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Synthesis of Linear, β-Cyclodextrin-Based Polymers and Their Camptothecin Conjugates

Cheng, Jianjun and Khin, Kay T. and Jensen, Gregory S. and Liu, Aijie and Davis, Mark E. (2003) Synthesis of Linear, β-Cyclodextrin-Based Polymers and Their Camptothecin Conjugates. Bioconjugate Chemistry, 14 (5). pp. 1007-1017. ISSN 1043-1802. doi:10.1021/bc0340924. https://resolver.caltech.edu/CaltechAUTHORS:20170125-084653099

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Abstract

6^A,6^D-Bis-(2-amino-2-carboxylethylthio)-6^A,6^D-dideoxy-β-cyclodextrin 1, a diamino acid derivative of β-cyclodextrin, is synthesized and condensed with difunctionalized PEG comonomers to give linear, high molecular weight (M_w over 50 kDa) β-cyclodextrin-based polymers (2−4) with pendant functionality (carboxylate). 2−4 are all highly soluble in aqueous solutions (over 200 mg/mL). 20-O-trifluoroglycinylcamptothecin, 5a, and 20-O-trifluoroglycinylglycinylglycinylcamptothecin, 5b, are synthesized and conjugated to 2 to give polymer−camptothecin (CPT) prodrugs. The solubility of CPT is increased by more than three orders of magnitude when it is conjugated to 2. The rates of CPT release from the conjugates HGGG6 (high molecular weight polymer (M_w 97 kDa), glyglygly linker and 6 wt % CPT loading) and HG6 (high MW polymer (M_w 97 kDa), gly linker and 6 wt % CPT loading) in either mouse or human plasma are dramatically accelerated over the rates of pure hydrolysis at pH = 7.4, indicating the presence of enzymatic cleavage as a rate-determining step at this pH in the release of the CPT. The pH of aqueous solution has a large effect on hydrolysis rate of CPT from HGGG6 and HG6; the lower the pH, the slower the rate in the range at 4.1 ≤ pH ≤ 13.1. The IC50's of polymer 2e, CPT, and the CPT conjugates HG6 and HGGG6 are found to be cell-line dependent with LS174T, HT29, A2780, and PC3 cells using in vitro MTT assays. The parent polymer 2e has very low toxicity to all cultured cells tested.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/bc0340924DOIArticle
http://pubs.acs.org/doi/abs/10.1021/bc0340924PublisherArticle
ORCID:
AuthorORCID
Davis, Mark E.0000-0001-8294-1477
Alternate Title:Synthesis of linear, beta-cyclodextrin-based polymers and their camptothecin conjugates.
Additional Information:© 2003 American Chemical Society. Received 29 May 2003; Published online 27 August 2003; Published in print 1 September 2003. We thank Drs. Nathalie Bellocq, Leonard Borrmann, Christopher Dartt, and Suzie Hwang Pun of Insert Therapeutics, Inc., for their helpful discussions. M. E. Davis is a consultant to and has financial interest in Insert Therapeutics, Inc.
Issue or Number:5
DOI:10.1021/bc0340924
Record Number:CaltechAUTHORS:20170125-084653099
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170125-084653099
Official Citation:Synthesis of Linear, β-Cyclodextrin-Based Polymers and Their Camptothecin Conjugates Jianjun Cheng,†, Kay T. Khin,†, Gregory S. Jensen,†, Aijie Liu,† and, and Mark E. Davis*,‡ Bioconjugate Chemistry 2003 14 (5), 1007-1017 DOI: 10.1021/bc0340924
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:73697
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:25 Jan 2017 19:12
Last Modified:11 Nov 2021 05:20

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