Synthesis of a family of amphiphilic glycopolymers via controlled ring-opening polymerization of functionalized cyclic carbonates and their application in drug delivery

Abstract

Polymers bearing pendant carbohydrates have a variety of biomedical applications especially in the area of targeted drug delivery. Here we report the synthesis of a family of amphiphilic block glycopolymers containing d glucose, d galactose and d mannose via metal-free organocatalyzed ring-opening polymerization of functional cyclic carbonates generating narrowly dispersed products of controlled molecular weight and end-group fidelity, and their application in drug delivery. These glycopolymers self-assemble into micelles having a high density of sugar molecules in the shell, a size less than 100 nm with narrow size distribution even after drug loading, and little cytotoxicity, which are important for drug delivery. Using galactose-containing micelles as an example, we demonstrate their strong targeting ability towards ASGP-R positive HepG2 liver cancer cells in comparison with ASGP-R negative HEK293 cells although the galactose is attached to the carbonate monomer at 6-position. The enhanced uptake of DOX-loaded galactose-containing micelles by HepG2 cells significantly increases cytotoxicity of DOX as compared to HEK293. This new family of amphiphilic block glycopolymers has great potential as carriers for targeted drug delivery.

Introduction

Non-cytotoxic and biodegradable polymers which assemble into well-defined nanostructures such as micelles are of increasing interest as a means for drug transport and release. Nanoscale micellar carriers are particularly advantageous for passive drug targeting into solid tumors, as the hyperpermeable angiogenic vasculature of tumor tissues exhibits enhanced permeability and retention of carriers ≤100 nm [1]. In contrast to passive drug delivery, active targeting based on specific ligand–receptor interactions has recently received significant attention. Polymers bearing pendant carbohydrates are particularly useful for delivery applications that require the targeting of carbohydrate-binding proteins known as lectins. Protein–carbohydrate interactions mediate a number of biological processes, including cell growth, inflammation, infections and adhesion, via multivalent interactions [2], [3], [4]. The enhancement in binding, as a consequence of polyvalent interactions, is known as the glycoside cluster effect [5]. Carbohydrate-bearing polymers present a platform for which multiple copies of a saccharide can be presented simultaneously, thus enhancing their affinity and selectivity for lectins. A number of carbohydrate-bearing polymeric architectures have been developed over recent years including dendrimers [6], [7], [8], [9], [10], [11], linear polymers [12], [13], [14], [15], and micelles [16], [17], [18]. The block copolymers bearing the carbohydrates as the targeting groups are expected to have utility in receptor-mediated targeting of genes and drugs to specific tissues/cells [19]. For example, the asialoglycoprotein receptors (ASGP-R) on the surface of hepatocytes have been proposed as a target permitting organ-specific therapy of various diseases [20], including viral [21], parasitic [22], and malignant [21] disorders.

In our effort to create well-defined non-cytotoxic and biodegradable polymeric nanocarriers, carbohydrate-bearing block copolymers have been synthesized via organocatalytic ring-opening polymerization (ROP) of functional trimethylene carbonate (TMC) derivatives. Herein, we describe the synthesis and polymerization of cyclic carbonates containing diacetonide-protected glucose, galactose and mannose to afford carbohydrate-bearing polymers, and demonstrate that these sugar-functionalized polycarbonate block copolymers can self-assemble into micelles having surfaces with a high density of sugar molecules. Glucose-, galactose and mannose-coated micelles are designed for targeting cancer (as many types of cancer cells over-express glucose transporters) [23], liver [24], [25], [26] and dendritic [27] cells, respectively. We will use galactose-containing micelles as an example, and prove their ability of loading doxorubicin (a drug used for liver cancer treatment) as well as targeting liver cancer cells through qualitative and quantitative cellular uptake, competition and cytotoxicity studies.