Abstract 3641: Biodegradable polysaccharides based paclitaxel formation for ovarian cancer therapy

Abstract

Over 90% of pipeline therapeutic molecules have low solubility and lack of suitable delivery vehicle, which results the treatment potential could be limited. To address this challenge, ZY Therapeutics developed a tunable biodegradable polysaccharide-based nanoparticle drug delivery platform. The first candidate ZY-010-PNP is a nanoformulation using folate-modified polysaccharide encapsulating paclitaxel (PTX). ZY-010-PNP is supplied as a lyophilized powder that is readily reconstituted in saline to form a transparent suspension. The reconstituted formulation has an average particle size Drug release profile of ZY-010-PNP in human plasma was evaluated from 20 min to 4 hrs at different concentrations, using the stable isotope tracer ultrafiltration assay developed at NCI. The ZY-010-PNP formulation released 20-40% of the encapsulated PTX in human plasma within 20 min, and 60-100% was released over the subsequent 4-hour period. The data clearly showed that the drug release profile of ZY-010-PNP was time / concentrations dependent in serum, in contrast with burst release of all other marketed Taxane formulations. The in vitro efficacy was evaluated in human ovarian cancer SKOV3 cells. ZY-010-PNP induced dose- and time-dependent cell death and showed a similar potency as the benchmark drug in terms of cytotoxicity. However, the vehicle showed very low toxicity on SKOV3 and THLE-2 epithelial cells. The PK properties of ZY-010-PNP were also studied. ZY-010-PNP administrated on rats yielded the highest total plasma PTX level (Cmax), followed by a rapid declining and relatively longer elimination phase (t1/2) in comparison with the benchmark drug. The in vivo efficacy of ZY-010-PNP was demonstrated in two xenograft models, Triple Negative Breast Cancer (4T1) and Ovarian Cancer (SKOV3). In the SKOV3 study, multiple doses (10, 30 and 45 mg/kg) of ZY-010-PNP were tested in comparison to the benchmark drug. ZY-010-PNP at doses of over 30 mg/kg demonstrated complete tumor growth inhibition. Body weight (group means up to 15%) dropped during 30 and 45 mg/kg dosing period, but it was regained quickly post administration. In summary, a lyophilized dosage form of PTX formulation was developed with time and concentration dependent drug release profile. The in vitro and in vivo efficacy studies showed a similar tumor growth inhibition effect compared to the benchmark formulation. The PK profile demonstrated that ZY formulation yielded the highest total plasma Taxane level and relatively longer elimination phase. ZY’s vitamin-modified-polysacchride drug delivery platform showed advantages on improved stability, easy reconstitution, no foaming and no immunogenicity in compare to other benchmark delivery vehicle. The proprietary tunable platform can be applied to other high potency with low solubility molecules to increase the tolerance and reduce the toxicity of these drugs. Citation Format: Jian Bao, Hui Zhang, Aili Rong, Bajin Han, Nazar Filonov, Jun Li. Biodegradable polysaccharides based paclitaxel formation for ovarian cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3641.