HDAC Inhibitor Conjugated Polymeric Prodrug Micelles for Doxorubicin Delivery.

Amphiphilic diblock copolymers bearing histone deacetylase inhibitors (HDACi) (4-phenyl butyric acid and valproic acid) were synthesized by the ring-opening polymerization of γ-4-phenylbutyrate-ε-caprolactone (PBACL), γ-valproate-ε-caprolactone (VPACL), and ε-caprolactone (CL) from a poly(ethylene glycol) macroinitiator (PEG). These amphiphilic diblock copolymers self-assembled into stable pro-drug micelles and demonstrated excellent biocompatibility. High loading of doxorubicin (DOX) up to 5.1 wt% was achieved. Optimized micelles enabled sustained drug release in a concentration-dependent manner over time to expand the therapeutic window of cytotoxic small molecule drugs.

PEG based anti-cancer drug conjugated prodrug micelles for the delivery of anti-cancer agents.

Due to the high cost and uncertain success of new drug development, tremendous effort is devoted to increasing the efficacy of established anti-cancer drugs. Development of polymer prodrug conjugates has evolved recently in the nano-medicine field for cancer diagnosis and treatment. The major advantage of using polymer drug conjugates is that the chemical and physical properties of polymers can be tuned to increase the efficacy and to reduce the toxicity of the drug. The stimuli responsiveness provides the release of the prodrug in a controlled manner which avoids undesired side effects, organ damage, and toxicity caused by the fluctuations associated with periodic administration. A large number of anti-cancer drug polymer conjugates have been studied for cancer therapy due to their promising clinical applications in chemotherapy. In this paper, poly(ethylene glycol) (PEG) based anti-cancer drug conjugates will be discussed followed by a review of different types of PEG-b-poly(ε-caprolactone) (PEG-b-PCL) copolymer drug conjugates and histone deacetylase inhibitor polymer conjugates as novel therapeutics. The pH sensitive release of prodrugs will be discussed for polymer prodrug conjugates that are currently under investigation.

Fine-tuning thermoresponsive functional poly(ε-caprolactone)s to enhance micelle stability and drug loading.

Block copolymers synthesized by the ring-opening polymerization of γ-2-[2-(2-methoxyethoxy)ethoxy]ethoxy-ε-caprolactone (ME3CL), γ-2-methoxyethoxy-ε-caprolactone (ME1CL), and ε-caprolactone (CL) are reported. Previously, diblock copolymers of PME3CL-b-PME1CL displayed excellent thermoresponsive tunability (31-43 °C) and self-assembled into micelles with moderate thermodynamic stability. In this report, two strategies are employed to enhance thermodynamic stability of PME3CL/PME1CL-type block copolymer micelles while maintaining their attractive thermoresponsive qualities: modification of the end group position and alteration of hydrophobic block composition by using both ME1CL and CL. These new thermoresponsive amphiphilic block copolymers showed lower critical micelle concentration (CMC) values by one order of magnitude and formed thermodynamically stable micelles. Furthermore they demonstrated good biocompatibility and up to 4.97 wt% doxorubicin loading, more than double the amount loaded into the PME3CL-type polymeric micelles previously reported.