Well-Defined Degradable Brush Polymer–Drug Conjugates for Sustained Delivery of Paclitaxel

Abstract

To achieve a conjugated drug delivery system with high drug loading but minimal long-term side effects, a degradable brush polymer-drug conjugate (BPDC) was synthesized through azide-alkyne click reaction of acetylene-functionalized polylactide (PLA) with azide-functionalized paclitaxel (PTXL) and poly(ethylene glycol) (PEG). Well-controlled structures of the resulting BPDC and its precursors were verified by (1)H NMR and gel permeation chromatography (GPC) characterizations. With nearly quantitative click efficiency, drug loading amount of the BPDC reached 23.2 wt %. Both dynamic light scattering (DLS) analysis and transmission electron microscopy (TEM) imaging indicated that the BPDC had a nanoscopic size around 10-30 nm. The significant hydrolytic degradability of the PLA backbone of the BPDC was confirmed by GPC analysis of its incubated solution. Drug release study showed that PTXL moieties can be released through the cleavage of the hydrolyzable conjugation linkage in pH 7.4 at 37 °C, with 50% release in about 22 h. As illustrated by cytotoxicity study, while the polymeric scaffold of the BPDC is nontoxic, the BPDC exhibited higher therapeutic efficacy toward MCF-7 cancer cells than free PTXL at 0.1 and 1 μg/mL. Using Nile red as encapsulated fluorescence probe, cell uptake study showed effective internalization of the BPDC into the cells.