Abstract
In order to improve the antitumor activity and water solubility of 10-hydroxycamptothecin (HCPT), a series of novel HCPT conjugates were designed and synthesized by conjugating polyethylene glycol (PEG) to the 10-hydroxyl group of HCPT via a valine spacer. The in vitro stability of these synthesized compounds was determined in pH 7.4 buffer at 37 °C, and the results showed that they released HCPT at different rates. All the compounds demonstrated significant antitumor activity in vitro against K562, HepG2 and HT-29 cells. Among them, compounds, 4a, 4d, 4e and 4f, exhibited 2–5 times higher potency than HCPT. The stability and antitumor activity of these conjugates were found to be closely related to the length of PEG and the linker type, conjugates with a relatively short PEG chain and carbamate linkages (compounds 4a and 4f) exhibited controlled release of HCPT and excellent antitumor in vitro activity.
Highlights
Camptothecin (CPT) and 10-hydroxycamptothecin (HCPT) are natural occurred topoisomerase I inhibitors with strong antitumor activity both in vitro and in vivo [1,2]
Our results demonstrated that the HCPT release and the antitumor activity are strongly dependent on the polyethylene glycol (PEG) length and the linker properties
In order to improve the pharmacokinetic properties of HCPT and find new water soluble camptothecin type drugs with higher potency and lower side effects, eight novel conjugates of HCPT
Summary
Camptothecin (CPT) and 10-hydroxycamptothecin (HCPT) are natural occurred topoisomerase I inhibitors with strong antitumor activity both in vitro and in vivo [1,2]. The clinical use of these two compounds is limited by their low solubility in water and high toxicity. The potential of synthetic macromolecules as carriers of anticancer drugs has attracted immense interest. Polymeric prodrugs of various cytotoxic agents with soluble polymers such as PEG have been extensively investigated. The polymeric conjugates could simultaneously act as both a transport form and a prodrug to enhance drug distribution in tumor sites by enhanced permeability and retention (EPR) effects and improved drug pharmacokinetic properties [3,4,5,6]. In the past few years, CPT has been covalently coupled at C-20 to various water-soluble polymers to improve its solubility [7], i.e., PEG, poly(L-glutamic acid), β-cyclodextrin-based polymers, poly[N-(2-hydroxypropyl)-methacrylamide], poly[(N-carboxybutyl)-L-aspartamide] and poly(amido-amine)
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