The AAPS Journal

, Volume 12, Issue 2, pp 171–180

Augmentation of Therapeutic Efficacy in Drug-Resistant Tumor Models Using Ceramide Coadministration in Temporal-Controlled Polymer-Blend Nanoparticle Delivery Systems

  • Lilian E. van Vlerken
  • Zhenfeng Duan
  • Steven R. Little
  • Michael V. Seiden
  • Mansoor M. Amiji
Research Article

DOI: 10.1208/s12248-010-9174-4

Cite this article as:
van Vlerken, L.E., Duan, Z., Little, S.R. et al. AAPS J (2010) 12: 171. doi:10.1208/s12248-010-9174-4

Abstract

The development of multidrug resistance (MDR) is a major hindrance to cancer eradication as it renders tumors unresponsive to most chemotherapeutic treatments and is associated with cancer resurgence. This study describes a novel mechanism to overcome MDR through a polymer-blend nanoparticle platform that delivers a combination therapy of C6-ceramide (CER), a synthetic analog of an endogenously occurring apoptotic modulator, together with the chemotherapeutic drug paclitaxel (PTX), in a single formulation. The PTX/CER combination therapy circumvents another cellular mechanism whereby MDR develops, by lowering the threshold for apoptotic signaling. In vivo studies in a resistant subcutaneous SKOV3 human ovarian and in an orthotopic MCF7 human breast adenocarcinoma xenograft showed that the PTX and CER nanoparticle combination therapy reduced the final tumor volume at least twofold over treatment with the standard PTX therapy alone. The study also revealed that the cotherapy accomplished this enhanced efficacy by generating an enhancement in apoptotic signaling in both tumor types. Additionally, acute evaluation of safety with the combination therapy did not show significant changes in body weight, white blood cell counts, or liver enzyme levels. The temporal-controlled nanoparticle delivery system presented in this study allows for a simultaneous delivery of PTX + CER in breast and ovarian tumor model drug, leading to a modulation of the apoptotic threshold. This strategy has tremendous potential for effective treatment of refractory disease in cancer patients.

Key words

combination therapy intracellular ceramide modulation multidrug resistance temporal-controlled polymeric nanoparticle delivery 

Copyright information

© American Association of Pharmaceutical Scientists 2010

Authors and Affiliations

  • Lilian E. van Vlerken
    • 1
  • Zhenfeng Duan
    • 2
  • Steven R. Little
    • 3
  • Michael V. Seiden
    • 4
  • Mansoor M. Amiji
    • 1
  1. 1.Department of Pharmaceutical Sciences, School of PharmacyNortheastern UniversityBostonUSA
  2. 2.Department of Orthopedic SurgeryMassachusetts General HospitalBostonUSA
  3. 3.Departments of Chemical Engineering, Bioengineering, Immunology, and The McGowan Institute of Regenerative MedicineUniversity of PittsburghPittsburghUSA
  4. 4.Fox Chase Cancer CenterPhiladelphiaUSA

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