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

Abstract

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 (n > 1) which shows that it is a highly controlled process.

Copper Wire–Catalyzed RDRP in Nonpolar Media as a Route to Ultrahigh Molecular Weight Organic–Inorganic Hybrid Polymers

“…Our results highlight the specific character of the i BuPOSSMA monomer whose behavior can serve as an important model for similar systems incorporating sterically demanding groups in the methacrylate side chain and for monomers with low ceiling temperature in general. For instance, Plichta et al have recently recognized the depropagation‐related effects in polymerization of bulky methacrylate‐based macromonomers aimed at drug delivery applications …”

Tailoring of advanced poly(lactic acid)‐based materials: A review

“…In some cases, it can enhance films properties, such as adhesion 156 . Vacuum‐drying is usually utilized for drying PLA films at room or slightly elevated temperature 120,122,123,125,156–161 . For instance, PLA‐based films with plasticizers polyethene glycol and tributyl citrate were prepared by solvent casting method and vacuum drying at 50°C for 4 h to obtain coating material for controlled release of fertilizer in agriculture 162 …”

“…Functional properties of PLA materials can be further improved by development of ternary blends 8,22,57,58,60,63,66,67,77,124,159,167 . Klinkajorn & Tanrattanakul 62 added maleic anhydride (0.3–0.6 wt%) to blend of PLA 3 and rubber and improved material mechanical properties (tensile strength from 8 to 24 MPa).…”

Amphiphilic well‐defined degradable star block copolymers by combination of ring‐opening polymerization and atom transfer radical polymerization: Synthesis and application as drug delivery carriers

“… 53,60,68,76,77,99,103–110 The ability of such structures to encapsulate hydrophobic drugs, along with the degradable character of the polymers, make these polymers highly valuable for drug delivery 111 . In fact, this is the most investigated biomedical application for star BCPs prepared by combination of ROP and ATRP, with several examples describing the encapsulation of hydrophobic molecules, such as doxorubicin (DOX) or paclitaxel (PTX), or even genetic material by different core‐shell systems for anticancer therapy 112–121 . For example, Li and co‐workers synthesized 3‐ and 6‐arm PCL‐ b ‐PHEMA (PHEMA: Poly(hydroxyethyl methacrylate)) star BCPs by “core‐first,” starting with the ROP of CL followed by the ATRP of HEMA, as effective carriers for PTX delivery 113 .…”

“…111 In fact, this is the most investigated biomedical application for star BCPs prepared by combination of ROP and ATRP, with several examples describing the encapsulation of hydrophobic molecules, such as doxorubicin (DOX) or paclitaxel (PTX), or even genetic material by different core-shell systems for anticancer therapy. [112][113][114][115][116][117][118][119][120][121] For example, Li and co-workers synthesized 3-and 6-arm PCL-b-PHEMA (PHEMA: Poly(hydroxyethyl methacrylate)) star BCPs by "core-first," starting with the ROP of CL followed by the ATRP of HEMA, as effective carriers for PTX delivery. 113 Results showed that drug loading and drug encapsulation efficiencies of the micelles formed in aqueous medium were influenced by both the number of arms and composition of the stars.…”