A critical barrier to effective cancer chemotherapy is the development of multidrug resistance (MDR) in cancer cells. The broad and long-term objective of this project is to develop advanced nanomedicinal approaches for the treatment of multidrug resistant cancers. We believe that nanomedicinal therapy, which can simultaneously deliver RNAi therapeutics to suppress MDR and chemotherapeutic agents to induce the death of cancer cells, will be of particular interest in addressing the challenge of MDR in cancer chemotherapy. Specifically, we will design and develop nanoparticulate platforms for the effective co-delivery of RNAi and anti-cancer agents with a synergistic drug ratio to taxane-resistant lung and prostate cancer cells, by using biodegradable and biocompatible polymers and lipids. The contribution of different drug-resistant proteins to cancer MDR will be compared. The physicochemical properties of the nanoparticles will also be optimized to overcome the physiological barriers in vivo, while keeping the co-delivery of RNAi and chemotherapy safe and effective. Furthermore, in the R00 independent phase, the nanoparticulate platform will be precisely engineered to control the temporal release of individual agents and to achieve targeted drug delivery. We hypothesize that the spatiotemporal controlled delivery of nanotherapeutics can maximize the desired effects of RNAi and anti-cancer agents for multidrug resistant cancers, while minimizing their toxic side effects. If successful, this project will lay the groundwork for wider applications of the nanotechnology-based targeted combination therapy for cancer and other diseases.

Public Health Relevance

In this project we will use double-emulsion technology combined with self-assembly for nanoparticle synthesis. A library of the hybrid lipid-polymer nanoparticles will be formulated by tuning particle surface characteristics, components, drug loading/ratio, drug release profile, and targeting ligand density to optimize the co-delivery of RNAi and anti-cancer agents for multidrug resistant cancers (e.g., lung and prostate cancers). This nanoparticulate platform may be useful for the generation of versatile vehicles for targeted delivery of diverse drug combinations for a variety of therapeutic applications.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Career Transition Award (K99)
Project #
5K99CA160350-02
Application #
8304898
Study Section
Subcommittee G - Education (NCI)
Program Officer
Schmidt, Michael K
Project Start
2011-08-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$132,710
Indirect Cost
$9,830
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Xu, Xiaoyang; Xie, Kun; Zhang, Xue-Qing et al. (2013) Enhancing tumor cell response to chemotherapy through nanoparticle-mediated codelivery of siRNA and cisplatin prodrug. Proc Natl Acad Sci U S A 110:18638-43