Abstract B40: Concomitant delivery of paclitaxel and NuBCP9 peptide, for the enhancement of synergistic effect, in cancer therapy
Authors: Gupta Dikshi , Kapoor Sumeet , Tyagi Priyanka , Kumar Manoj , Tyagi Amit Kumar , Kharbanda Surender , Singh Harpal 
Published: May 2016

Introduction: Paclitaxel (PTX) is a powerful chemotherapeutic agent that binds to microtubules to prevent tumour cell division. However, a traditional high dose of Paclitaxel may also induce apoptosis in normal cells. NuBCP9, an anticancer peptide (ACP), which selectively binds to the Bcl-2 protein overexpressed almost in all the cancers and convert the anti-apoptotic Bcl-2 to pro-apoptotic and initiate apoptosis. The combination of two or more therapeutic drugs is feasible means to overcome the limitations. Present study explores the synergistic potential of this anticancer peptide in combination with traditional cytotoxic chemotherapeutic drug, to minimize the amount of each drug, for cancer therapy.

Method: Drug-containing nanoparticles composed of biodegradable amphiphilic block copolymers of Polylactic acid-polyethylene glycol-polypropylene glycol-polyethylene glycol (PLA-PEG-PPG-PEG, MW = 70K-12K) were synthesized and nanoparticle size was examined. At varying ratios of drugs, loading efficiency and release behaviour was determined. In vitro growth inhibition of these nanoparticle formulations were evaluated in MCF-7 and MDA-MB 231 breast cancer cells by XTT cell proliferation assay, after which IC50 analyses and combination index calculations were conducted. To assess the antitumor effects of nanoparticles in vivo, we treated Balb/c mice bearing established (∼200 mm3) subcutaneous BCL-2-positive Ehrlich syngeneic tumors, intraperitoneally once a week for the duration of three weeks.

Results: Developed biodegardable polymeric core-shell nanoparticles were spherical, with an average diameter of ∼90 nm. Both paclitaxel and NuBCP9 peptide loaded favourably in different ratios within nanoparticles. The drug-loaded NPs possessed a better polydispersity (PDI), indicating that they are more readily subject to controlled size distribution. Studies on cellular uptake and drug release from the system demonstrated that both drugs were effectively taken up by the cells and also releases simultaneously for up to 30 days. Combination indices demonstrated that 1:1 ratio of PTX: ACP had the most synergy in both MCF7 and MDA-MB 231 breast cancer cells and IC50 was found to be 30 fold less than the drugs alone in vitro. Significant tumor regression was observed in vivo in combination of PTX-ACP nanoparticles as compared upon single drug administration.

Conclusion: Polylactic acid based biodegradable polymeric nanoparticles have the great potential of prolonged delivery of synergistic agents against breast cancer. The synergy shown here permits the use of relatively low concentrations of peptides and drugs to achieve significant anticancer effects in vitro and in vivo. This dose reduction minimizes drug effects on normal cells, enabling an effective apoptosis-mediated anticancer effect without inducing harmful adverse events. Nanoparticle delivery of drugs may also yield enhanced understanding of mechanisms of synergy between molecular-targeted drugs and traditional chemotherapeutics in vivo, resulting in novel and more efficacious treatment regimens.

Citation Format: Dikshi Gupta, Sumeet Kapoor, Priyanka Tyagi, Manoj Kumar, Amit Kumar Tyagi, Surender Kharbanda, Harpal Singh. Concomitant delivery of paclitaxel and NuBCP9 peptide, for the enhancement of synergistic effect, in cancer therapy. [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 B40.