Original Article

Citation: Cell Death and Disease (2014) 5, e1454; doi:10.1038/cddis.2014.413
Published online 9 October 2014

Nanoencapsulation of ABT-737 and camptothecin enhances their clinical potential through synergistic antitumor effects and reduction of systemic toxicity
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D Schmid1,2, G E Jarvis3, F Fay1,5, D M Small4, M K Greene1, J Majkut2, S Spence4, K M McLaughlin2, K D McCloskey2, P G Johnston2, A Kissenpfennig4, D B Longley2,6 and C J Scott1,2,6

  1. 1School of Pharmacy, Queen’s University Belfast, Belfast, UK
  2. 2Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK
  3. 3Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
  4. 4Centre for Infection and Immunity, Queen’s University Belfast, Belfast, UK

Correspondence: CJ Scott, School of Pharmacy, Queen’s University Belfast, 97 Lisburn Road BT9 7BL, Belfast, UK. Tel: +44 0 28 9097 2350; Fax: +44 0 28 9024 7794; E-mail: c.scott@qub.ac.uk

5Current address: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

6These authors contributed equally to this work.

Received 9 June 2014; Revised 28 August 2014; Accepted 29 August 2014

Edited by A Stephanou

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Abstract

The simultaneous delivery of multiple cancer drugs in combination therapies to achieve optimal therapeutic effects in patients can be challenging. This study investigated whether co-encapsulation of the BH3-mimetic ABT-737 and the topoisomerase I inhibitor camptothecin (CPT) in PEGylated polymeric nanoparticles (NPs) was a viable strategy for overcoming their clinical limitations and to deliver both compounds at optimal ratios. We found that thrombocytopenia induced by exposure to ABT-737 was diminished through its encapsulation in NPs. Similarly, CPT-associated leukopenia and gastrointestinal toxicity were reduced compared with the administration of free CPT. In addition to the reduction of dose-limiting side effects, the co-encapsulation of both anticancer compounds in a single NP produced synergistic induction of apoptosis in both in vitro and in vivo colorectal cancer models. This strategy may widen the therapeutic window of these and other drugs and may enhance the clinical efficacy of synergistic drug combinations.

Abbreviations:

CPT, camptothecin; PLGA, poly-lactide-co-glycolide acid; PEG, polyethylene glycol; NP, nanoparticle; GI, gastrointestinal; MPS, mononuclear phagocyte system