Developing Body-Components-Based Theranostic Nanoparticles for Targeting Ovarian Cancer.

Ovarian cancer mortality is the highest among gynecologic malignancies. Hence, the major challenges are early diagnosis and efficient targeted therapy. Herein, we devised model theranostic nanoparticles (NPs) for combined diagnostics and delivery of chemotherapeutics, targeted to ovarian cancer cells. These NPs were made of natural biocompatible and biodegradable body components: hyaluronic acid (HA) and serum albumin (SA). The hydrophilic HA served as the targeting ligand for cancer cells overexpressing CD44, the HA receptor. SA, the natural carrier of various ligands through the blood, served as the hydrophobic block of the self-assembling block copolymeric Maillard-conjugates. We show the successful construction of fluorescently-labeled SA-HA conjugate-based theranostic NPs, their loading with paclitaxel (PTX) (association constant (8.6 ± 0.8) × 103 M-1, maximal loading capacity of 4:1 PTX:BSA, and 96% encapsulation efficiency), selective internalization and cytotoxicity to CD44-overexpressing ovarian cancer cells (IC50: 26.4 ± 2.3 nM, compared to 115.0 ± 17.4 of free PTX, and to 58.6 ± 19.7 nM for CD44-lacking cognate ovarian cancer cells). Fluorescein isothiocyanate (FITC) was used for in vitro imaging, whereas long wavelength fluorophores or other suitable tracers would be used for future in vivo diagnostic imaging. Collectively, our findings demonstrate that fluorescent HA-SA NPs harboring a cytotoxic drug cargo can specifically target, label CD44-expressing ovarian cancer cells and efficiently eradicate them.

Albumin and Hyaluronic Acid-Coated Superparamagnetic Iron Oxide Nanoparticles Loaded with Paclitaxel for Biomedical Applications.

Super paramagnetic iron oxide nanoparticles (SPION) were augmented by both hyaluronic acid (HA) and bovine serum albumin (BSA), each covalently conjugated to dopamine (DA) enabling their anchoring to the SPION. HA and BSA were found to simultaneously serve as stabilizing polymers of Fe3O4·DA-BSA/HA in water. Fe3O4·DA-BSA/HA efficiently entrapped and released the hydrophobic cytotoxic drug paclitaxel (PTX). The relative amount of HA and BSA modulates not only the total solubility but also the paramagnetic relaxation properties of the preparation. The entrapping of PTX did not influence the paramagnetic relaxation properties of Fe3O4·DA-BSA. Thus, by tuning the surface structure and loading, we can tune the theranostic properties of the system.

Hyaluronic acid-serum albumin conjugate-based nanoparticles for targeted cancer therapy.

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.