Abstract
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.
Highlights
Cancer is a global disease, which causes 8.2 million human deaths each year
hyaluronic acid (HA) was first covalently attached to a model diagnostic tracer, Fluorescein isothiocyanate (FITC), and to bovine serum albumin (BSA) via the Maillard reaction
Receptor-mediated endocytosis of FITC-HA-BSA conjugates to human ovarian cancer SKOV3 cells was via the CD44 receptor
Summary
Cancer is a global disease, which causes 8.2 million human deaths each year. Five percent of all cancer deaths among women are attributable to ovarian cancer [1]. Anti-microtubule agents of the class of Taxanes, including paclitaxel (PTX), docetaxel and cabazitaxel, are effective hydrophobic chemotherapeutic drugs that are widely used in the treatment of a spectrum of carcinomas including ovarian, breast, lung, stomach, prostate and head and neck cancers [9]. Given the lack of PTX selectivity, relatively high drug doses are administered, causing severe untoward toxicity. Various mechanisms of chemoresistance have been documented to these anti-microtubule agents. To overcome these impediments, a major goal of drug delivery systems (DDS) is to carry the drug selectively to the target tumor, achieve intracellular drug internalization and tumor cell eradication. Passive targeting into tumors may be achieved by long-circulating nanoparticles (NPs) [5,11], entering the tumor through its leaky vasculature, and remaining there due to its poor lymphatic drainage, based on the enhanced permeability and retention (EPR) effect [2,12]
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