Hyaluronic Acid-Based Nanogel–Drug Conjugates with Enhanced Anticancer Activity Designed for the Targeting of CD44-Positive and Drug-Resistant Tumors

Abstract

Many drug-resistant tumors and cancer stem cells (CSC) express elevated levels of CD44 receptor, a cellular glycoprotein binding hyaluronic acid (HA). Here, we report the synthesis of nanogel-drug conjugates based on membranotropic cholesteryl-HA (CHA) for efficient targeting and suppression of drug-resistant tumors. These conjugates significantly increased the bioavailability of poorly soluble drugs with previously reported activity against CSC, such as etoposide, salinomycin, and curcumin. The small nanogel particles (diam. 20–40 nm) with a hydrophobic core and high drug loads (up to 20%) formed after ultrasonication and demonstrated a sustained drug release following the hydrolysis of biodegradable ester linkage. Importantly, CHA-drug nanogels demonstrated 2–7 times higher cytotoxicity in CD44-expressing drug-resistant human breast and pancreatic adenocarcinoma cells compared to free drugs and non-modified HA-drug conjugates. These nanogels were efficiently internalized via CD44 receptor-mediated endocytosis and simultaneous interaction with the cancer cell membrane. Anchoring by cholesterol moieties in the cellular membrane after nanogel unfolding evidently caused more efficient drug accumulation in cancer cells compared to non-modified HA-drug conjugates. CHA-drug nanogels were able to penetrate multicellular cancer spheroids and displayed higher cytotoxic effect in the system modeling tumor environment than both free drugs and HA-drug conjugates. In conclusion, the proposed design of nanogel-drug conjugates allowed us to significantly enhance drug bioavailability, cancer cell targeting, and the treatment efficacy against drug-resistant cancer cells and multicellular spheroids.

GE11 peptide modified and reduction-responsive hyaluronic acid-based nanoparticles induced higher efficacy of doxorubicin for breast carcinoma therapy

“…It was demonstrated that the degree of modification of NPs with cholesteryl groups must range from 3% to 10% to ensure good solubility and effective cellular uptake. 48 The PS of HA-ssChol NPs decreased with increase in the DS of cholesterol group, suggesting that higher hydrophobicity induces easier formation of NPs and more compact interaction in hydrophobic inner core. According to the previous reports, NPs with size approximately 100-200 nm were likely to exhibit long blood circulation effect by avoiding the recognition of reticuloendothelial system (RES) and accumulate in tumors by "leaky" vasculature through enhanced permeability and retention (EPR) effect.…”

Nanomedicine-mediated cancer stem cell therapy

“…This targeted nanoparticle could effectively decrease the number of mammospheres and colonies formed in vitro, and in vivo studies in the MDA-MB-231 xenograft model showed that CD133NPs can markedly decrease the CSC population and improve therapeutic efficacy compared to that with free counterpart and non-targeted drug-loaded nanoparticles [159]. Hyaluronic acid (HA), an extracellular glycosaminoglycan matrix component, has been reported as a ligand binding to CD44, which is overexpressed in the majority of CSCs during carcinogenesis [129]. Such binding characteristics of HA can provide potential strategies for the development of CSCtargeted therapies.…”

Targeted and controlled drug delivery system loading artersunate for effective chemotherapy on CD44 overexpressing cancer cells

“…Hyaluronic acid (HA), a high molecular linear glycosaminoglycan composed of repeated disaccharide units of b-1,4-D-glucuronic acid-b-1,3-Nacetyl-D-glucosamine, highly binds with the CD44 receptor, which is expressed in different tissues, especially on the cancer cell surface. It thus can be used as a tumortargeting moiety (Park et al 2014a;Huang et al 2014;Wei et al 2013),…”