Hyaluronic acid is a natural anionic polysaccharide (a glycosaminoglycan), and a chief component of the extracellular matrix in the human body. It contributes significantly to cell proliferation and migration, hence is sought by certain cancer types for tumor development and metastasis. Hence, such tumor cells overexpress the CD44 receptor to uptake HA from the circulation.
Conventional chemotherapy requires sequential high doses of drug combinations which cause severe toxic side effects and exhibits limited efficacy due to the frequent emergence of drug resistance phenomena, particularly multidrug resistance (MDR), i.e. efflux of a multitude of drugs by ATP driven transporters of the ABC superfamily, such as P-glycoprotein. An additional challenge posed by cancer is the diagnostic localization of tumors and their distant metastases.
In the current research we developed a novel nanomedicine platform which we term a “quadrugnostic nanoparticle”(QNPs), that is envisioned to be the next generation platform for simultaneous cancer diagnostics and therapeutics (theranostics): These QNPs harbor in the same vehicle, four synergistic components, including a selective targeting moiety, a cytotoxic drug, a chemosensitizer for overcoming a well-defined mechanism of MDR, and a diagnostic element for the localization of the malignant tumor and its distant metastases. The prototype QNPs are based on self-assembling conjugates of HA and a partly hydrophobic molecule (bovine serum albumin (BSA)). HA serves here in a dual function, as it also acts as the active-targeting moiety, targeting cancer cells overexpressing CD44 (e.g. ovarian cancer). Moreover, this QNP harbors a cytotoxic drug, and a chemosensitizer that overcomes MDR by blocking a specific ABC drug efflux transporter. The QNP are decorated by an imaging-aid. Preliminary results reveal that the conjugates formed self-assembled NPs and bound hydrophobic cytotoxic drugs (Paclitaxel and C-1375 Imidazoacridinone). BSA-HA conjugates are selectively taken up by cells overexpressing CD44 receptor but not by cells lacking CD44.
