ATRP of Methacrylic Derivative of Camptothecin Initiated with PLA toward Three-Arm Star Block Copolymer Conjugates with Favorable Drug Release

Three-arm polylactides (PLA) containing 0.2, 7.6, and 13% of d-lactic acid monomeric units were obtained and refunctionalized into ATRP macroinitiators via esterification of hydroxyl groups with 2-bromoisobutyryl bromide. These polymeric matrices underwent enzymatic degradation with various rates and revealed negative results on cytotoxicity and genotoxicity tests. Camptothecin (CPT), which is an anticancer active substance, was transformed into acrylic monomers; however, simple CPT acrylate was not able to polymerization whereas methacrylate with a linker was ready for FRP and ATRP. The latter monomer was used for ATRP initiated with various PLA macroinitiators in order to form block copolymer conjugates of CPT with high load of drug. Based on kinetic studies at various temperatures, it was found out that the polymerization stopped at certain monomer conversion because of the ceiling temperature. The content of CPT in these conjugates was estimated by means of ¹H NMR, quadruple detection array GPC, and elemental analysis and was in the range 8.0–16.9 wt %. The products were morphologically heterogeneous, and the shapes and size of the nano-/microstructures were influenced by crystallinity of the PLA segment which was shown in AFM images. Terpolymer block conjugates consisting of addition PEGMA monomeric units were synthesized as well in order to increase hydrophilicity of the polymers and to protect a lactone ring in CPT structure. The studies on CPT release were carried out in vitro and revealed that the rate of CPT discharge was influenced by the structure of PLA and conjugate composition; however, it was near to zero-order kinetics. The analysis using the Korsmeyer–Peppas model suggests that drug release was governed rather according supercase II transport (<i>n</i> > 1) which shows that it is a highly controlled process