Abstract
Low molecular weight gelators (LMWGs) of chemotherapeutic drugs represent a valid alternative to the existing polymer-based formulations used for targeted delivery of anticancer drugs. Herein we report the design and development of novel self-assembling gelators of the antitumor benzothiazole 5F 203 (1). Two different types of derivatives of 1 were synthesized, formed by an amide (2) and a carbamate (3a-3d) linker, respectively, which showed potent in vitro antitumor activity against MCF-7 mammary and IGROV-1 ovarian carcinoma cells. In contrast, MRC-5 fibroblasts were inherently resistant to the above derivatives (GI50 > 10 μM), thus revealing stark selectivity against the malignant cell lines over the nontransformed fibroblasts. Western blots assays demonstrated induction of CYP1A1 by 1 and its derivatives only in sensitive malignant cells (MCF-7), corroborating conservation of a CYP1A1-mediated mechanism of action. The ability to form stable gels under relatively high strains was supported by rheological tests; in addition, their inner morphology was characterized as possessing a crossed-linked nanostructure, with the formation of thick aggregates with variable widths between 1100 and 400 nm and lengths from 8 to 32 μm. Finally, in vitro dissolution studies proved the ability of hydrogel 2 to release 48% of 2 within 80 h, therefore demonstrating its ability to act as a platform for localized delivery.
Highlights
Low molecular weight gelators (LMWGs) have recently become an attractive group of soft biomaterials with exceptional tunable properties that make them suitable for drug delivery applications.[1,2,3] They have been reported to be viable alternatives to the extensively explored polymer-based drug delivery systems, due to their biocompatibility, biodegradability and ability to control drug release
LMWGs of chemotherapeutic drugs represent a valid alternative to the existing polymer-based formulations used for targeted delivery of anticancer drugs, because of their higher drug loading, lack of excipients, and consequent increased in situ drug concentrations.[3]
The design choice was based on the analysis of the most commonly used linkers in the synthesis of stable prodrugs of amines, such as amides, esters, carbamates, phosphates or oximes.[23]
Summary
Low molecular weight gelators (LMWGs) have recently become an attractive group of soft biomaterials with exceptional tunable properties that make them suitable for drug delivery applications.[1,2,3] They have been reported to be viable alternatives to the extensively explored polymer-based drug delivery systems, due to their biocompatibility, biodegradability and ability to control drug release. 3, 6, 7 In particular, LMWGs of chemotherapeutic drugs represent a valid alternative to the existing polymer-based formulations used for targeted delivery of anticancer drugs, because of their higher drug loading, lack of excipients, and consequent increased in situ drug concentrations.[3] To date, most of the examples in the literature of chemotherapeutic LMWGs are those reported by Xu and Yang, based on the anticancer drug paclitaxel. They exploited short peptides and folic acid as functional moieties to create several examples of Taxol®
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