Paclitaxel anti-cancer therapeutics: from discovery to clinical use

Abstract

Paclitaxel (PTX), a valuable natural product derived from Taxus species, exhibits remarkable anti-cancer properties. It penetrates nanopores in microtubule walls, interacting with tubulin on the lumen surface and disrupting microtubule dynamics, thereby inducing cytotoxic effects in cancer cells. PTX and its derivatives have gained approval for treating various diseases due to their low toxicity, high efficiency, and broad-spectrum application. The widespread success and expanding applications of PTX have led to increased demand, raising concerns about accessibility. Consequently, researchers globally have focused on developing alternative production methods and applying nanocarriers in PTX delivery systems to enhance bioavailability. This review examines the challenges and advancements in PTX sourcing, production, physicochemical properties, anti-cancer mechanisms, clinical applications, trials, and chemo-immunotherapy. It aims to provide a comprehensive reference for the rational development and effective utilization of PTX.

Keywords

Paclitaxel / Synthesis / Chemotherapeutics / Chemo-immunotherapy / Anti-cancer / Drug delivery

References

[1] Saif MW.US Food and Drug Administration approves paclitaxel protein-bound particles (Abraxane^®) in combination with gemcitabine as first-line treatment of patients with metastatic pancreatic cancer. JOP. 2013; 14(6):686-688. https://doi.org/10.6092/1590-8577/2028.

[2] 360iResearch, paclitaxel market by type (endophytic fungus synthesis, semi synthesis, total synthesis), application (breast cancer, lung cancer, ovarian cancer). end-user: global forecast. 2025-2030. https://www.giiresearch.com/report/ires1595180-paclitaxel-market-by-type-endophytic-fungus.html. 2024 (assessed 6 March 2025). https://www.giiresearch.com/report/ires1595180-paclitaxel-market-by-type-endophytic-fungus.html.

[3] Wani MC, Taylor HL, Wall ME, et al.Plant antitumor agents. VI. Isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Ame Chem Soc. 1971; 93(9):2325-2327. https://doi.org/10.1021/ja00738a045.

[4] Yang Y, Mao J, Tan X.Research progress on the source, production, and anti-cancer mechanisms of paclitaxel. Chin J Nat Med. 2020; 18(12):890-897. https://doi.org/10.1016/s1875-5364(20)60032-2.

[5] Zhang Y, Wiese L, Fang H, et al. Synthetic biology identifies the minimal gene set required for paclitaxel biosynthesis in a plant chassis. Mol Plant. 2023; 16(12):1951-1961. https://doi.org/10.1016/j.molp.2023.10.016.

[6] Jiang B, Gao L, Wang H, et al. Characterization and heterologous reconstitution of Taxus biosynthetic enzymes leading to baccatin III. Science. 2024; 383(6683):622-629. https://doi.org/10.1126/science.adj3484.

[7] Zhou M, Han S, Aras O, et al. Recent advances in paclitaxel-based self-delivery nanomedicines for cancer therapy. Curr Med Chem. 2021; 28(31):6358. https://doi.org/10.2174/0929867327666201111143725.

[8] Halwani AA. Development of pharmaceutical nanomedicines: from the bench to the market. Pharmaceutics. 2022; 14(1):106. https://doi.org/10.3390/pharmaceutics14010106.

[9] Yusuf A, Almotairy ARZ, Henidi H, et al. Nanoparticles as drug delivery systems: a review of the implication of nanoparticles’ physicochemical properties on responses in biological systems. Polymers. 2023; 15(7):1596. https://doi.org/10.3390/polym15071596.

[10] Wileński S, Koper A, Śledzińska P, et al. Innovative strategies for effective paclitaxel delivery: recent developments and prospects. J Oncol Pharm Pract. 2024; 30(2):367-384. https://doi.org/10.1177/10781552231208978.

[11] Ali ES, Sharker SM, Islam MT, et al. Targeting cancer cells with nanotherapeutics and nanodiagnostics: current status and future perspectives. Semin Cancer Biol. 2021; 69:52-68. https://doi.org/10.1016/j.semcancer.2020.01.011.

[12] Ying N, Liu S, Zhang M, et al. Nano delivery system for paclitaxel: recent advances in cancer theranostics. Colloids Surf B Biointerfaces. 2023;228:113419. https://doi.org/10.1016/j.colsurfb.2023.113419.

[13] Liu J, Milne RI, Möller M, et al.Integrating a comprehensive DNA barcode reference library with a global map of yews (Taxus L.) for forensic identification. Mol Ecol Resour. 2018; 18(5):1115-1131. https://doi.org/10.1111/1755-0998.12903.

[14] Gao X, Zhang N, Xie W. Advancements in the cultivation, active components, and pharmacological activities of Taxus mairei. Molecules. 2024; 29(5):1128. https://doi.org/10.3390/molecules29051128.

[15] Xiong X, Gou J, Liao Q, et al. The Taxus genome provides insights into paclitaxel biosynthesis. Nat Plants. 2021; 7(8):1026-1036. https://doi.org/10.1038/s41477-021-00963-5.

[16] Stierle A, Strobel G, Stierle D. Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of Pacific yew. Science. 1993; 260(5105):214-216. https://doi.org/10.1126/science.8097061.

[17] McElroy C, Jennewein S. Taxol^® biosynthesis and production: from forests to fermenters. Biotechnol Nat Prod. 2018; 11:145-185. https://doi.org/10.1007/978-3-319-67903-7_7.

[18] Christen AA, Gibson DM, Bland J. Production of taxol or taxol-like compounds in cell culture. 1991, US-5019504-A.

[19] Kochkin DV, Demidova EV, Globa EB, et al. Profiling of taxoid compounds in plant cell cultures of different species of yew (Taxus spp.). Molecules. 2023; 28(5):2178. https://doi.org/10.3390/molecules28052178.

[20] Meyer HP, Schmidhalter D. Industrial Scale Suspension Culture of Living Cells. John Wiley & Sons. 2014.

[21] Wildung MR, Croteau R. A cDNA clone for taxadiene synthase, the diterpene cyclase that catalyzes the committed step of taxol biosynthesis. J Biol Chem. 1996; 271(16):9201-9204. https://doi.org/10.1074/jbc.271.16.9201.

[22] Jennewein S, Wildung MR, Chau M, et al. Random sequencing of an induced Taxus cell cDNA library for identification of clones involved in taxol biosynthesis. Proc Natl Acad Sci U S A. 2004; 101(24):9149-9154. https://doi.org/10.1073/pnas.0403009101.

[23] Chau M, Croteau R. Molecular cloning and characterization of a cytochrome P450 taxoid 2α-hydroxylase involved in taxol biosynthesis. Arch Biochem Biophys. 2004; 427(1):48-57. https://doi.org/10.1016/j.abb.2004.04.016.

[24] Chau M, Jennewein S, Walker K, et al. Taxol biosynthesis: molecular cloning and characterization of a cytochrome P450 taxoid 7 beta-hydroxylase. Chem Biol. 2004; 11(5): 663-672. https://doi.org/10.1016/j.chembiol.2004.02.025.

[25] Schoendorf A, Rithner CD, Williams RM, et al. Molecular cloning of a cytochrome P450 taxane 10β-hydroxylase cDNA from Taxus and functional expression in yeast. Proc Natl Acad Sci U S A. 2001; 98(4):1501-1506. https://doi.org/10.1073/pnas.98.4.1501.

[26] Jennewein S, Rithner CD, Williams RM, et al. Taxol biosynthesis: taxane 13α-hydroxylase is a cytochrome P450-dependent monooxygenase. Proc Natl Acad Sci U S A. 2001; 98(24):13595-13600. https://doi.org/10.1073/pnas.251539398.

[27] Walker K, Schoendorf A, Croteau R. Molecular cloning of a taxa-4(20., 11(12)-dien-5α-ol-O-acetyl transferase cDNA from Taxus and functional expression in Escherichia coli. Arch Biochem Biophys. 2000; 374(2):371-380. https://doi.org/10.1006/abbi.1999.1609.

[28] Walker K, Croteau R.Molecular cloning of a 10-deacetylbaccatin III-10-O-acetyl transferase cDNA from Taxus and functional expression in Escherichia coli. Proc Natl Acad Sci U S A, 2000; 97(2):583-587. https://doi.org/10.1073/pnas.97.2.583.

[29] Walker K, Croteau R.Taxol biosynthesis: molecular cloning of a benzoyl-CoA: taxane 2α-O-benzoyltransferase cDNA from Taxus and functional expression in Escherichia coli. Proc Natl Acad Sci U S A. 2000; 97(25):13591-13596. https://doi.org/10.1073/pnas.250491997.

[30] Cheng J, Wang X, Liu X, et al. Chromosome-level genome of Himalayan yew provides insights into the origin and evolution of the paclitaxel biosynthetic pathway. Mol Plant. 2021; 14(7):1199-1209. https://doi.org/10.1016/j.molp.2021.04.015.

[31] Song C, Fu F, Yang L, et al. Taxus yunnanensis genome offers insights into gymnosperm phylogeny and taxol production. Commun Biol. 2021; 4(1):1203. https://doi.org/10.1038/s42003-021-02697-8.

[32] Li C, Yin X, Wang S, et al. A cytochrome P450 enzyme catalyses oxetane ring formation in paclitaxel biosynthesis. Angew Chem Int Ed Engl. 2024; 63(31):e202407070. https://doi.org/10.1002/anie.202407070.

[33] Walker KD, Klettke K, Akiyama T, et al. Cloning, heterologous expression, and characterization of a phenylalanine aminomutase involved in taxol biosynthesis. J Biol Chem. 2004; 279(52):53947. https://doi.org/10.1074/jbc.M411215200.

[34] Ramírez-Estrada K, Altabella T, Onrubia M, et al. Transcript profiling of jasmonate‐elicited Taxus cells reveals a β‐phenylalanine‐CoA ligase. Plant Biotechnol J. 2016; 14(1):85-96. https://doi.org/10.1111/pbi.12359.

[35] Walker K, Fujisaki S, Long R, et al. Molecular cloning and heterologous expression of the C-13 phenylpropanoid side chain-CoA acyltransferase that functions in taxol biosynthesis. Proc Natl Acad Sci U S A. 2002; 99(20):12715-12720. https://doi.org/10.1073/pnas.192463699.

[36] Walker K, Long R, Croteau R.The final acylation step in taxol biosynthesis: cloning of the taxoid C13-side-chain N-benzoyltransferase from Taxus. Proc Natl Acad Sci U S A. 2002; 99(14):9166-9171. https://doi.org/10.1073/pnas.082115799.

[37] El-Sayed ASA, Abdel-Ghany SE, Ali GS. Genome editing approaches: manipulating of lovastatin and taxol synthesis of filamentous fungi by CRISPR/Cas9 system. Appl Microbiol Biot. 2017; 101(10):3953-3976. https://doi.org/10.1007/s00253-017-8263-z.

[38] Kusari S, Singh S, Jayabaskaran C. Rethinking production of taxol^® (paclitaxel) using endophyte biotechnology. Trends Biotechnol. 2014; 32(6):304-311. https://doi.org/10.1016/j.tibtech.2014.03.011.

[39] Dixon RA, Dickinson AJ. A century of studying plant secondary metabolism—from “what?” to “where, how, and why?”. Plant Physiol. 2024; 195(1):48-66. https://doi.org/10.1093/plphys/kiad596.

[40] Zhan X, Qiu T, Zhang H, et al. Mass spectrometry imaging and single-cell transcriptional profiling reveal the tissue-specific regulation of bioactive ingredient biosynthesis in Taxus leaves. Plant Commun. 2023; 4(5):100630. https://doi.org/10.1016/j.xplc.2023.100630.

[41] Liu F, Xi M, Liu T, et al. The central role of transcription factors in bridging biotic and abiotic stress responses for plants’ resilience. New Crops. 2024;1:10005. https://doi.org/10.1016/j.ncrops.2023.11.003.

[42] Cao X, Xu L, Li L, et al.TcMYB29a, an ABA-responsive R2R3-MYB transcriptional factor, upregulates taxol biosynthesis in Taxus chinensis. Front Plant Sci. 2022;13:804593. https://doi.org/10.3389/fpls.2022.804593.

[43] Yu CN, Huang JF, Wu QC, et al.Role of female-predominant MYB39-bHLH 13 complex in sexually dimorphic accumulation of taxol in Taxus media. Hortic Res. 2022;9:uhac062. https://doi.org/10.1093/hr/uhac062.

[44] Zheng H, Fu X, Shao J, et al. Transcriptional regulatory network of high-value active ingredients in medicinal plants. Trends Plant Sci. 2023; 28(4):429-446. https://doi.org/10.1016/j.tplants.2022.12.007.

[45] Ajikumar PK, Xiao WH, Tyo KE, et al. Isoprenoid pathway optimization for taxol precursor overproduction in Escherichia coli. Science. 2010; 330(6000):70-74. https://doi.org/10.1126/science.1191652.

[46] Wu QY, Huang ZY, Wang JY, et al. Construction of an Escherichia coli cell factory to synthesize taxadien-5α-ol, the key precursor of anti-cancer drug paclitaxel. Bioresour Bioprocess. 2022; 9(1):82. https://doi.org/10.1186/s40643-022-00569-5.

[47] Zhong J, Wang Y, Chen Z, et al. Engineering cyanobacteria as a new platform for producing taxol precursors directly from carbon dioxide. Biotechnol Biofuels Bioprod. 2024; 17(1):99. https://doi.org/10.1186/s13068-024-02555-9.

[48] Zhou K, Qiao K, Edgar S, et al. Distributing a metabolic pathway among a microbial consortium enhances production of natural products. Nat Biotechnol. 2015; 33(4):377-383. https://doi.org/10.1038/nbt.3095.

[49] Nowrouzi B, Li RA, Walls LE, et al. Enhanced production of taxadiene in Saccharomyces cerevisiae. Microb Cell Fact. 2020; 19(1):200. https://doi.org/10.1186/s12934-020-01458-2.

[50] Walls LE, Koray M, Nowrouzi B, et al. Optimizing the biosynthesis of oxygenated and acetylated taxol precursors in Saccharomyces cerevisiae using advanced bioprocessing strategies. Biotechnol Bioeng. 2021; 118(1):279-293. https://doi.org/10.1002/bit.27569.

[51] Walls LE, Martinez JL, Rios-Solis L. Enhancing Saccharomyces cerevisiae taxane biosynthesis and overcoming nutritional stress-induced pseudohyphal growth. Microorganisms. 2022; 10(1):163. https://doi.org/10.3390/microorganisms10010163.

[52] Yang C, Wang Y, Su Z, et al. Biosynthesis of the highly oxygenated tetracyclic core skeleton of taxol. Nat Commun. 2024; 15(1):2339. https://doi.org/10.1038/s41467-024-46583-3.

[53] Xu M, Xie W, Luo Z, et al. Improving solubility and copy number of taxadiene synthase to enhance the titer of taxadiene in Yarrowia lipolytica. Synth Syst Biotechnol. 2023; 8(2):331-338. https://doi.org/10.1016/j.synbio.2023.04.002.

[54] Li J, Mutanda I, Wang K, et al. Chloroplastic metabolic engineering coupled with isoprenoid pool enhancement for committed taxanes biosynthesis in Nicotiana benthamiana. Nat Commun. 2019; 10(1):4850. https://doi.org/10.1038/s41467-019-12879-y.

[55] Fu J, Xu W, Huang W, et al. Importation of taxadiene synthase into chloroplast improves taxadiene production in tobacco. Planta. 2021; 253(5):107. https://doi.org/10.1007/s00425-021-03626-z.

[56] Liu JCT, De La Peña R, Tocol C, et al. Reconstitution of early paclitaxel biosynthetic network. Nat Commun. 2024; 15(1):1419. https://doi.org/10.1038/s41467-024-45574-8.

[57] Colin M, Guenard D, Gueritte-Voegelein F, et al. Process for preparing derivatives of baccatine III and of 10-deacetyl baccatine III and of 10-deacetyl baccatine III. US, AU19890032426, 1989-10-12. .

[58] Denis JN, Greene AE, Guenard D, et al. Highly efficient,practical approach to natural taxol. J Am Chem Soc. 1988; 110(17):5917-5919. https://doi.org/10.1021/ja00225a063.

[59] Holton RA. Method for preparation of taxol. US, 07/968003, 1994-08-09..

[60] Ojima I, Habus I, Zhao M, et al. Efficient and practical asymmetric synthesis of the taxol C-13 side chain, N-benzoyl-(2R,3S)-3-phenylisoserine, and its analogs via chiral 3-hydroxy-4-aryl-beta-lactams through chiral ester enolate-imine cyclocondensation. J Org Chem. 1991; 56(5):1681-1683. https://doi.org/10.1021/jo00005a003.

[61] Mak JYW, Pouwer RH, Williams CM. Natural products with anti-bredt and bridgehead double bonds. Angew Chem Int Ed Engl. 2014; 53(50):13664-13688. https://doi.org/10.1002/anie.201400932.

[62] Liu J, Liu X, Wu J, et al. Total synthesis of natural products containing a bridgehead double bond. Chem. 2020; 6(3):579-615. https://doi.org/10.1016/j.chempr.2019.12.027.

[63] Tessier G, Barriault L.The conquest of vinigrol. Creativity, frustrations, and hope. Org Prep Proced Int. 2007; 39(4):311-353. https://doi.org/10.1080/00304940709458591.

[64] Nicolaou KC, Yang Z, Liu JJ, et al.Total synthesis of taxol. Nature. 1994; 367(6464):630-634. https://doi.org/10.1038/367630a0.

[65] Nicolaou KC, Nantermet PG, Ueno H, et al. Total synthesis of taxol. 1. Retrosynthesis, degradation, and reconstitution. J Am Chem Soc. 1995; 117(2):624-633. https://doi.org/10.1021/ja00107a006.

[66] Nicolaou KC, Liu JJ, Yang Z, et al. Total synthesis of taxol. 2. Construction of A and C ring intermediates and initial attempts to construct the ABC ring system. J Am Chem Soc. 1995; 117(2):634-644. https://doi.org/10.1021/ja00107a007.

[67] Nicolaou KC, Yang Z, Liu JJ, et al. Total synthesis of taxol. 3. Formation of taxol’s ABC ring skeleton. J Am Chem Soc. 1995; 117(2):645-652. https://doi.org/10.1021/ja00107a008.

[68] Nicolaou KC, Ueno H, Liu JJ, et al. Total synthesis of taxol. 4. The final stages and completion of the synthesis. J Am Chem Soc. 1995; 117(2):653-659. https://doi.org/10.1021/ja00107a009.

[69] Holton RA, Somoza C, Kim HB, et al. First total synthesis of taxol. 1. Functionalization of the B ring. J Am Chem Soc. 1994; 116(4):1597-1598. https://doi.org/10.1021/ja00083a066.

[70] Holton RA, Kim HB, Somoza C, et al. First total synthesis of taxol. 2. Completion of the C and D rings. J Am Chem Soc. 1994; 116(4):1599-1600. https://doi.org/10.1021/ja00083a067.

[71] Masters JJ, Link JT, Snyder LB, et al.A total synthesis of taxol. Angew Chem Int Edit Engl. 1995; 34(16):1723-1726. https://doi.org/10.1002/anie.199517231.

[72] Danishefsky SJ, Masters JJ, Young WB, et al. Total synthesis of baccatin III and taxol. J Am Chem Soc. 1996; 118(12):2843-2859. https://doi.org/10.1021/ja952692a.

[73] Wender PA, Badham NF, Conway SP, et al. The pinene path to taxanes. 5. Stereocontrolled synthesis of a versatile taxane precursor. J Am Chem Soc. 1997; 119(11):2755-2756. https://doi.org/10.1021/ja9635387.

[74] Wender PA, Badham NF, Conway SP, et al. The pinene path to taxanes. 6. A concise stereocontrolled synthesis of taxol. J Am Chem Soc. 1997; 119(11):2757-2758. https://doi.org/10.1021/ja963539z.

[75] Mukaiyama T, Shiina I, Iwadare H, et al.Asymmetric total synthesis of taxol. Proc Jpn Acad Ser B Phys Biol Sci. 1997; 73(6):95-100. https://doi.org/10.2183/pjab.73.95.

[76] Mukaiyama T, Shiina I, Iwadare H, et al.Asymmetric total synthesis of taxol^@. Chem Eur J. 1999; 5(1):121-161 https://doi.org/10.1002/(SICI)1521-3765(19990104)5:1<121::AID-CHEM121>3.0.CO;2-O. doi: 10.1002/(SICI)1521-3765(19990104)5:1<121::AID-CHEM121>3.0.CO;2-O

[77] Morihira K, Hara R, Kawahara S, et al.Enantioselective total synthesis of taxol. J Am Chem Soc. 1998; 120(49):12980-12981. https://doi.org/10.1021/ja9824932.

[78] Kusama H, Hara R, Kawahara S, et al.Enantioselective total synthesis of (-)-taxol. J Am Chem Soc. 2000; 122(16):3811-3820. https://doi.org/10.1021/ja9939439.

[79] Kanda Y, Nakamura H, Umemiya S, et al.Two-phase synthesis of taxol. J Am Chem Soc. 2020; 142(23):10526-10533. https://doi.org/10.1021/jacs.0c03592.

[80] Hu YJ, Gu CC, Wang XF, et al.Asymmetric total synthesis of taxol. J Am Chem Soc. 2021; 143(42):17862-17870. https://doi.org/10.1021/jacs.1c09637.

[81] Iiyama S, Fukaya K, Yamaguchi Y, et al.Total synthesis of paclitaxel. Org Lett. 2022; 24(1):202-206. https://doi.org/10.1021/acs.orglett.1c03851.

[82] Imamura Y, Takaoka K, Komori Y, et al. Total synthesis of taxol enabled by inter- and intramolecular radical coupling reactions. Angew Chem Int Edit Engl. 2023; 62(10):e202219114. https://doi.org/10.1002/anie.202219114.

[83] Watanabe T, Oga K, Matoba H, et al. Total synthesis of taxol enabled by intermolecular radical coupling and Pd-catalyzed cyclization. J Am Chem Soc. 2023; 145(47):25894-25902. https://doi.org/10.1021/jacs.3c10658.

[84] Doi T, Fuse S, Miyamoto S, et al. A formal total synthesis of taxol aided by an automated synthesizer. Chem Asian J. 2006; 1(3):370-383. https://doi.org/10.1002/asia.200600156.

[85] Fukaya K, Tanaka Y, Sato AC, et al. Synthesis of paclitaxel. 1. Synthesis of the ABC ring of paclitaxel by SmI2-mediated cyclization. Org Lett. 2015; 17(11):2570-2573. https://doi.org/10.1021/acs.orglett.5b01173.

[86] Fukaya K, Kodama K, Tanaka Y, et al. Synthesis of paclitaxel. 2. Construction of the ABCD ring and formal synthesis. Org lett. 2015; 17(11):2574-2577. https://doi.org/10.1021/acs.orglett.5b01174.

[87] Hirai S, Utsugi M, Iwamoto M, et al. Formal total synthesis of (-)-taxol through Pd-catalyzed eight-membered carbocyclic ring formation. Chemistry. 2015; 21(1):355-359. https://doi.org/10.1002/chem.201404295.

[88] Lim J. Total Synthesis of Taxol. Harvard Universtiy, 2000.

[89] Alves RC, Fernandes RP, Eloy JO, et al. Characteristics, properties and analytical methods of paclitaxel: a review. Crit Rev Anal Chem. 2018; 48(2):110-118. https://doi.org/10.1080/10408347.2017.1416283.

[90] Voci S, Gagliardi A, Molinaro R, et al. Recent advances of taxol-loaded biocompatible nanocarriers embedded in natural polymer-based hydrogels. Gels. 2021; 7(2):33. https://doi.org/10.3390/gels7020033.

[91] Kehrein J, Bunker A, Luxenhofer R. POxload: machine learning estimates drug loadings of polymeric micelles. Mol Pharm. 2024; 21(7):3356-3374. https://doi.org/10.1021/acs.molpharmaceut.4c00086.

[92] Lim C, Hwang D, Yazdimamaghani M, et al. High-dose paclitaxel and its combination with CSF1R inhibitor in polymeric micelles for chemoimmunotherapy of triple negative breast cancer. Nano Today. 2023;51:101884. https://doi.org/10.1016/j.nantod.2023.101884.

[93] Bisch SP, Sugimoto A, Prefontaine M, et al. Treatment tolerance and side effects of intraperitoneal carboplatin and dose-dense intravenous paclitaxel in ovarian cancer. J Obstet Gynaecol Can. 2018; 40(10):1283-1287.e1. https://doi.org/10.1016/j.jogc.2018.01.028.

[94] Nicolaou KC, Riemer C, Kerr MA, et al. Design, synthesis and biological activity of protaxols. Nature. 1993; 364(6436):464-466. https://doi.org/10.1038/364464a0.

[95] Spencer CM, Faulds D. Paclitaxel. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of cancer. Drugs. 1994; 48(5):794-847. https://doi.org/10.2165/00003495-199448050-00009.

[96] Spratlin J, Sawyer MB.Pharmacogenetics of paclitaxel metabolism. Crit Rev Oncol Hematol. 2007; 61(3):222-229. https://doi.org/10.1016/j.critrevonc.2006.09.006.

[97] Cardonick E, Broadrup R, Xu P, et al. Preliminary results of identification and quantification of paclitaxel and its metabolites in human meconium from newborns with gestational chemotherapeutic exposure. PLoS One. 2019; 14(2):e0211821. https://doi.org/10.1371/journal.pone.0211821.

[98] Cardonick EH, O'Laughlin AE, So SC, et al. Paclitaxel use in pregnancy: neonatal follow-up of infants with positive detection of intact paclitaxel and metabolites in meconium at birth. Eur J Pediatr. 2022; 181(4):1763-1766. https://doi.org/10.1007/s00431-021-04260-3.

[99] Monsarrat B, Mariel E, Cros S, et al. Taxol metabolism. Isolation and identification of three major metabolites of taxol in rat bile. Drug Metab Dispos. 1990; 18(6):895-901. https://doi.org/10.1016/S0090-9556(25)08688-X.

[100] Rahman A, Korzekwa KR, Grogan J, et al. Selective biotransformation of taxol to 6 alpha-hydroxytaxol by human cytochrome P450 2C8. Cancer Res. 1994; 54(21):5543-5546.

[101] Harris JW, Rahman A, Kim BR, et al. Metabolism of taxol by human hepatic microsomes and liver slices: participation of cytochrome P450 3A4 and an unknown P450 enzyme. Cancer Res. 1994; 54(15):4026-4035.

[102] MacEachern-Keith GJ, Wagner BLJ, Incorvia MMJ.Paclitaxel stability in solution. Anal Chem. 1997; 69(1):72-77. https://doi.org/10.1021/ac9606822.

[103] Zhang YY, Liu Y, Zhang JW, et al. Characterization of human cytochrome P450 isoforms involved in the metabolism of 7-epi-paclitaxel. Xenobiotica. 2009; 39(4):283-292. https://doi.org/10.1080/00498250802714907.

[104] Vaclavikova R, Soucek P, Svobodova L, et al. Different in vitro metabolism of paclitaxel and docetaxel in humans, rats, pigs, and minipigs. Drug Metab Dispos. 2004; 32(6):666-674. https://doi.org/10.1124/dmd.32.6.666.

[105] Meng Z, Chen J, Xu L, et al. Study on cytochrome P450 metabolic profile of paclitaxel on rats using QTOF-MS. Curr Drug Metab. 2024; 25(5):330-339. https://doi.org/10.2174/0113892002308509240711100502.

[106] Nguyen TT, Duong VA, Maeng HJ. Pharmaceutical formulations with P-glycoprotein inhibitory effect as promising approaches for enhancing oral drug absorption and bioavailability. Pharmaceutics. 2021; 13(7):1103. https://doi.org/10.3390/pharmaceutics13071103.

[107] Choi JS, Shin SC. Enhanced paclitaxel bioavailability after oral coadministration of paclitaxel prodrug with naringin to rats. Int J Pharm. 2005; 292(1-2):149-156. https://doi.org/10.1016/j.ijpharm.2004.11.031.

[108] Li F, Zhang H, He M, et al. Different nanoformulations alter the tissue distribution of paclitaxel, which aligns with reported distinct efficacy and safety profiles. Mol Pharm. 2018; 15(10):4505-4516. https://doi.org/10.1021/acs.molpharmaceut.8b00527.

[109] Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature. 1979; 277(5698):665-667. https://doi.org/10.1038/277665a0.

[110] Long BH, Fairchild CR. Paclitaxel inhibits progression of mitotic cells to G₁ phase by interference with spindle formation without affecting other microtubule functions during anaphase and telephase. Cancer Res. 1994; 54(16):4355-4361.

[111] Wang TH, Wang HS, Soong YK. Paclitaxel-induced cell death: where the cell cycle and apoptosis come together. Cancer. 2000; 88(11):2619-2628 https://doi.org/10.1002/1097-0142(20000601)88:11<2619::aid-cncr26>3.0.co;2-j. doi: 10.1002/1097-0142(20000601)88:11<2619::aid-cncr26>3.0.co;2-j

[112] Cao X, Xie H, Song M, et al. Cut-dip-budding delivery system enables genetic modifications in plants without tissue culture. Innovation (Camb). 2023; 4(1):100345. https://doi.org/10.1016/j.xinn.2022.100345.

[113] Igney FH, Krammer PH. Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer. 2002; 2(4):277-288. https://doi.org/10.1038/nrc776.

[114] Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012; 13(2):89-102. https://doi.org/10.1038/nrm3270.

[115] Glover HL, Schreiner A, Dewson G, et al.Mitochondria and cell death. Nat Cell Biol. 2024; 26(9):1434-1446. https://doi.org/10.1038/s41556-024-01429-4.

[116] Varbiro G, Veres B, Gallyas F, et al. Direct effect of taxol on free radical formation and mitochondrial permeability transition. Free Radic Biol Med. 2001; 31(4):548-558. https://doi.org/10.1016/s0891-5849(01)00616-5.

[117] Zhang Y, Tang Y, Tang X, et al. Paclitaxel induces the apoptosis of prostate cancer cells via ROS-mediated HIF-1alpha expression. Molecules. 2022; 27(21):7183. https://doi.org/10.3390/molecules2721718.

[118] Lan YY, Chen YH, Liu C, et al. Role of JNK activation in paclitaxel-induced apoptosis in human head and neck squamous cell carcinoma. Oncol Lett. 2021; 22(4):705. https://doi.org/10.3892/ol.2021.12966.

[119] Peng ZG, Liu DC, Yao YB, et al. Paclitaxel induces apoptosis in leukemia cells through a JNK activation-dependent pathway. Genet Mol Res. 2016; 15(1):15013904. https://doi.org/10.4238/gmr.15013904.

[120] Yu-Wei D, Li ZS, Xiong SM, et al. Paclitaxel induces apoptosis through the TAK1-JNK activation pathway. FEBS Open Bio. 2020; 10(8):1655-1667. https://doi.org/10.1002/2211-5463.12917.

[121] Khing TM, Choi WS, Kim DM, et al. The effect of paclitaxel on apoptosis, autophagy and mitotic catastrophe in AGS cells. Sci Rep. 2021; 11(1):23490. https://doi.org/10.1038/s41598-021-02503-9.

[122] Kroemer G, Martin SJ. Caspase-independent cell death. Nat Med. 2005; 11(7):725-730. https://doi.org/10.1038/nm1263.

[123] Ofir R, Seidman R, Rabinski T, et al. Taxol-induced apoptosis in human SKOV3 ovarian and MCF7 breast carcinoma cells is caspase-3 and caspase-9 independent. Cell Death Differ. 2002; 9(6):636-642. https://doi.org/10.1038/sj.cdd.4401012.

[124] Huisman C, Ferreira CG, Broker LE, et al.Paclitaxel triggers cell death primarily via caspase-independent routes in the non-small cell lung cancer cell line NCI-H460. Clin Cancer Res. 2002; 8(2):596-606.

[125] Ling Z, Pan J, Zhang Z, et al. Small-molecule molephantin induces apoptosis and mitophagy flux blockage through ROS production in glioblastoma. Cancer Lett. 2024;592:216927. https://doi.org/10.1016/j.canlet.2024.216927.

[126] Xu Z, Li Y, Pi P, et al. B. glomerulata promotes neuroprotection against ischemic stroke by inhibiting apoptosis through the activation of PI3K/AKT/mTOR pathway. Phytomedicine. 2024;132:155817. https://doi.org/10.1016/j.phymed.2024.155817.

[127] Ren X, Zhao B, Chang H, et al. Paclitaxel suppresses proliferation and induces apoptosis through regulation of ROS and the AKT/MAPK signaling pathway in canine mammary gland tumor cells. Mol Med Rep. 2018; 17(6):8289-8299. https://doi.org/10.3892/mmr.2018.8868.

[128] Li G, Xu D, Sun J, et al. Paclitaxel inhibits proliferation and invasion and promotes apoptosis of breast cancer cells by blocking activation of the PI3K/AKT signaling pathway. Adv Clin Exp Med. 2020; 29(11):1337-1345. https://doi.org/10.17219/acem/127681.

[129] Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011; 12(1):21-35. https://doi.org/10.1038/nrm3025.

[130] Li J, Zhang D, Wang S, et al. Baicalein induces apoptosis by inhibiting the glutamine-mTOR metabolic pathway in lung cancer. J Adv Res. 2025; 68:341-357. https://doi.org/10.1016/j.jare.2024.02.023.

[131] Su Y, Wu M, Zhou B, et al. Paclitaxel mediates the PI3K/AKT/mTOR pathway to reduce proliferation of FLT3-ITD⁽⁺⁾ AML cells and promote apoptosis. Exp Ther Med. 2024; 27(4):161. https://doi.org/10.3892/etm.2024.12449.

[132] Wu W, Wei T, Li Z, et al. p53-Dependent apoptosis is essential for the antitumor effect of paclitaxel response to DNA damage in papillary thyroid carcinoma. Int J Med Sci. 2021; 18(14):3197-3205. https://doi.org/10.7150/ijms.61944.

[133] Huang X, Wu W, Jing D, et al. Engineered exosome as targeted lncRNA MEG3 delivery vehicles for osteosarcoma therapy. J Control Release. 2022; 343:107-117. https://doi.org/10.1016/j.jconrel.2022.01.026.

[134] Xu J, Su C, Zhao F, et al. Paclitaxel promotes lung cancer cell apoptosis via MEG3-P53 pathway activation. Biochem Biophys Res Commun. 2018; 504(1):123-128. https://doi.org/10.1016/j.bbrc.2018.08.142.

[135] Ng KY, Chan LH, Chai S, et al. TP53INP1 downregulation activates a p73-dependent DUSP10/ERK signaling pathway to promote metastasis of hepatocellular carcinoma. Cancer Res. 2017; 77(17):4602-4612. https://doi.org/10.1158/0008-5472.CAN-16-3456.

[136] Xiao WY, Zong Z, Qiu ML, et al. Paclitaxel induce apoptosis of giant cells tumor of bone via TP53INP1 signaling. Orthop Surg. 2019; 11(1):126-134. https://doi.org/10.1111/os.12414.

[137] Yan M, Wang C, He B, et al. Aurora-A kinase: a potent oncogene and target for cancer therapy. Med Res Rev. 2016; 36(6):1036-1079. https://doi.org/10.1002/med.21399.

[138] Tan J, Xu W, Lei L, et al. Inhibition of aurora kinase A by alisertib reduces cell proliferation and induces apoptosis and autophagy in HuH-6 human hepatoblastoma cells. Onco Targets Ther. 2020; 13:3953-3963. https://doi.org/10.2147/OTT.S228656.

[139] Chen X, Du S, Zhang Y, et al. Caspase-mediated AURKA cleavage at Asp(132) is essential for paclitaxel to elicit cell apoptosis. Theranostics. 2024; 14(10):3909-3926. https://doi.org/10.7150/thno.97842.

[140] Broz P, Pelegrin P, Shao F. The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol. 2020; 20(3):143-157. https://doi.org/10.1038/s41577-019-0228-2.

[141] Hu Y, Liu Y, Zong L, et al. The multifaceted roles of GSDME-mediated pyroptosis in cancer: therapeutic strategies and persisting obstacles. Cell Death Dis. 2023; 14(12):836. https://doi.org/10.1038/s41419-023-06382-y.

[142] Zhang CC, Li CG, Wang YF, et al. Chemotherapeutic paclitaxel and cisplatin differentially induce pyroptosis in A549 lung cancer cells via caspase-3/GSDME activation. Apoptosis. 2019; 24(3-4):312-325. https://doi.org/10.1007/s10495-019-01515-1.

[143] Yang X, Li C, Liao X, et al. Paclitaxel induces pyroptosis by inhibiting the volume-sensitive chloride channel leucine-rich repeat-containing 8a in ovarian cancer cells. Oncol Rep. 2023; 49(6):115. https://doi.org/10.3892/or.2023.8552.

[144] Xu PP, Wu J, Zhang J, et al. Paclitaxel may inhibit migration and invasion of gastric cancer cells via nod-like receptor family pyrin domain-containing 3/caspase-1/gasdermin E mediated pyroptosis pathway. Chem Biol Drug Des. 2024; 103(1):e14325. https://doi.org/10.1111/cbdd.14325.

[145] Wang X, Li H, Li W, et al. The role of caspase-1/GSDMD-mediated pyroptosis in taxol-induced cell death and a taxol-resistant phenotype in nasopharyngeal carcinoma regulated by autophagy. Cell Biol Toxicol. 2020; 36(5):437-457. https://doi.org/10.1007/s10565-020-09514-8.

[146] Wang J, Wu Z, Zhu M, et al. ROS induced pyroptosis in inflammatory disease and cancer. Front Immunol. 2024;15:1378990. https://doi.org/10.3389/fimmu.2024.1378990.

[147] Tian A, Wu T, Zhang Y, et al. Triggering pyroptosis enhances the antitumor efficacy of PARP inhibitors in prostate cancer. Cell Oncol (Dordr). 2023; 46(6):1855-1870. https://doi.org/10.1007/s13402-023-00860-3.

[148] Zhao W, Zhang L, Zhang Y, et al. The CDK inhibitor AT7519 inhibits human glioblastoma cell growth by inducing apoptosis, pyroptosis and cell cycle arrest. Cell Death Dis. 2023; 14(1):11. https://doi.org/10.1038/s41419-022-05528-8.

[149] Steeg PS. Targeting metastasis. Nat Rev Cancer. 2016; 16(4):201-218. https://doi.org/10.1038/nrc.2016.25.

[150] Xu Z, Xiang W, Chen W, et al. Circ-IGF1R inhibits cell invasion and migration in non-small cell lung cancer. Thorac Cancer. 2020; 11(4):875-887. https://doi.org/10.1111/1759-7714.13329.

[151] Ying J, Yang Y, Zhang X, et al.Stearoylation cycle regulates the cell surface distribution of the PCP protein Vangl2. Proc Natl Acad Sci U S A. 2024; 121(29):e2400569121. https://doi.org/10.1073/pnas.2400569121.

[152] Duan W, Zhang YP, Hou Z, et al. Novel insights into NeuN: from neuronal marker to splicing regulator. Mol Neurobiol. 2016; 53(3):1637-1647. https://doi.org/10.1007/s12035-015-9122-5.

[153] Xu Z, Zheng L, Li S. Paclitaxel-induced inhibition of NSCLC invasion and migration via RBFOX3-mediated circIGF1R biogenesis. Sci Rep. 2024; 14(1):774. https://doi.org/10.1038/s41598-024-51500-1.

[154] Kuhn JG.Pharmacology and pharmacokinetics of paclitaxel. Ann Pharmacother. 1994; 28(5 Suppl):S15-S17. https://doi.org/10.1177/10600280940280S504.

[155] Bachelot T, Ciruelos E, Schneeweiss A, et al. Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE). Ann Oncol. 2019; 30(5):766-773. https://doi.org/10.1093/annonc/mdz061.

[156] Kwapisz D. Pembrolizumab and atezolizumab in triple-negative breast cancer. Cancer Immunol Immunother. 2021; 70(3):607-617. https://doi.org/10.1007/s00262-020-02736-z.

[157] Potthoff K, Stötzer O, Söling U, et al. Effectiveness and tolerability of nab-paclitaxel in younger versus elderly patients with metastatic HR-positive/HER2-negative breast cancer: results from the noninterventional, prospective study NABUCCO. Clin Breast Cancer. 2020; 20(3):E315-E326. https://doi.org/10.1016/j.clbc.2019.11.003.

[158] Rugo HS, Umanzor GA, Barrios FJ, et al. Open-label, randomized, multicenter, phase III study comparing oral paclitaxel plus encequidar versus intravenous paclitaxel in patients with metastatic breast cancer. J Clin Oncol. 2023; 41(1):65-74. https://doi.org/10.1200/jco.21.02953.

[159] Kang YK, Kim HD, Yook JH, et al. Neoadjuvant docetaxel, oxaliplatin, and S-1 plus surgery and adjuvant S-1 for resectable advanced gastric cancer: updated overall survival outcomes from phase III prodigy. J Clin Oncol. 2024; 42(25):2961-2965. https://doi.org/10.1200/jco.23.02167.

[160] Shitara K, Ozguroglu M, Bang YJ, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018; 392(10142):123-133. https://doi.org/10.1016/s0140-6736(18)31257-1.

[161] Chung HC, Kang YK, Chen ZD, et al. Pembrolizumab versus paclitaxel for previously treated advanced gastric or gastroesophageal junction cancer (KEYNOTE-063): a randomized, open-label, phase 3 trial in Asian patients. Cancer. 2022; 128(5):995-1003. https://doi.org/10.1002/cncr.34019.

[162] Gou MM, Zhang Y, Wang ZK, et al. PD-1 inhibitor combined with albumin paclitaxel and apatinib as second-line treatment for patients with metastatic gastric cancer: a single-center, single-arm, phase II study. Invest New Drugs. 2024; 42(2):171-178. https://doi.org/10.1007/s10637-024-01425-3.

[163] Kang YK, Ryu MH, Park SH, et al.Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy. Ann Oncol. 2018; 29(5):1220-1226. https://doi.org/10.1093/annonc/mdy055.

[164] Goldstein D, El-Maraghi RH, Hammel P, et al. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst. 2015; 107(2):dju413. https://doi.org/10.1093/jnci/dju413.

[165] Tempero MA, Pelzer U, O'Reilly EM, et al. Adjuvant nab-paclitaxel plus gemcitabine in resected pancreatic ductal adenocarcinoma: results from a randomized, open-label, phase III trial. J Clin Oncol. 2023; 41(11):2007-2019. https://doi.org/10.1200/Jco.22.01134.

[166] Kunzmann V, Siveke JT, Algül H, et al. Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by FOLFIRINOX induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol. 2021; 6(2):128-138. https://doi.org/10.1016/S2468-1253(20)30330-7.

[167] Weniger M, Moir J, Damm M, et al. Respect: a multicenter retrospective study on preoperative chemotherapy in locally advanced and borderline resectable pancreatic cancer. Pancreatology. 2020; 20(6):1131-1138. https://doi.org/10.1016/j.pan.2020.06.012.

[168] Mizutani Y, Iida T, Ohno E, et al. Safety and efficacy of MIKE-1 in patients with advanced pancreatic cancer: a study protocol for an open-label phase I/II investigator-initiated clinical trial based on a drug repositioning approach that reprograms the tumour stroma. BMC Cancer. 2022; 22(1):205. https://doi.org/10.1186/s12885-022-09272-2.

[169] Seufferlein T, Uhl W, Kornmann M, et al. Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)da randomized phase II trial of the AIO pancreatic cancer group. Ann Oncol. 2023; 34(1):91-100. https://doi.org/10.1016/j.annonc.2022.09.161.

[170] Lao DH, Chen Y, Fan J, et al. Assessing taxane-associated adverse events using the FDA adverse event reporting system database. Chin Med J. 2021; 134(12):1471-1476. https://doi.org/10.1097/Cm9.0000000000001562.

[171] Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005; 23(31):7794-7803. https://doi.org/10.1200/jco.2005.04.937.

[172] Novello S, Kowalski DM, Luft A, et al. Pembrolizumab plus chemotherapy in squamous non small-cell lung cancer: 5-year update of the phase III KEYNOTE-407 study. J Clini Oncol. 2023; 41(11):1999-2006. https://doi.org/10.1200/Jco.22.01990.

[173] Ren SX, Chen JH, Xu XX, et al. Camrelizumab plus carboplatin and paclitaxel as first-line treatment for advanced squamous NSCLC (CameL-Sq): a phase 3 trial. J Thorac Oncol. 2022; 17(4):544-557. https://doi.org/10.1016/j.jtho.2021.11.018.

[174] Watanabe S, Furuya N, Nakamura A, et al. A phase II study of atezolizumab with bevacizumab, carboplatin, and paclitaxel for patients with EGFR-mutated NSCLC after TKI treatment failure (NEJ043 study). Eur J Cancer. 2024;197:113469. https://doi.org/10.1016/j.ejca.2023.113469.

[175] Hao Z, Veedu JS. Current strategies for extensive stage small cell lung cancer beyond first-line therapy. Clin Lung Cancer. 2022; 23(1):14-20. https://doi.org/10.1016/j.cllc.2021.09.003.

[176] Annic J, Babey H, Corre R, et al. Real-life second-line epirubicin-paclitaxel regimen as treatment of relapsed small-cell lung cancer: EpiTax study. Cancer Med. 2023; 12(3):2658-2665. https://doi.org/10.1002/cam4.5143.

[177] Josefsson A, Jellvert A, Holmberg E, et al. Effect of docetaxel added to bicalutamide in hormone-naive non-metastatic prostate cancer with rising PSA, a randomized clinical trial (SPCG-14). Acta Oncol. 2023; 62(4):372-380. https://doi.org/10.1080/0284186x.2023.2199940.

[178] Rosenthal SA, Hu C, Sartor O, et al. Effect of chemotherapy with docetaxel with androgen suppression and radiotherapy for localized high-risk prostate cancer: the randomized phase III NRG oncology RTOG 0521 trial. J Clin Oncol. 2019; 37(14):1159-1168. https://doi.org/10.1200/jco.18.02158.

[179] Peltekian S, Sajwani S, Wang X, et al. Incidence, predictors, and outcomes of febrile neutropenia and neutropenia in patients with metastatic castrate-resistant prostate cancer receiving docetaxel. Support Care Cancer. 2023; 31(5):311. https://doi.org/10.1007/s00520-023-07776-6.

[180] Oudard S, Fizazi K, Sengelov L, et al. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: a randomized phase III trial-FIRSTANA. J Clin Oncol. 2017; 35(28):3189-3197. https://doi.org/10.1200/jco.2016.72.1068.

[181] Baciarello G, Delva R, Gravis G, et al. Patient preference between cabazitaxel and docetaxel for first-line chemotherapy in metastatic castration-resistant prostate cancer: the CABADOC trial. Eur Urol. 2022; 81(3):234-240. https://doi.org/10.1016/j.eururo.2021.10.016.

[182] de Wit R, Freedland SJ, Oudard S, et al. Real-world evidence of patients with metastatic castration-resistant prostate cancer treated with cabazitaxel: comparison with the randomized clinical study CARD. Prostate Cancer Prostatic Dis. 2023; 26(1):67-73. https://doi.org/10.1038/s41391-021-00487-1.

[183] Fleshner NE, Sayyid RK, Hansen AR, et al. Neoadjuvant cabazitaxel plus abiraterone/leuprolide acetate in patients with high-risk prostate cancer: ACDC-RP phase II trial. Clin Cancer Res. 2023; 29(19):3867-3874. https://doi.org/10.1158/1078-0432.Ccr-23-0731.

[184] Moore KN, Bookman M, Sehouli J, et al. Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: placebo-controlled randomized phase III trial (IMagyn050/GOG3015/ENGOT-OV39). J Clin Oncol. 2021; 39(17):1842-1855. https://doi.org/10.1200/jco.21.00306.

[185] Sa-Nguansai S, Sukphinetkul R. Development and validation of a clinical prediction model for paclitaxel hypersensitivity reaction on the basis of real-world data: Pac-HSR score. JCO Glob Oncol. 2024(10):e2400318. https://doi.org/10.1200/go-24-00318.

[186] Uenami T, Mori M, Ageshio F, et al. Safe treatment of lung squamous cell carcinoma with nanoparticle albumin-bound paclitaxel in a patient with a previous hypersensitivity reaction after docetaxel administration. Gan To Kagaku Ryoho. 2015; 42(3):375-377.

[187] Pellegrino B, Boggiani D, Tommasi C, et al. Nab-paclitaxel after docetaxel hypersensitivity reaction: case report and literature review. Acta Biomed. 2017; 88(3):329-333. https://doi.org/10.23750/abm.v88i3.6138.

[188] Li B, Chen X, Ding T, et al. Nanoparticle albumin-bound paclitaxel versus solvent-based paclitaxel in breast cancer: a protocol for systemic review and meta-analysis. Medicine (Baltimore). 2021; 100(7):e24514. https://doi.org/10.1097/md.0000000000024514.

[189] Janowitz T, Kleeman S, Vonderheide RH. Reconsidering dexamethasone for antiemesis when combining chemotherapy and immunotherapy. Oncologist. 2021; 26(4):269-273. https://doi.org/10.1002/onco.13680.

[190] Dieras V, Limentani S, Romieu G, et al. Phase II multicenter study of larotaxel (XRP9881), a novel taxoid, in patients with metastatic breast cancer who previously received taxane-based therapy. Ann Oncol. 2008; 19(7):1255-1260. https://doi.org/10.1093/annonc/mdn060.

[191] Robert F, Harper K, Ackerman J, et al. A phase I study of larotaxel (XRP9881) administered in combination with carboplatin in chemotherapy-naive patients with stage IIIB or stage IV non-small cell lung cancer. Cancer Chemother Pharmacol. 2010; 65(2):227-234. https://doi.org/10.1007/s00280-009-1026-5.

[192] Zatloukal P, Gervais R, Vansteenkiste J, et al. Randomized multicenter phase II study of larotaxel (XRP9881) in combination with cisplatin or gemcitabine as first-line chemotherapy in nonirradiable stage IIIB or stage IV non-small cell lung cancer. J Thorac Oncol. 2008; 3(8):894-901. https://doi.org/10.1097/JTO.0b013e31817e6669.

[193] Sternberg CN, Skoneczna IA, Castellano D, et al. Larotaxel with cisplatin in the first-line treatment of locally advanced/metastatic urothelial tract or bladder cancer: a randomized, active-controlled, phase III trial (CILAB). Oncology. 2013; 85(4):208-215. https://doi.org/10.1159/000354085.

[194] Li X, Li J, Xu J, et al. Nanostructure of functional larotaxel liposomes decorated with guanine-rich quadruplex nucleotide-lipid derivative for treatment of resistant breast cancer. Small. 2021; 17(13):e2007391. https://doi.org/10.1002/smll.202007391.

[195] Silvani A, De Simone I, Fregoni V, et al. Multicenter single arm, phase II trial on the efficacy of ortataxel in recurrent glioblastoma. J Neuro Oncol. 2019; 142(3):455-462. https://doi.org/10.1007/s11060-019-03116-z.

[196] Bissery MC.Preclinical evaluation of new taxoids. Curr Pharm Des. 2001; 7(13):1251-1257. https://doi.org/10.2174/1381612013397465.

[197] Temel JS, Petrillo LA, Greer JA. Patient-centered palliative care for patients with advanced lung cancer. J Clin Oncol. 2022; 40(6):626-634. https://doi.org/10.1200/JCO.21.01710.

[198] van Driel WJ, Koole SN, Sikorska K, et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med. 2018; 378(3):230-240. https://doi.org/10.1056/NEJMoa1708618.

[199] Yu Y, Meng Y, Xu X, et al. A ferroptosis-inducing and leukemic cell-targeting drug nanocarrier formed by redox-responsive cysteine polymer for acute myeloid leukemia therapy. ACS Nano. 2023; 17(4):3334-3345. https://doi.org/10.1021/acsnano.2c06313.

[200] Pease-Raissi SE, Pazyra-Murphy MF, Li Y, et al. Paclitaxel reduces axonal Bclw to initiate IP(3)R1-dependent axon degeneration. Neuron. 2017; 96(2):373-386.e6. https://doi.org/10.1016/j.neuron.2017.09.034.

[201] Chen D, Zhang G, Li R, et al. Biodegradable, hydrogen peroxide, and glutathione dual responsive nanoparticles for potential programmable paclitaxel release. J Am Chem Soc. 2018; 140(24):7373-7376. https://doi.org/10.1021/jacs.7b12025.

[202] Yang M, Li J, Gu P, et al. The application of nanoparticles in cancer immunotherapy: targeting tumor microenvironment. Bioact Mater. 2021; 6(7):1973-1987. https://doi.org/10.1016/j.bioactmat.2020.12.010.

[203] Mu W, Chu Q, Liu Y, et al. A review on nano-based drug delivery system for cancer chemoimmunotherapy. Nanomicro Lett. 2020; 12(1):142. https://doi.org/10.1007/s40820-020-00482-6.

[204] de Lazaro I, Mooney DJ. Obstacles and opportunities in a forward vision for cancer nanomedicine. Nat Mater. 2021; 20(11):1469-1479. https://doi.org/10.1038/s41563-021-01047-7.

[205] Zhang Z, Mei L, Feng SS.Paclitaxel drug delivery systems. Expert Opin Drug Deliv. 2013; 10(3):325-340. https://doi.org/10.1517/17425247.2013.752354.

[206] Binkhathlan Z, Ali R, Alomrani AH, et al. Role of polymeric micelles in ocular drug delivery: an overview of decades of research. Mol Pharm. 2023; 20(11):5359-5382. https://doi.org/10.1021/acs.molpharmaceut.3c00598.

[207] Qian X, Yang H, Ye Z, et al. Celecoxib augments paclitaxel-induced immunogenic cell death in triple-negative breast cancer. ACS Nano. 2024; 18(24):15864-15877. https://doi.org/10.1021/acsnano.4c02947.

[208] Anirudhan TS, Varghese S, Manjusha V. Hyaluronic acid coated pluronic F127/pluronic P123 mixed micelle for targeted delivery of paclitaxel and curcumin. Int J Biol Macromol. 2021; 192:950-957. https://doi.org/10.1016/j.ijbiomac.2021.10.061.

[209] Qiu X, Qu Y, Guo B, et al. Micellar paclitaxel boosts ICD and chemo-immunotherapy of metastatic triple negative breast cancer. J Control Release. 2022; 341:498-510. https://doi.org/10.1016/j.jconrel.2021.12.002.

[210] Song X, Yuan K, Li H, et al. Dual pseudo and chemical crosslinked polymer micelles for effective paclitaxel delivery and release. ACS Appl Bio Mater. 2020; 3(4):2455-2465. https://doi.org/10.1021/acsabm.0c00184.

[211] Wang QY, Yali X, Hu QH, et al. Surface charge switchable nano-micelle for pH/redox-triggered and endosomal escape mediated co-delivery of doxorubicin and paclitaxel in treatment of lung adenocarcinoma. Colloids Surf B Biointerfaces. 2022;216:112588. https://doi.org/10.1016/j.colsurfb.2022.112588.

[212] Liu C, Liu W, Liu Y, et al. Versatile flexible micelles integrating mucosal penetration and intestinal targeting for effectively oral delivery of paclitaxel. Acta Pharm Sin B. 2023; 13(8):3425-3443. https://doi.org/10.1016/j.apsb.2023.05.029.

[213] Guo C, Zhang W, Zhang Q, et al. Novel dual CAFs and tumour cell targeting pH and ROS dual sensitive micelles for targeting delivery of paclitaxel to liver cancer. Artif Cells Nanomed Biotechnol. 2023; 51(1):170-179. https://doi.org/10.1080/21691401.2023.2193221.

[214] Soga O, van Nostrum CF, Fens M, et al. Thermosensitive and biodegradable polymeric micelles for paclitaxel delivery. J Control Release. 2005; 103(2):341-353. https://doi.org/10.1016/j.jconrel.2004.12.009.

[215] Gupta A, Costa AP, Xu X, et al. Continuous processing of paclitaxel polymeric micelles. Int J Pharm. 2021;607:120946. https://doi.org/10.1016/j.ijpharm.2021.120946.

[216] Wu M, Xue L, Guo Y, et al. Microenvironmentally responsive chemotherapeutic prodrugs and CHEK2 inhibitors self-assembled micelles: protecting fertility and enhancing chemotherapy. Adv Mater. 2023; 35(11):e2210017. https://doi.org/10.1002/adma.202210017.

[217] Liu J, Zhang Y, Liu C, et al. Paclitaxel prodrug-encapsulated polypeptide micelles with redox/pH dual responsiveness for cancer chemotherapy. Int J Pharm. 2023;645:123398. https://doi.org/10.1016/j.ijpharm.2023.123398.

[218] Ma P, Wei G, Chen J, et al. GLUT1 targeting and hypoxia-activating polymer-drug conjugate-based micelle for tumor chemo-thermal therapy. Drug Deliv. 2021; 28(1):2256-2267. https://doi.org/10.1080/10717544.2021.1992039.

[219] Lang T, Liu Y, Zheng Z, et al. Cocktail strategy based on spatio-temporally controlled nano device improves therapy of breast cancer. Adv Mater. 2019; 31(5):e1806202. https://doi.org/10.1002/adma.201806202.

[220] Shah S, Dhawan V, Holm R, et al. Liposomes: advancements and innovation in the manufacturing process. Adv Drug Deliv Rev. 2020;154-155:102-122. https://doi.org/10.1016/j.addr.2020.07.002.

[221] Kaddah S, Khreich N, Kaddah F, et al. Cholesterol modulates the liposome membrane fluidity and permeability for a hydrophilic molecule. Food Chem Toxicol. 2018; 113:40-48. https://doi.org/10.1016/j.fct.2018.01.017.

[222] Torchilin V.Antibody-modified liposomes for cancer chemotherapy. Expert Opin Drug Deliv. 2008; 5(9):1003-1025. https://doi.org/10.1517/17425247.5.9.1003.

[223] Yasmin F, Najeeb H, Shaikh S, et al. Novel drug delivery systems for inflammatory bowel disease. World J Gastroenterol. 2022; 28(18):1922-1933. https://doi.org/10.3748/wjg.v28.i18.1922.

[224] Zhou H, Yan J, Chen W, et al. Population pharmacokinetics and exposure-safety relationship of paclitaxel liposome in patients with non-small cell lung cancer. Front Oncol. 2020;10:1731. https://doi.org/10.3389/fonc.2020.01731.

[225] Erez R, Segal E, Miller K, et al. Enhanced cytotoxicity of a polymer-drug conjugate with triple payload of paclitaxel. Bioorg Med Chem. 2009; 17(13):4327-4335. https://doi.org/10.1016/j.bmc.2009.05.028.

[226] Yu LY, Shueng PW, Chiu HC, et al. Glucose transporter 1-mediated transcytosis of glucosamine-labeled liposomal ceramide targets hypoxia niches and cancer stem cells to enhance therapeutic efficacy. ACS Nano. 2023; 17(14):13158-13175. https://doi.org/10.1021/acsnano.2c12123.

[227] Ghosh S, Javia A, Shetty S, et al. Triple negative breast cancer and non-small cell lung cancer: clinical challenges and nano-formulation approaches. J Control Release. 2021; 337:27-58. https://doi.org/10.1016/j.jconrel.2021.07.014.

[228] Roque MC, da Silva CD, Lempek MR, et al. Preclinical toxicological study of long-circulating and fusogenic liposomes co-encapsulating paclitaxel and doxorubicin in synergic ratio. Biomed Pharmacother. 2021;144:112307. https://doi.org/10.1016/j.biopha.2021.112307.

[229] Bottger R, Pauli G, Chao PH, et al. Lipid-based nanoparticle technologies for liver targeting. Adv Drug Deliv Rev. 2020;154-155:79-101. https://doi.org/10.1016/j.addr.2020.06.017.

[230] Sun L, Liu H, Ye Y, et al.Smart nanoparticles for cancer therapy. Signal Transduct Target Ther. 2023; 8(1):418. https://doi.org/10.1038/s41392-023-01642-x.

[231] Fan Z, Sun L, Huang Y, et al. Bioinspired fluorescent dipeptide nanoparticles for targeted cancer cell imaging and real-time monitoring of drug release. Nat Nanotechnol. 2016; 11(4):388-394. https://doi.org/10.1038/nnano.2015.312.

[232] Liu Y, Qiao Z, Gao J, et al. Hydroxyapatite-bovine serum albumin-paclitaxel nanoparticles for locoregional treatment of osteosarcoma. Adv Healthc Mater. 2021; 10(2):e2000573. https://doi.org/10.1002/adhm.202000573.

[233] Zhu L, Li Y, Jiang M, et al. Self-assembly of precisely fluorinated albumin for dual imaging-guided synergistic chemo-photothermal-photodynamic cancer therapy. ACS Appl Mater Interfaces. 2023; 15(2):2665-2678. https://doi.org/10.1021/acsami.2c19161.

[234] Martinez-Relimpio AM, Benito M, Perez-Izquierdo E, et al. Paclitaxel-loaded folate-targeted albumin-alginate nanoparticles crosslinked with ethylenediamine. synthesis and in vitro characterization. Polymers (Basel). 2021; 13(13):2083. https://doi.org/10.3390/polym13132083.

[235] Vishwanath K, Wilson B, Geetha KM, et al. Polysorbate 80-coated albumin nanoparticles to deliver paclitaxel into the brain to treat glioma. Ther Deliv. 2023; 14(3):193-206. https://doi.org/10.4155/tde-2022-0056.

[236] Gao G, Zhou W, Jiang X, et al. Bovine serum albumin and folic acid-modified aurum nanoparticles loaded with paclitaxel and curcumin enhance radiotherapy sensitization for esophageal cancer. Int J Radiat Biol. 2024; 100(3):411-419. https://doi.org/10.1080/09553002.2023.2281524.

[237] Girase ML, Sugandhi VV, Ige PP, et al. Design of surface tailored carboxymethyl dextran-protein based nanoconjugates for paclitaxel: spectroscopical characterizations and cytotoxicity assay. Int J Biol Macromol. 2022; 222(Pt B):1818-1829. https://doi.org/10.1016/j.ijbiomac.2022.09.271.

[238] Zhou K, Zhu Y, Chen X, et al. Redox- and MMP-2-sensitive drug delivery nanoparticles based on gelatin and albumin for tumor targeted delivery of paclitaxel. Mater Sci Eng C Mater Biol Appl. 2020;114:111006. https://doi.org/10.1016/j.msec.2020.111006.

[239] Song N, Sun Z, Wang B, et al. Suicide gene delivery by morphology-adaptable enantiomeric peptide assemblies for combined ovarian cancer therapy. Acta Biomater. 2024; 175:250-261. https://doi.org/10.1016/j.actbio.2023.12.020.

[240] Hu Q, Li H, Wang L, et al.DNA nanotechnology-enabled drug delivery systems. Chem Rev. 2019; 119(10):6459-6506. https://doi.org/10.1021/acs.chemrev.7b00663.

[241] Seeman NC.Nucleic acid junctions and lattices. J Theor Biol. 1982; 99(2):237-247. https://doi.org/10.1016/0022-5193(82)90002-9.

[242] Chen JH, Seeman NC. Synthesis from DNA of a molecule with the connectivity of a cube. Nature. 1991; 350(6319):631-633. https://doi.org/10.1038/350631a0.

[243] Winfree E, Liu F, Wenzler LA, et al. Design and self-assembly of two-dimensional DNA crystals. Nature. 1998; 394(6693):539-544. https://doi.org/10.1038/28998.

[244] Guo Y, Zhang J, Ding F, et al. Stressing the role of DNA as a drug carrier: synthesis of DNA-drug conjugates through grafting chemotherapeutics onto phosphorothioate oligonucleotides. Adv Mater. 2019; 31(16):e1807533. https://doi.org/10.1002/adma.201807533.

[245] Xie X, Shao X, Ma W, et al. Overcoming drug-resistant lung cancer by paclitaxel loaded tetrahedral DNA nanostructures. Nanoscale. 2018; 10(12):5457-5465. https://doi.org/10.1039/c7nr09692e.

[246] Shi S, Fu W, Lin S, et al. Targeted and effective glioblastoma therapy via aptamer-modified tetrahedral framework nucleic acid-paclitaxel nanoconjugates that can pass the blood brain barrier. Nanomedicine. 2019;21:102061. https://doi.org/10.1016/j.nano.2019.102061.

[247] Guo W, Mashimo Y, Kobatake E, et al. Construction of DNA-displaying nanoparticles by enzymatic conjugation of DNA and elastin-like polypeptides using a replication initiation protein. Nanotechnology. 2020; 31(25):255102. https://doi.org/10.1088/1361-6528/ab8042.

[248] Kianfar E, Hajimirzaee S, Mousavian S, et al. Zeolite-based catalysts for methanol to gasoline process: a review. Microchem J. 2020;156:104822. https://doi.org/10.1016/j.microc.2020.104822.

[249] Kianfar E, Cao V. Polymeric membranes on base of polymethyl methacrylate for air separation: a review. J Mater Res Technol. 2021; 10:1437-1461. https://doi.org/10.1016/j.jmrt.2020.12.061.

[250] Zeiri O. Metallic-nanoparticle-based sensing: utilization of mixed-ligand monolayers. ACS Sens. 2020; 5(12):3806-3820. https://doi.org/10.1021/acssensors.0c02124.

[251] Paciotti GF, Myer L, Weinreich D, et al. Colloidal gold: a novel nanoparticle vector for tumor directed drug delivery. Drug Deliv. 2004; 11(3):169-183. https://doi.org/10.1080/10717540490433895.

[252] Cai Q, Li X, Xiong H, et al. Optical blood-brain-tumor barrier modulation expands therapeutic options for glioblastoma treatment. Nat Commun. 2023; 14(1):4934. https://doi.org/10.1038/s41467-023-40579-1.

[253] Wang Y, Pasternak M, Sathiyamoorthy K, et al. Anti-HER2 PLGA-PEG polymer nanoparticle containing gold nanorods and paclitaxel for laser-activated breast cancer detection and therapy. Biomed Opt Express. 2021; 12(4):2171-2185. https://doi.org/10.1364/BOE.419252.

[254] Irani M, Nodeh SM. PVA/kappa-carrageenan/Au/camptothecin/pegylated-polyurethane/paclitaxel nanofibers against lung cancer treatment. RSC Adv. 2022; 12(25):16310-16318. https://doi.org/10.1039/d2ra02150a.

[255] Alsadooni JFK, Haghi M, Barzegar A, et al. The effect of chitosan hydrogel containing gold nanoparticle complex with paclitaxel on colon cancer cell line. Int J Biol Macromol. 2023;247:125612. https://doi.org/10.1016/j.ijbiomac.2023.125612.

[256] Zhan H, Song W, Gu M, et al. A new gold nanoparticles and paclitaxel co-delivery system for enhanced anti-cancer effect through chemo-photothermal combination. J Biomed Nanotechnol. 2022; 18(4):957-975. https://doi.org/10.1166/jbn.2022.3309.

[257] Lee YJ, Kim YJ, Park Y. Folic acid and chitosan-functionalized gold nanorods and triangular silver nanoplates for the delivery of anticancer agents. Int J Nanomedicine. 2022; 17:1881-1902. https://doi.org/10.2147/IJN.S354866.

[258] Hao Y, Chen Y, He X, et al. RGD peptide modified platinum nanozyme co-loaded glutathione-responsive prodrug nanoparticles for enhanced chemo-photodynamic bladder cancer therapy. Biomaterials. 2023;293:121975. https://doi.org/10.1016/j.biomaterials.2022.121975.

[259] Farka Z, Jurik T, Kovar D, et al. Nanoparticle-based immunochemical biosensors and assays: recent advances and challenges. Chem Rev. 2017; 117(15):9973-10042. https://doi.org/10.1021/acs.chemrev.7b00037.

[260] Wang Z, Xianyu Y, Liu W, et al. Nanoparticles-enabled surface-enhanced imaging ellipsometry for amplified biosensing. Anal Chem. 2019; 91(10):6769-6774. https://doi.org/10.1021/acs.analchem.9b00846.

[261] Li YE. Sustainable biomass materials for biomedical applications. ACS Biomater Sci Eng. 2019; 5(5):2079-2092. https://doi.org/10.1021/acsbiomaterials.8b01634.

[262] Estrader M, Soulantica K, Chaudret B. Organometallic synthesis of magnetic metal nanoparticles. Angew Chem Int Edit Engl. 2022; 61(35):e202207301. https://doi.org/10.1002/anie.202207301.

[263] Rivera-Rodriguez A, Chiu-Lam A, Morozov VM, et al. Magnetic nanoparticle hyperthermia potentiates paclitaxel activity in sensitive and resistant breast cancer cells. Int J Nanomedicine. 2018; 13:4771-4779. https://doi.org/10.2147/IJN.S171130.

[264] Ni Y, Deng P, Yin R, et al. Effect and mechanism of paclitaxel loaded on magnetic Fe₃O₄@mSiO₂-NH₂-FA nanocomposites to MCF-7 cells. Drug Deliv. 2023; 30(1):64-82. https://doi.org/10.1080/10717544.2022.2154411.

[265] Tan X, Li S, Sheng R, et al. Biointerfacial giant capsules with high paclitaxel loading and magnetic targeting for breast tumor therapy. J Colloid Interface Sci. 2023; 633:1055-1068. https://doi.org/10.1016/j.jcis.2022.11.151.

[266] Manjusha V, Rajeev MR, Anirudhan TS. Magnetic nanoparticle embedded chitosan-based polymeric network for the hydrophobic drug delivery of paclitaxel. Int J Biol Macromol. 2023;235:123900. https://doi.org/10.1016/j.ijbiomac.2023.123900.

[267] Tran TT, Tran PH, Yoon TJ, et al. Fattigation-platform theranostic nanoparticles for cancer therapy. Mater Sci Eng C Mater Biol Appl. 2017; 75:1161-1167. https://doi.org/10.1016/j.msec.2017.03.012.

[268] Oliveira RR, Cintra ER, Sousa-Junior AA, et al. Paclitaxel-loaded lipid-coated magnetic nanoparticles for dual chemo-magnetic hyperthermia therapy of melanoma. Pharmaceutics. 2023; 15(3):818. https://doi.org/10.3390/pharmaceutics15030818.

[269] Lamsam L, Johnson E, Connolly ID, et al. A review of potential applications of MR-guided focused ultrasound for targeting brain tumor therapy. Neurosurg Focus. 2018; 44(2):E10. https://doi.org/10.3171/2017.11.FOCUS17620.

[270] Cong C, He Y, Zhao S, et al. Diagnostic and therapeutic nanoenzymes for enhanced chemotherapy and photodynamic therapy. J Mater Chem B. 2021; 9(18):3925-3934. https://doi.org/10.1039/d0tb02791j.

[271] Yu H, Wang Y, Wang S, et al. Paclitaxel-loaded core-shell magnetic nanoparticles and cold atmospheric plasma inhibit non-small cell lung cancer growth. ACS Appl Mater Interfaces. 2018; 10(50):43462-43471. https://doi.org/10.1021/acsami.8b16487.

[272] Ursachi VC, Dodi G, Rusu AG, et al. Paclitaxel-loaded magnetic nanoparticles based on biotinylated n-palmitoyl chitosan: synthesis, characterization and preliminary in vitro studies. Molecules. 2021; 26(11):3467. https://doi.org/10.3390/molecules26113467.

[273] AshaRani PV, Low KMG, Hande MP, et al. Cytotoxicity and genotoxicity of silver nanoparticles in human cells. ACS Nano. 2009; 3(2):279-290. https://doi.org/10.1021/nn800596w.

[274] Bhargava A, Dev A, Mohanbhai SJ, et al. Pre-coating of protein modulate patterns of corona formation, physiological stability and cytotoxicity of silver nanoparticles. Sci Total Environ. 2021;772:144797. https://doi.org/10.1016/j.scitotenv.2020.144797.

[275] Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020; 367(6478):eaau6977. https://doi.org/10.1126/science.aau6977.

[276] Wang P, Wang H, Huang Q, et al. Exosomes from M1-polarized macrophages enhance paclitaxel antitumor activity by activating macrophages-mediated inflammation. Theranostics. 2019; 9(6):1714-1727. https://doi.org/10.7150/thno.30716.

[277] Wang J, Yeung BZ, Cui M, et al. Exosome is a mechanism of intercellular drug transfer: application of quantitative pharmacology. J Control Release. 2017; 268:147-158. https://doi.org/10.1016/j.jconrel.2017.10.020.

[278] Saari H, Lisitsyna E, Rautaniemi K, et al. FLIM reveals alternative EV-mediated cellular up-take pathways of paclitaxel. J Control Release. 2018; 284:133-143. https://doi.org/10.1016/j.jconrel.2018.06.015.

[279] Wang J, Yeung BZ, Wientjes MG, et al. A Quantitative pharmacology model of exosome-mediated drug efflux and perturbation-induced synergy. Pharmaceutics. 2021; 13(7):997. https://doi.org/10.3390/pharmaceutics13070997.

[280] Han D, Wang K, Zhang T, et al. Natural killer cell-derived exosome-entrapped paclitaxel can enhance its anti-tumor effect. Eur Rev Med Pharmacol Sci. 2020; 24(10):5703-5713. https://doi.org/10.26355/eurrev_202005_21362.

[281] Kandimalla R, Aqil F, Alhakeem SS, et al. Targeted oral delivery of paclitaxel using colostrum-derived exosomes. Cancers (Basel). 2021; 13(15):3700. https://doi.org/10.3390/cancers13153700.

[282] Wang K, Ye H, Zhang X, et al. An exosome-like programmable-bioactivating paclitaxel prodrug nanoplatform for enhanced breast cancer metastasis inhibition. Biomaterials. 2020;257:120224. https://doi.org/10.1016/j.biomaterials.2020.120224.

[283] Al Faruque H, Choi ES, Kim JH, et al. Enhanced effect of autologous EVs delivering paclitaxel in pancreatic cancer. J Control Release. 2022; 347:330-346. https://doi.org/10.1016/j.jconrel.2022.05.012.

[284] Huang H, Shao L, Chen Y, et al. Synergistic strategy with hyperthermia therapy based immunotherapy and engineered exosomes-liposomes targeted chemotherapy prevents tumor recurrence and metastasis in advanced breast cancer. Bioeng Transl Med. 2022; 7(2):e10284. https://doi.org/10.1002/btm2.10284.

[285] Pinheiro A, Silva AM, Teixeira JH, et al. Extracellular vesicles: intelligent delivery strategies for therapeutic applications. J Control Release. 2018; 289:56-69. https://doi.org/10.1016/j.jconrel.2018.09.019.

[286] Alqahtani FY, Aleanizy FS, El Tahir E, et al. Paclitaxel. Profiles Drug Subst Excip Relat Methodol. 2019; 44:205-238. https://doi.org/10.1016/bs.podrm.2018.11.001.

[287] Yu DL, Lou ZP, Ma FY, et al. The interactions of paclitaxel with tumour microenvironment. Int Immunopharmacol. 2022;105:108555. https://doi.org/10.1016/j.intimp.2022.108555.

[288] Chen Y, Liu R, Li C, et al. Nab-paclitaxel promotes the cancer-immunity cycle as a potential immunomodulator. Am J Cancer Res. 2021; 11(7):3445-3460. https://doi.org/ajcr0129309.

[289] Shurin MR, Yurkovetsky ZR, Tourkova IL, et al. Inhibition of CD 40 expression and CD40-mediated dendritic cell function by tumor-derived IL-10. Int J Cancer. 2002; 101(1):61-68. https://doi.org/10.1002/ijc.10576.

[290] Hu Y, Lou X, Zhang K, et al. Tumor necrosis factor receptor 2 promotes endothelial cell-mediated suppression of CD8⁺ T cells through tuning glycolysis in chemoresistance of breast cancer. J Transl Med. 2024; 22(1):672. https://doi.org/10.1186/s12967-024-05472-5.

[291] Zhang W, Zhai Y, Cai Y, et al. Enhancing immunotherapy efficacy against MHC-I deficient triple-negative breast cancer using LCL161-loaded macrophage membrane-decorated nanoparticles. Acta Pharm Sin B. 2024; 14(7):3218-3231. https://doi.org/10.1016/j.apsb.2024.04.009.

[292] Choi Y, Kim SA, Jung H, et al. Novel insights into paclitaxel’s role on tumor-associated macrophages in enhancing PD-1 blockade in breast cancer treatment. J Immunother Cancer. 2024; 12(7):e008864. https://doi.org/10.1136/jitc-2024-008864.

[293] Zhou M, Wang X, Lin S, et al. Multifunctional sting-activating Mn₃O₄@Au-dsDNA/DOX nanoparticle for antitumor immunotherapy. Adv Healthc Mater. 2020; 9(13):e2000064. https://doi.org/10.1002/adhm.202000064.

[294] Lan Y, Liang Q, Sun Y, et al. Codelivered chemotherapeutic doxorubicin via a dual-functional immunostimulatory polymeric prodrug for breast cancer immunochemotherapy. ACS Appl Mater Interfaces. 2020; 12(28):31904-31921. https://doi.org/10.1021/acsami.0c06120.

[295] Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018; 379(22):2108-2121. https://doi.org/10.1056/NEJMoa1809615.

[296] Gu W, Meng F, Haag R, et al. Actively targeted nanomedicines for precision cancer therapy: concept, construction, challenges and clinical translation. J Control Release. 2021; 329:676-695. https://doi.org/10.1016/j.jconrel.2020.10.003.

[297] Wang Y, Yu J, Li D, et al. Paclitaxel derivative-based liposomal nanoplatform for potentiated chemo-immunotherapy. J Control Release. 2022; 341:812-827. https://doi.org/10.1016/j.jconrel.2021.12.023.

[298] Emens LA, Cruz C, Eder JP, et al. Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: a phase 1 study. JAMA Oncol. 2019; 5(1):74-82. https://doi.org/10.1001/jamaoncol.2018.4224.

[299] Brewer M, Angioli R, Scambia G, et al. Front-line chemo-immunotherapy with carboplatin-paclitaxel using oregovomab indirect immunization in advanced ovarian cancer: a randomized phase II study. Gynecol Oncol. 2020; 156(3):523-529. https://doi.org/10.1016/j.ygyno.2019.12.024.

[300] Zhang F, Parayath NN, Ene CI, et al. Genetic programming of macrophages to perform anti-tumor functions using targeted mRNA nanocarriers. Nat Commun. 2019; 10(1):3974. https://doi.org/10.1038/s41467-019-11911-5.

[301] Wu D, Li Y, Xu P, et al. Neoadjuvant chemo-immunotherapy with camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced squamous cell carcinoma of the head and neck: a pilot phase II trial. Nat Commun. 2024; 15(1):2177. https://doi.org/10.1038/s41467-024-46444-z.

[302] Dai W, Qiu X, Lu C, et al. AGIG chemo-immunotherapy in patients with advanced pancreatic cancer: a single-arm, single-center, phase 2 study. Front Oncol. 2021;11:693386. https://doi.org/10.3389/fonc.2021.693386.

[303] Jiao J, Li WW, Shang YH, et al. Clinical effects of chemotherapy combined with immunotherapy in patients with advanced NSCLC and the effect on their nutritional status and immune function. Pak J Med Sci. 2023; 39(2):404-408. https://doi.org/10.12669/pjms.39.2.6365.

[304] Zhang Z, Liu N, Sun M. Research progress of immunotherapy for gastric cancer. Technol Cancer Res Treat. 2023;22:15330338221150555. https://doi.org/10.1177/15330338221150555.

[305] Jokhadze N, Das A, Dizon DS. Global cancer statistics: a healthy population relies on population health. CA Cancer J Clin. 2024; 74(3):224-226. https://doi.org/10.3322/caac.21838.