Synthesis of Amphiphilic Biodegradable Dendrimer-Like Star Polymers for Targeted Drug Delivery

Unimolecular micelles have attracted much attention in drug delivery, because they can decrease unwanted side effects, prolong the circulation time, and reduce uptake by the reticuloendothelial system (RES). In this work, several dendrimer-like star polymers (DLSPs) with a hydrophobic PLLA star polymer core and a hydrophilic dendron shell [a PAMAM dendron or a polyester dendron based on 2,2-bis(hydroxymethyl)propionic acid (bis-MPA)] were developed to form unimolecular micelles for targeted drug delivery. Their chemical structures were confirmed by proton (¹H) and carbon 13 (¹³C) nuclear magnetic resonance (NMR) spectroscopy as well as size-exclusion chromatography analysis. As determined by dynamic light scattering (DLS) and transmission electron microscopy (TEM), these DLSPs formed unimolecular micelles with a mean size of 10∼20 nm depending upon the star chain length and generations of dendrons. To improve the binding specificity, a carboxylic acid-functionalized DLSP with polyester dendrons based on bis-MPA, was selected to conjugate with amine-modified folic acid (FA) and flow cytometry and confocal microscopy analysis revealed that this FA-DLSP hybrid has the potential to be used in cancer diagnosis.

In order to improve the water solubility, the carboxylic acid groups on the surface were further conjugated with amine-modified FA and PEG oligomer. The drug release from the FA-DLSP micelles was then studied in vitro. The degradation behavior showed that the degradation was pH-dependent and the degradation started gradually from the hydrophilic shell to the PLLA core. Flow cytometry, confocal microscopy and MTT analysis showed that the FA-DLSP hybrid has potentials to be an excellent nanocarrier for targeted drug delivery.

However, FA lacks specificity in binding to the target cells because FA can bind to many human tumor cells. To increase the binding specificity, an amino-modified sgc8c aptamer that has specific binding to the human T lymphocytic leukemia cell line, CCRF-CEM, was attached to the carboxylic acid-functionalized DLSP. Flow cytometry analysis indicated that this aptamer-functionalized DLSP hybrid had strong specific binding with the CCRF-CEM cells which over-express the receptors. In contrast, the binding was not enhanced in Ramos cells that do not express the receptors.