Abstract
Multiple carcinomas including breast, ovarian, colon, lung and stomach cancer, overexpress the hyaluronic acid (HA) receptor, CD44. Overexpression of CD44 contributes to key cancer processes including tumor invasion, metastasis, recurrence, and chemoresistance. Herein, we devised novel targeted nanoparticles (NPs) for delivery of anticancer chemotherapeutics, comprised of self-assembling Maillard reaction-based conjugates of HA and bovine serum albumin (BSA). HA served as the hydrophilic block, and as the ligand for actively targeting cancer cells overexpressing CD44. We demonstrate that Maillard reaction-based covalent conjugates of BSA-HA self-assemble into NPs, which efficiently entrap hydrophobic cytotoxic drugs including paclitaxel and imidazoacridinones. Furthermore, BSA-HA conjugates stabilized paclitaxel and prevented its aggregation and crystallization. The diameter of the NPs was < 15 nm, thus enabling CD44 receptor-mediated endocytosis. These NPs were selectively internalized by ovarian cancer cells overexpressing CD44, but not by cognate cells lacking this HA receptor. Moreover, free HA abolished the endocytosis of drug–loaded BSA-HA conjugates. Consistently, drug-loaded NPs were markedly more cytotoxic to cancer cells overexpressing CD44 than to cells lacking CD44, due to selective internalization, which could be competitively inhibited by excess free HA. Finally, a CD44-targeted antibody which blocks receptor activity, abolished internalization of drug-loaded NPs. In conclusion, a novel cytotoxic drug-loaded nanomedicine platform has been developed, which is based on natural biocompatible biopolymers, capabale of targeting cancer cells with functional surface expression of CD44.
Highlights
Active targeting based on molecular recognition is an effective modality to enhance drug selectivity and efficacy, and to reduce chemotherapeutic drug doses and side effects [1,2,3]
We demonstrate that Maillard reaction-based covalent conjugates of bovine serum albumin (BSA)-hyaluronic acid (HA) self-assemble into NPs, which efficiently entrap hydrophobic cytotoxic drugs including paclitaxel and imidazoacridinones
BSA-HA Maillard conjugates were prepared as described in the Methods section, and analyzed by SDS– PAGE
Summary
Active targeting based on molecular recognition is an effective modality to enhance drug selectivity and efficacy, and to reduce chemotherapeutic drug doses and side effects [1,2,3]. One approach to achieve active targeting is by designing NPs decorated with hyaluronic acid (HA), to target the CD44 receptor, which is overexpressed on the surface of various carcinomas [4, 5]. HA is a glycosaminoglycan of the extracellular matrix consisting of tandem repeats of D-glucuronic acid and N-acetyl-Dglucosamine [6]. Many of the downstream pathways following CD44 activation become deregulated in cancer, leading to tumor growth, progression and metastasis [5, 8]. Expression of the standard CD44 form is up-regulated in various carcinomas including breast, ovarian, colon, lung and stomach cancer [9, 10]. HA oligosaccharides show high affinity to CD44 receptors [5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
