Abstract B176: In vitro and in vivo studies demonstrating sustained drug release for multiple anticancer payloads and improved anticancer effects of a cabazitaxel β-cyclodextrin-PEG copolymer-based nanoparticle-drug conjugate (NDC)

Abstract

Abstract We have demonstrated the ability to generate nanoparticle-drug conjugates (NDCs) with tunable and diverse in vitro and in vivo drug release kinetics by the conjugation of multiple anticancer agents (docetaxel, cabazitaxel, and gemcitabine) to a β-cyclodextrin-PEG (CDP) copolymer through a variety of linker strategies. Linker molecules included glycinate, alaninate, hexanoate, and diester linker β-alanine-glycolate, which were conjugated via ester linkages to the anticancer payloads. In vitro release studies demonstrated that the β-alanine-glycolate linker released drug from the CDP copolymer relatively faster than the glycinate and alaninate linkers, while the hexanoate linker showed much slower drug release. Release studies in native and heat-inactivated plasma had no influence on the release kinetics, indicating that drug release was pH- but not enzyme-triggered. The in vitro release profiles for the respective linkers varied slightly (more so in vivo) depending on the API (Active Pharmaceutical Ingredient) payload, demonstrating that release kinetics can be varied through selection of linker molecules and that NDC chemistry is customizable with respect to API. In vivo PK studies with cabazitaxel (CBTX) NDCs demonstrated that the hexanoate-containing NDC (slower releasing linker) led to higher total (conjugated drug + released) drug levels and lower released drug levels compared to the glycinate NDC (faster releasing linker) and the separately dosed cabazitaxel. This likely led to the greater tolerability (i.e., higher MTD) observed for the CBTX-hexanoate NDC. Both the CBTX-hexanoate and -glycinate NDCs led to high and sustained levels of released drug in tumor tissues (>72 hrs). The maximum drug concentrations in the blood (Cmax) of released drug was lower for all NDCs tested compared to similarly dosed parent drug, thereby addressing Cmax-related toxicities. Two CBTX NDCs (hexanoate and glycinate) were chosen for in vivo efficacy studies in mouse tumor models. Both demonstrated vastly improved efficacy (and survival) over the parent drug, cabazitaxel, at similar doses including efficacy against docetaxel-resistant UISO-BCA-1 tumor cells. The CBTX-hexanoate NDC showed a greater therapeutic index (TI) compared to parent drug as well as the CBTX-glycinate NDC. Citation Format: Chester Metcalf, III, Donna Brown, Jungyeon Hwang, Sujan Kabir, Douglas Lazarus, Pochi Shum, Snehlata Tripathi, Scott Eliasof. In vitro and in vivo studies demonstrating sustained drug release for multiple anticancer payloads and improved anticancer effects of a cabazitaxel β-cyclodextrin-PEG copolymer-based nanoparticle-drug conjugate (NDC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B176.