Abstract B34: Coordinated delivery of anticancer drug combinations incorporating molecularly targeted agents provides markedly increased plasma drug exposure, decreased toxicity and increased efficacy in preclinical tumor models
Authors: Mayer Lawrence D. , Tardi Paul , Xie Sherwin , Liboiron Barry , Lui Winnie , Wan Leon 
Published: May 2016

Abstract
Background: Coordinated delivery of established chemotherapy combinations at synergistic drug ratios via nano-scale delivery vehicles has provided marked improvements in efficacy both preclinically and clinically. Many molecularly targeted agent (MTA) combinations have experienced difficulties in achieving optimal target inhibition without inducing dose limiting toxicities. Here we report the application of CombiPlex® technology to combinations incorporating MTAs for which optimal therapeutic effects require simultaneous tumor cell exposure.
Methods: Prodrugs conjugates were synthesized for the HSP90 inhibitor AUY922 (AUY), docetaxel (DOC), the MEK inhibitor selumetinib (SEL) and Akt inhibitor ipatasertib (IPA) using cholesterol as a hydrophobic anchor joined via hydrolysable linkers that regenerate the parent drugs upon cleavage. These prodrugs were co-formulated in hydrophobic prodrug nanoparticles (HPN) by rapid mixing in the presence of surface stabilizing block co-polymers. Formulation compositions were iteratively optimized to achieve prolonged plasma drug concentrations while coordinating the PK of the combined agents. The tolerability and efficacy of the HPN combinations were compared to the free drug combinations administered in their conventional formulations.
Results: AUY and DOC anchored to cholesterol via a diglycolate linker could be stably co-formulated in HPNs with a mean diameter of ∼65nm using a range of surface stabilizing block co-polymers. Using PLA-PEG block co-polymers, HPN-associated drugs exhibited no early distribution phase and virtually identical PK for AUY and DOC with a plasma half-life in mice of &gt;12hr. Plasma concentrations of both agents over 24h were 2- to 4-orders of magnitude higher than for the free drugs. Similar PK results were obtained with the SEL:IPA combination. Combined IV treatment with DOC and AUY as the conventional free drugs led to significant increases in toxicity such that the DOC dose had to be reduced by 67% and the AUY dose had to be reduced by 60%. In contrast, when co-formulated in HPNs, both drugs could be administered with only a 30% dose reduction. In human xenograft tumor models (taxane resistant as well as taxane sensitive), the HPN formulation of AUY:DOC provided increased tumor growth inhibition; quantitative analysis of tumor growth delay revealed a 5-fold increase in antitumor activity compared to the free drug combination in the HCT15 model. A range of AUY:DOC drug ratio HPN formulations were also tested to identify the optimally efficacious drug ratio. HPN formulations of SEL:IPA also displayed improved tolerability compared to the free drug combination, particularly in view of the lower bioavailability for the agents administered in their oral dosing forms, while providing significant antitumor efficacy.
Conclusions: HPN-mediated coordinated delivery of drug combinations incorporating molecularly targeted agents can favorably shift the PK/PD profile resulting in an improved therapeutic index. Initial results suggest this may expand the utility of combinations that to date have been limited by toxicities associated with dosing regimens aimed at ensuring simultaneous and durable multi-target inhibition.
Citation Format: Lawrence D. Mayer, Paul Tardi, Sherwin Xie, Barry Liboiron, Winnie Lui, Leon Wan. Coordinated delivery of anticancer drug combinations incorporating molecularly targeted agents provides markedly increased plasma drug exposure, decreased toxicity and increased efficacy in preclinical tumor models. [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 B34.