Polymeric nanoparticles (NPs) are important carriers for the delivery of chemotherapeutics because they can provide prolonged systemic circulation and improved tumor accumulation compared to unformulated drugs. Although significant progress has been made in the past 2-3 decades, challenges of precisely controlling drug loading and release still remain to be overcome. Typical formulation drawbacks in current NPs include low drug loading, low incorporation efficiency and drug burst release. Non-encapsulated drugs may self-aggregate and are thus difficult to be removed from the NP formulation. These drawbacks increase the difficulties of handling for large-scale production of NP delivery vehicles, and prevent the NPs from achieving their full potential in drug delivery.

Supported by DMF-DMR Career Award (DMR-0748834), we successfully developed nanoconjugation, a new technique of preparing polymeric NPs. Nanoconjugation contains two steps. The first step involves hydroxyl-containing therapeutics initiated ring-opening polymerizations of cyclic esters in the presence of rationally-designed metal catalysts ((BDI)ZnN(TMS)₂, [(BDI) = 2-((2,6-diisopropylphenyl)amido)-4-((2,6-diisopropylphenyl)-imino)-2-pentene]) to make polyester-drug conjugates. The second step is the nanoprecipitation of the polyester-drug conjugates to make conjugated polymer-drug nanoparticles, or called nanoconjugates (NCs) in this report. Because of quantitative initiation in these living polymerizations, all drugs are incorporated in the polyesters (100% encapsulation efficiency) with predetermined drug loading by monomer/initiator (cyclic ester/drug) ratio. The resulting NCs have uniform particle sizes in a range of 60-120 nm. Drugs were released from NCs in a sustained manner without burst effect. Coating NCs with poly(lactide-co-glycolic acid)-mPEG (PLGA-mPEG) results in core-shell nanostructures with significantly improved stability against particle aggregation in salt solution. Using nanoconjugation, a handful of NCs of dye and therapeutic molecules with very high loading and nearly quantitative incorporation efficiency were prepared. Using catalyst with bulky BDI ligand, we were able to control regio- and chemoselectivity of the nanoconjugation for multifunctional therapeutic molecules. For instance, when paclitaxel, a complex chemotherapeutic molecule with three hydroxyl group at C2’-, C1- and C7-positions, was used as initiator, polymerization can be specifically controlled at the C2’-position with very high efficiency. Other potent anticancer drugs, including doxorubicin (Doxo) and camptothecin (CPT) have also been successful formulated into nanoparticles using our drug-PLA strategy. Nanoprecipitation of drug-PLA forms NCs with sub-100 nm sizes, narrow particle size distributions and quantitative drug loading efficiency. Sustained release of authentic drug was achieved without burst release effect thanks to the prodrug strategy. The kinetics of the drug release from the NCs was further improved by incorporation of a hydrophilic linker (α-amine substituted ester) and showed better therapeutic effect of camptothecin containing NCs.

Besides developing drug-initiated LA polymerization, we also tested the polymerization of other monomers including trimethylene carbonate, and O-carboxyanhydride (OCA). Notably, similar polymerization and drug loading was achieved while the drug-poly-OCA NCs coated with amphiphilic polymer showed remarkable stability improvement in physiological buffer than that of drug-PLA NCs. Various in vitro and In vivo tumor models have been established during the funding period and the results indicated a good therapeutic anticancer efficacy of the drug-polymer nanoparticles.

Last Modified: 04/01/2015
Modified by: Jianjun Cheng