Abstract
Abstract One of major challenges of current anticancer therapies is the overcoming of emerging drug resistances and the preventing of tumor relapse. Among different causes of tumor resistance to therapy, the most important is probably the presence of a population of cancer initiating/stem cells (CSC) distinguished from other cancer cells by low metabolic activity, protective apoptotic signaling pathways and overexpression of drug efflux transporters [1, 2]. Many drug-resistant tumors and CSC display the overexpressed levels of CD44 receptor, a cellular glycoprotein binding hyaluronic acid (HA) [3]. The HA-CD44 interaction plays a prominent part in mediating cellular and intercellular events during cancer development. For biomedical applications, HA has been actively studied as a scaffold for tissue engineering and targeting moiety for drug delivery [4]. Here, we report an advanced design of HA-based polymeric nanogel-drug formulations with stronger activity compared to free drugs, which can potentially target CD44-expressing drug-resistant tumor cells. The novel nanogels are based on the biocompatible and biodegradable HA-drug conjugates with a high drug load and linked hydrophobic moieties (e.g., cholesterol), which are capable of folding into nanogels in aqueous media. A set of nanogel conjugates of poorly soluble anticancer drug, including curcumin, etoposide and salinomycin, was obtained, characterized and studied in cancer cell cultures. Cholesterol is a common cellular component that was expected to facilitate nanogel-membrane interaction and the intracellular transport of these drugs. The drug content in nanogel conjugates was as high as 15–20% (NMR analysis). These nanogels formed very small and uniform particles of 30–40 nm in diameter as determined by dynamic light scattering. The small size of nanogels can facilitate passive tumor accumulation through leaky neovasculature (EPR effect) and drug distribution in tumor tissue. Cytotoxicity assays (MTT) demonstrated stronger anticancer activity of nanogel-drug conjugates compared to free drugs and HA-drug conjugates in human breast carcinoma cells in vitro. Fluorescent microscopy confirmed that these nanogels are internalized by receptor-mediated endocytosis depending on the expression of CD44 receptors on the surface of cancer cells. Potential further developments would include an optimization of the hydrophilic-lipophilic balance of these nanogel-drug conjugates, introduction of diagnostic and vector molecules, and the development of dual-drug nanoformulations. In conclusion, we developed and characterized in vitro a novel HA-based nanogel drug delivery and theranostic platform that exhibits high anticancer activity and has a potential to become a novel therapy for overcoming tumor drug resistance.
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