta ¹*, Malay K Das ¹*, Sanjoy Das ¹

This review addresses advancements in paclitaxel drug delivery, emphasizing innovative methods to enhance efficacy and combat resistance.

Abstract

Paclitaxel, the first taxane alkaloid to be widely used as a cancer treatment, has revolutionized chemotherapy, especially for breast, ovarian, and lung cancers. Despite its efficacy, paclitaxel's clinical use faces significant challenges, including poor solubility, high systemic toxicity, and the emergence of drug resistance. Early research efforts have focused on developing novel delivery methods to improve the drug’s efficacy while minimizing adverse effects. This review explores various paclitaxel delivery systems, including conventional methods, nanotechnology-based solutions, and targeted drug delivery. The review highlights persistent limitations, such as the lack of widespread clinical adoption of nanocarriers and the need for individualized drug delivery systems to address resistance. Key future research areas include the development of multipurpose nanoparticles, the integration of personalized medicine, and exploration of alternative delivery strategies. These innovations could pave the way for more effective and patient-specific chemotherapy treatments.

Keywords: Paclitaxel, Nanotechnology, Drug Resistance, Chemotherapy, Targeted Delivery

References

AbbVie Inc., 2021. Study of Paclitaxel Nanoparticle Injection in Metastatic Cancer. ClinicalTrials.gov.

Allen, T. M. & Cullis, P. R., 2004. Drug delivery systems: entering the mainstream. Science, 303(5665), pp. 1818-1822.

Allen, T. M. & Cullis, P. R., 2013. Liposomal drug delivery systems: from concept to clinical applications. Advanced Drug Delivery Reviews, 65(1), pp. 36-48.

Amgen Inc., 2023. Investigation of Paclitaxel-Loaded Micelles in Cancer Treatment. ClinicalTrials.gov.

Apotex, 2012. ANDA 201522 Approval. U.S. Food and Drug Administration.

Barok, M., et al., 2014. Trastuzumab emtansine: a maytansinoid-containing antibody–drug conjugate. Nature Reviews Clinical Oncology, 11(11), pp. 637-648.

Bissery, M. C., et al., 1995. Preclinical evaluation of TXD258, a new taxoid. Investigational New Drugs, 13(3), pp.247-255.

Chen, X., Liu, Y., Zhao, L. and Zhang, J., 2023. MicroRNA regulation in paclitaxel resistance. Journal of Cancer Research, 15(2), pp.154-162.

Cheng, R., et al., 2011. pH-responsive polymeric micelles for cancer therapy based on hydrophobic poly(β-amino ester) as a pH-sensitive moiety. Biomaterials, 32(26), pp. 6884-6891.

Chow, E.K., Zhang, X.Q., Chen, M., Lam, R., Robinson, E., Huang, H., Schaffer, D., & Chen, Y., 2011. Nanodiamond therapeutic delivery agents mediate enhanced chemoresistant tumor treatment. Science Translational Medicine, 3(73), p.73ra21.

Crown, J., O'Leary, M. & Ooi, W. S., 2004. Docetaxel and paclitaxel in the treatment of breast cancer: a review of clinical experience. Oncologist, 9(Suppl 2), pp. 24-32.

Curnis, F., et al., 2010. Critical role of flt1 receptor and organ-specific metastasis in the antiangiogenic effect of NGR–tumor necrosis factor. Journal of the National Cancer Institute, 102(6), pp. 428-442.

Danhier, F., et al., 2012. PLGA-based nanoparticles: an overview of biomedical applications. Journal of Controlled Release, 161(2), pp. 505-522.

DrugBank, 2003. Abraxane patent. https://go.drugbank.com/drugs/DB01229

Duan, X., et al., 2020. Hybrid nanoparticles with co-encapsulation of paclitaxel and verapamil overcome multidrug resistance in breast cancer. Journal of Nanobiotechnology, 18(1), pp. 1-14.

Eli Lilly and Company, 2022. Evaluation of Targeted Delivery Systems for Paclitaxel in Oncology. ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT05274288

FDA, 1994. Approval package for: NDA 020262. U.S. Food and Drug Administration.

FDA, 2013. Approval package for: NDA 202408. U.S. Food and Drug Administration.

Feng, S.-S., et al., 2019. Controlled delivery of paclitaxel using PLGA nanoparticles for the treatment of lung cancer. Journal of Nanomedicine & Nanotechnology, 10(2), pp. 1-7. Ferrari, M., 2005. Cancer nanotechnology: opportunities and challenges. Nature Reviews Cancer, 5(3), pp. 161-171.

Gao, Y., et al., 2013. Liposomal paclitaxel formulations: New options for efficient and safe cancer therapy. Current Pharmaceutical Design, 19(37), pp. 6653-6663.

Gao, Z., Zhang, L., Hu, J., & Sun, Y., 2011. Targeting delivery of paclitaxel using folate-conjugated polymeric micelles. Biomaterials, 32(34), pp.8548-8556.

Gelderblom, H., et al., 2001. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. European Journal of Cancer, 37(13), pp. 1590-1598.

Genentech, Inc., 2019. Phase I/II Study of Antibody-drug Conjugates with Paclitaxel in Cancer. ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT03945855

Ghosh, P., et al. (2009). "Surface-modified dendrimers for controlled paclitaxel release: a strategy to manage drug release profiles." Advanced Drug Delivery Reviews, 61(6), 555-568

Gómez-Gaete, C., et al., 2009. Nanoparticles and microparticles as controlled drug delivery devices for the treatment of infectious diseases and cancer. International Journal of Nanomedicine, 4, pp. 299-311.

Gong, J., et al., 2014. Targeting the PI3K/Akt/mTOR signaling pathway in cancer. Expert Opinion on Therapeutic Targets, 18(5), pp. 621-635.

Gottesman, M. M., 2002. Mechanisms of cancer drug resistance. Annual Review of Medicine, 53(1), pp. 615-627.

Gradishar, W. J., et al., 2005. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. Journal of Clinical Oncology, 23(31), pp. 7794-7803.

Gupta, R., Singh, P. and Verma, R., 2022. The impact of β-tubulin mutations on paclitaxel resistance. Journal of Cancer Biology, 16(3), pp.227-235.

Ibrahim, N. K., et al., 2002. Phase I and pharmacokinetic study of ABI-007, a cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clinical Cancer Research, 8(5), pp. 1038-1044.

Inovio Pharmaceuticals, 2020. A study of INO-5401 and INO-9012 in combination with Paclitaxel-loaded nanoparticles. ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT04579469

Jain, T.K., Morales, M.A., Sahoo, S.K., Leslie-Pelecky, D.L., & Labhasetwar, V., 2008. Iron oxide nanoparticles for sustained delivery of anticancer agents. Molecular Pharmaceutics, 5(2), pp.316-327.

Jeon, H., et al., 2013. Targeted cancer therapy using antibody-conjugated dendrimer nanocarriers. Journal of Controlled Release, 172(3), pp. 634-641.

Jiang, F. & Doudna, J. A., 2017. CRISPR–Cas9 structures and mechanisms. Annual Review of Biophysics, 46, pp. 505-529.

Jiang, W., et al., 2006. Adenovirus-mediated delivery of tumor suppressor genes enhances the antitumor activity of paclitaxel in ovarian cancer. Cancer Research, 66(18), pp. 9255-9260.

Jones, D.S., Green, J.L. and Brown, R.T., 2021. The tumor microenvironment's role in paclitaxel resistance. Oncology Reports, 39(5), pp.220-229.

Khandare, J., et al., 2012. Dendrimer-entrapped gold nanoparticles as delivery platforms: paclitaxel delivery and efficacy in prostate and pancreatic cancer. Journal of Controlled Release, 160(2), pp. 239-244.

Kim, Rowinsky, E. K. and Donehower, R. C., 1995. Taxol®: the first of the taxanes, an important new class of antitumor agents. Annals of Oncology, 6(6), pp.733-740.

Kim, T.-Y., et al., 2007. Phase I and pharmacokinetic study of Genexol-PM, a cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies. Clinical Cancer Research, 13(11), pp. 3300-3308.

Kong, T., Zhang, D., Qiao, S., & Huang, J., 2007. Functionalized gold nanoparticles for targeted delivery of paclitaxel. Journal of Biomedical Nanotechnology, 3(3), pp.333-340

Koren, E., & Torchilin, V. P., 2012. Cell-penetrating peptides: breaking through to the other side. Trends in Molecular Medicine, 18(7), pp. 385-393.

Kumar, N., Gupta, S. K. S., & Rai, D. K. (2017). Advanced drug delivery systems: Basics, applications, and recent advances. Molecular Pharmaceutics, 14(9), 2931-2951. doi:10.1021/acs.molpharmaceut.7b00396

Lammers, T., et al., 2011. Theranostic nanomedicine. Accounts of Chemical Research, 44(10), pp. 1029-1038.

Lee, H.J. and Kim, M.S., 2023. Autophagy as a survival mechanism in paclitaxel resistance. Cancer Therapy Reviews, 18(1), pp.47-55.

Liang, J., Xu, W. and Liu, Y., 2021. Tumor microenvironment and paclitaxel resistance. Molecular Cancer Therapeutics, 20(5), pp.809-818.

Liu, Y., et al., 2020. Dendrimers in drug delivery: design, synthesis, and application in cancer therapy. Advanced Drug Delivery Reviews, 146, pp. 105-118.

Liu, Z., Sun, X., Nakayama-Ratchford, N., & Dai, H., 2008. Supramolecular chemistry on water-soluble carbon nanotubes for drug loading and delivery. ACS Nano, 2(1), pp.50-56.

Luo, C., et al., 2012. Preparation and evaluation of paclitaxel-loaded D-α-tocopheryl polyethylene glycol 1000 succinate micelles. Asian Journal of Pharmaceutical Sciences, 7(4), pp. 314-326.

Lv, H., et al., 2006. Cationic polymer-mediated gene delivery: Challenges and perspectives. Journal of Controlled Release, 114(1), pp. 100-109.

Mamaeva, V., Sahlgren, C., & Linden, M., 2013. Mesoporous silica nanoparticles in medicine—recent advances. Advanced Drug Delivery Reviews, 65(5), pp.689-702.

McGuire, W. P., et al., 1996. Taxol: a review of its pharmacology and clinical efficacy in the management of ovarian cancer. Drugs, 51(5), pp. 747-764.

Merck & Co., Inc., 2021. Study of Liposomal Paclitaxel and Immune Checkpoint Inhibitors in Advanced Solid Tumors. ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT04916070

Minko, T., et al., 2012. Targeted delivery of anticancer agents to the folate receptor: strategies and perspectives. Journal of Drug Targeting, 20(7), pp. 569-584.

Mishra, A. K., et al., 2010. Mechanisms of resistance to taxanes and strategies to overcome resistance. Chemotherapy Research and Practice, 2010, pp. 1-10.

Moderna Inc., 2022. Phase I Study of Paclitaxel-Loaded Hydrogel Formulations in Cancer Patients. ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT05239817

Nanobiotix S.A., 2022. Phase I Study of Paclitaxel Encapsulated in Polymeric Micelles. ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT05282446

National Center for Biotechnology Information (2024). PubChem Compound Summary for CID 36314, Paclitaxel. Retrieved August 10, 2024 from https://pubchem.ncbi.nlm.nih.gov/compound/Paclitaxel

Nobili, S., et al., 2012. Overcoming tumor multidrug resistance using drugs and inhibitors of ABCG2. Current Medicinal Chemistry, 19(18), pp. 2871-2887.

Novartis AG, 2022. Evaluation of Paclitaxel with Dual Drug Delivery Systems in Oncology. ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT05332929

Park, S. B., et al., 2013. Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA: A Cancer Journal for Clinicians, 63(6), pp. 419-437.

Patel, K., Singh, A. and Verma, R., 2021. Epithelial-mesenchymal transition and paclitaxel resistance. Cancer Cell International, 21(3), pp.310-320.

Peer, D., et al., 2007. Nanocarriers as an emerging platform for cancer therapy. Nature Nanotechnology, 2(12), pp. 751-760.

Pfizer Inc., 2022. Study of PEGylated Nanoparticles for Delivery of Paclitaxel in Cancer. ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT05475263

Qiu, L., et al., 2014. Transferrin conjugated star-shaped copolymer for receptor-mediated delivery of paclitaxel. Biomaterials, 35(25), pp. 7388-7396.

Rao, S., Watkins, D., Cunningham, D., & Halbert, G., 2008. Phase I and pharmacokinetic study of liposomal entrapped paclitaxel easy to use (LEP-ETU) in patients with advanced solid tumors. Clinical Cancer Research, 14(6), pp.1835-1842.

References

Reis, C. P., et al., 2006. Nanoencapsulation I. Methods for preparation of drug-loaded polymeric nanoparticles. Nanomedicine: Nanotechnology, Biology and Medicine, 2(1), pp. 8-21.

Roche, 2021. Study of Paclitaxel in Combination with Immunotherapy for Advanced Cancer. ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT04653703

Roth, J. A. & Cristiano, R. J., 1997. Gene therapy for cancer: what have we done and where are we going?. Journal of the National Cancer Institute, 89(1), pp. 21-39.

Rowinsky, E. K. & Donehower, R. C., 1995. Paclitaxel (taxol). New England Journal of Medicine, 332(15), pp. 1004-1014.

Schiff, P. B., Fant, J. & Horwitz, S. B., 1979. Promotion of microtubule assembly in vitro by taxol. Nature, 277(5698), pp. 665-667.

Scripture, C. D., et al., 2006. Paclitaxel-induced peripheral neuropathy: clinical features, mechanisms, and management. Oncologist, 11(7), pp. 728-734.

Seidman, A. D., et al., 2000. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER2-positive patients and randomized HER2-negative patients: final results of Cancer and Leukemia Group B protocol 9840. Journal of Clinical Oncology, 26(10), pp. 1642-1649.

Senter, P. D., & Sievers, E. L., 2012. The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nature Biotechnology, 30(7), pp. 631-637.

Sharma, A., et al. (2011). "Dendritic nanocarriers for targeted delivery of paclitaxel: an in vitro and in vivo study." Molecular Pharmaceutics, 8(4), 1150-1158.

Shen, L., et al., 2012. Co-delivery of paclitaxel and MDR1 siRNA by liposome for enhanced therapy against multidrug-resistant tumors. Biomaterials, 33(32), pp. 8613-8624.

Shi, Y. and Zheng, X., 2009. Effect of liposome formulation on the pharmacokinetics of paclitaxel in rats. Pharmazie, 64(6), pp.392-397.

Sinha, R., et al. (2006). "Biodegradable dendrimers for targeted paclitaxel delivery: overcoming drug resistance." Journal of Controlled Release, 114(2), 228-237

Smith, A.J., Kline, C. and Thompson, W., 2022. Mechanisms of cancer resistance to paclitaxel. Journal of Chemotherapy, 34(7), pp.491-498.

Study of Paclitaxel Nanoparticle Injection in Metastatic Cancer. ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT04512359

Sun, D., Zhuang, X., Xiang, X., Liu, Y., Zhang, S., Liu, C., Barnes, S., Grizzle, W., Miller, D., Zhang, H.G., 2010. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Molecular Therapy, 18(9), pp.1606-1614.

T. Y., et al., 2004. Phase I and pharmacokinetic study of Genexol-PM, a Cremophor-free, polymeric micelle formulation of paclitaxel, in patients with advanced malignancies. Clinical Cancer Research, 10(11), pp.3708-3716.

Tong, R., et al., 2014. Smart micelles for controlled drug release and targeted delivery. Journal of Drug Targeting, 22(7), pp. 581-591.

Truong, J., et al., 2021. Cost-effectiveness of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in metastatic breast cancer. Breast Cancer Research and Treatment, 185(2), pp. 247-256.

Tuma RS (2003). Taxol’s journey from discovery to use: lessons and updates. Oncol Times 25, 52–57.

Wall, M. E. & Wani, M. C., 1995. Paclitaxel: Discovery, Chemistry, and Mechanism of Action. Journal of Natural Products, 57(6), pp. 920-927.

Wall, M. E., & Wani, M. C. (1989). Taxane derivatives as anticancer agents (U.S. Patent No. 4,814,470). United States Patent and Trademark Office

Wang, F., et al., 2014. Liposomal paclitaxel in the treatment of non-small-cell lung cancer. International Journal of Nanomedicine, 9, pp. 2119-2126.

Weiss, R. B., et al., 1990. Hypersensitivity reactions from taxol. Journal of Clinical Oncology, 8(7), pp. 1263-1268.

Yardley, D. A., 2013. nab-Paclitaxel mechanisms of action and delivery. Journal of Controlled Release, 170(3), pp. 365-372.

Ying, N., Liu, S., Zhang, M., Cheng, J., Luo, L., Jiang, J., Shi, G., Wu, S., Ji, J., Su, H., Pan, H., & Zeng, D. (2023). Nano delivery system for paclitaxel: Recent advances in cancer theranostics. Colloids and Surfaces B Biointerfaces, 228, 113419. https://doi.org/10.1016/j.colsurfb.2023.113419.

Youle, R. J. & Strasser, A., 2008. The BCL-2 protein family: opposing activities that mediate cell death. Nature Reviews Molecular Cell Biology, 9(1), pp. 47-59.

Yuan, Y., et al., 2014. Enzyme-sensitive polymeric micelles for targeted drug delivery and triggered release in cancer treatment. Molecular Pharmaceutics, 11(5), pp. 1583-1594.

Zhang, X., et al. (2012). "Hybrid nanoparticles for paclitaxel delivery: enhanced solubility, targeting, and therapeutic efficacy." ACS Nano, 6(9), 7611-7623

Zhang, Y., et al., 2021. Hybrid nanoparticles for synergistic chemo-photothermal cancer therapy. Biomaterials, 276, p. 120981.

Zhao, L., et al., 2013. Micelle-based paclitaxel delivery: enhancing therapeutic efficacy and safety. International Journal of Pharmaceutics, 454(1), pp. 555-562.

Zhou, H., Wei, L. and Wang, Z., 2023. ABC transporters and cancer resistance to paclitaxel. Pharmacology & Therapeutics, 238, p.108200.

Zhou, J., et al., 2014. Nanoparticle-based delivery of RNAi therapeutics: challenges and strategies. Nanomedicine: Nanotechnology, Biology and Medicine, 10(1), pp. 109-126.

Zymeworks Inc., 2023. Evaluation of Paclitaxel-Loaded Solid Lipid Nanoparticles in Solid Tumors. ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT05884224