Synthesis and characterization of transferrin-targeted chemotherapeutic delivery systems prepared via RAFT copolymerization of high molecular weight PEG macromonomers

Abstract

Reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to prepare a nanoparticulate drug delivery system for chemotherapeutics. The nanoparticles contain a PEG “stealth” corona as well as reactive anhydride functionality designed for conjugating targeting proteins. The multifunctional carrier functionality was achieved by controlling the copolymerization of the hydrophobic monomer lauryl methacrylate (LMA), with a reactive anhydride functional methacrylate (TMA), and a large polyethyleneglycol methacrylate monomer (Mn~950 Da) (O950). RAFT polymerization kinetics of O950 were evaluated as a function of target degrees of polymerization (DP), initial chain transfer agent to initiator ratio ([CTA]o/[I]o), and solvent concentration. Excellent control over the polymerization was observed for target DPs of 25 and 50 at [CTA]o/[I]o ratio of 10 as evidenced by narrow and symmetric molecular weight distributions and the ability to prepare block copolymers. The TMA-functional copolymers were conjugated to the tumor targeting protein transferrin (Tf). The targeted copolymer was shown to encapsulate docetaxel at concentrations comparable to the commercial single vial formulation of docetaxel (Taxotere). In vitro cytotoxicity studies conducted in HeLa cells show that the Tf targeting enhances the cancer killing properties relative to the polymer encapsulated docetaxel formulation.

Zwitterionic Nanocarrier Surface Chemistry Improves siRNA Tumor Delivery and Silencing Activity Relative to Polyethylene Glycol

“…32 While these POEGMA polymers were selected because the 950 Da side chains form more hydrophilic blocks than 300 Da OEGMAs, high molecular weight monomers are not as well studied as shorter OEGMA monomers, and their extended side chains may cause considerable steric repulsion between corona-forming blocks, a potentially destabilizing factor. 29,33 …”

Theranostic Oxygen Reactive Polymers for Treatment of Traumatic Brain Injury

“…The dense poly(PEGMA) brush copolymer was designed to facilitate facile administration and biocompatibility at high ORP concentrations (injection concentrations of ≈100 mg mL −1 ). Recently we developed conditions that allow PEGMA with a molecular weight of ≈1000 Da (≈19 ethylene glycol repeats) to be polymerized with a high level of control (polydispersity indexes, PDIs ≈1.10) . Our previous work with poly(PEGMA)‐based materials have shown no statistical change in enzyme levels even at polymer doses of 300 mg kg −1 .…”

Intracellular Delivery System for Antibody–Peptide Drug Conjugates

“…[23][24][25] The second incorporated a longer 950 Da PEGMA monomer (19 ethylene oxide units) that we recently described in a different polymer composition for small molecule delivery. 26 The longer 950 Da PEGMA monomer had not been characterized in vivo or in the context of a pH-responsive, endosomal-releasing diblock copolymer. The 950 Da PEGMA-containing diblock copolymer (Pol950) was compared to a 300 Da PEGMAcontaining diblock copolymer (Pol300) with antibody-targeting and peptide-conjugating elements incorporated into the coronaforming segment (Figure 1).…”