Prodrug Strategies for Paclitaxel

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Abstract

Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule modifications and macromolecule modifications have been developed by many research groups from all over the world. In this review, we discuss the different strategies especially prodrug strategies that are currently used to make paclitaxel more effective.

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Paclitaxel-functionalized gold nanoparticles.

Bishnu P. Khanal, D. Gibson, Eugene Zubarev (2007)

Here we describe the first example of 2 nm gold nanoparticles (Au NPs) covalently functionalized with a chemotherapeutic drug, paclitaxel. The synthetic strategy involves the attachment of a flexible hexaethylene glycol linker at the C-7 position of paclitaxel followed by coupling of the resulting linear analogue to phenol-terminated gold nanocrystals. The reaction proceeds under mild esterification conditions and yields the product with a high molecular weight, while exhibiting an extremely low polydispersity index (1.02, relative to linear polystyrene standards). TGA analysis of the hybrid nanoparticles reveals the content of the covalently attached organic shell as nearly 67% by weight, which corresponds to approximately 70 molecules of paclitaxel per 1 nanoparticle. The presence of a paclitaxel shell with a high grafting density renders the product soluble in organic solvents and allows for detailed (1)H NMR analysis and, therefore, definitive confirmation of its chemical structure. High-resolution TEM was employed for direct visualization of the inorganic core of hybrid nanoparticles, which were found to retain their average size, shape, and high crystallinity after multiple synthetic steps and purifications. The interparticle distance substantially increases after the attachment of paclitaxel as revealed by low-magnification TEM, suggesting the presence of a larger organic shell. The method described here demonstrates that organic molecules with exceedingly complex structures can be covalently attached to gold nanocrystals in a controlled manner and fully characterized by traditional analytical techniques. In addition, this approach gives a rare opportunity to prepare hybrid particles with a well-defined amount of drug and offers a new alternative for the design of nanosized drug-delivery systems.

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Enhanced anticancer activity of nanopreparation containing an MMP2-sensitive PEG-drug conjugate and cell-penetrating moiety.

Tao Wang, Lin Zhu, Vladimir P. Torchilin … (2013)

In response to the challenges of cancer chemotherapeutics, including poor physicochemical properties, low tumor targeting, insufficient tumor cell internalization/bioavailability, and side effects, we developed a unique tumor-targeted micellar drug-delivery platform. Using paclitaxel as a model therapeutic, a nanopreparation composed of a matrix metalloproteinase 2 (MMP2)-sensitive self-assembly PEG 2000-paclitaxel conjugate (as a prodrug and MMP 2-sensitive moiety), transactivating transcriptional activator peptide-PEG1000-phosphoethanolamine (PE) (a cell-penetrating enhancer), and PEG1000-PE (a nanocarrier building block) was prepared. Several major drug delivery strategies, including self-assembly, PEGylation, the enhanced permeability and retention effect, stimulus sensitivity, a cell-penetrating moiety, and the concept of prodrug, were used in design of this nanoparticle in a collaborative manner. The nanopreparation allowed superior cell internalization, cytotoxicity, tumor targeting, and antitumor efficacy in vitro and in vivo over its nonsensitive counterpart, free paclitaxel and conventional micelles. This uniquely engineered nanoparticle has potential for effective intracellular delivery of drug into cancer cells.

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Cytotoxic studies of paclitaxel (Taxol) in human tumour cell lines.

J. E. Liebmann, J A Cook, C. Lipschultz … (1993)

The cytotoxicity of paclitaxel against eight human tumour cell lines has been studied with in vitro clonogenic assays. The fraction of surviving cells fell sharply after exposure for 24 h to paclitaxel concentrations ranging from 2 to 20 nM; the paclitaxel IC50 was found to range between 2.5 and 7.5 nM. Increasing the paclitaxel concentration above 50 nM, however, resulted in no additional cytotoxicity after a 24 h drug exposure. Cells incubated in very high concentrations of paclitaxel (10,000 nM) had an increase in survival compared with cells treated with lower concentrations of the drug. Prolonging the time of exposure of cells to paclitaxel from 24 to 72 h increased cytotoxicity from 5 to 200 fold in different cell lines. Exponentially growing cells were more sensitive to paclitaxel than were cells in the plateau phase of growth. Cremophor EL, the diluent in which the clinical preparation of paclitaxel is formulated, antagonised paclitaxel at concentrations of 0.135% (v/v). These data suggest that paclitaxel will be most effective clinically when there is prolonged exposure of tumour to the drug. Further, it appears that modest concentrations (i.e., 50 nM) should be as effective as higher concentrations of paclitaxel. Finally, we have noted that Cremophor EL is a biologically active diluent and, at high concentrations (0.135% v/v), can antagonise paclitaxel cytotoxicity.

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Author and article information

Contributors

Katalin Prokai-Tatrai: Role: Academic Editor

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 23 May 2016

Publication date Collection: May 2016

Volume: 17

Issue: 5

Electronic Location Identifier: 796

Affiliations

[1 ]Institution for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 999077, China; 15484572@ 123456life.hkbu.edu.hk (Z.M.); lvquanxia@ 123456163.com (Q.L.); ljaaa111@ 123456163.com (J.L.); yaohouzong@ 123456163.com (H.Y.)

[2 ]Research Group of Precision Medicine and Innovative Drug, HKBU (Hong Kong Baptist University) (Haimen) Institute of Science and Technology, Haimen 226100, China; lxqd1@ 123456126.com

[3 ]The State Key Laboratory Base of Novel Functional Materials and Preparation Science, Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China

Author notes

[* ]Correspondence: jiangfenghz@ 123456163.com (F.J.); aipinglu@ 123456hkbu.edu.hk (A.L.); zhangge@ 123456hkbu.edu.hk (G.Z.); Tel.: +86-513-8210-6970 (F.J.); +852-3411-2456 (A.L.); +852-3411-2958 (G.Z.)

[†]

These authors contributed equally to this work.

Article

Publisher ID: ijms-17-00796

DOI: 10.3390/ijms17050796

PMC ID: 4881612

PubMed ID: 27223283

SO-VID: 0ececb42-f150-4ea1-8630-67263bd650a8

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This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

Prodrug Strategies for Paclitaxel

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Abstract

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Higher order chromatin architecture

Most cited references 129

Paclitaxel-functionalized gold nanoparticles.

Enhanced anticancer activity of nanopreparation containing an MMP2-sensitive PEG-drug conjugate and cell-penetrating moiety.

Cytotoxic studies of paclitaxel (Taxol) in human tumour cell lines.

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