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
Research Transition Award (R00)
Project #
4R00CA160350-03
Application #
8689250
Study Section
Special Emphasis Panel (NSS)
Program Officer
Fu, Yali
Project Start
2013-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$234,061
Indirect Cost
$91,614
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Liu, Yanlan; Gunda, Viswanath; Zhu, Xi et al. (2016) Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer. Proc Natl Acad Sci U S A 113:7750-5
Xu, Xiaoding; Wu, Jun; Liu, Yanlan et al. (2016) Ultra-pH-Responsive and Tumor-Penetrating Nanoplatform for Targeted siRNA Delivery with Robust Anti-Cancer Efficacy. Angew Chem Int Ed Engl 55:7091-4
Yu, Mikyung; Wu, Jun; Shi, Jinjun et al. (2016) Nanotechnology for protein delivery: Overview and perspectives. J Control Release 240:24-37
Xu, Yingjie; Yang, Wen; Shi, Jinjun et al. (2016) Prohibitin 1 regulates tumor cell apoptosis via the interaction with X-linked inhibitor of apoptosis protein. J Mol Cell Biol 8:282-5
Zhu, Xi; Wu, Jun; Shan, Wei et al. (2016) Polymeric Nanoparticles Amenable to Simultaneous Installation of Exterior Targeting and Interior Therapeutic Proteins. Angew Chem Int Ed Engl 55:3309-12
Wu, Jun; Zhao, Lili; Xu, Xiaoding et al. (2015) Hydrophobic Cysteine Poly(disulfide)-based Redox-Hypersensitive Nanoparticle Platform for Cancer Theranostics. Angew Chem Int Ed Engl 54:9218-23
Stary, Georg; Olive, Andrew; Radovic-Moreno, Aleksandar F et al. (2015) VACCINES. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells. Science 348:aaa8205
Zhu, Xi; Xu, Yingjie; Solis, Luisa M et al. (2015) Long-circulating siRNA nanoparticles for validating Prohibitin1-targeted non-small cell lung cancer treatment. Proc Natl Acad Sci U S A 112:7779-84
Islam, Mohammad Ariful; Reesor, Emma K G; Xu, Yingjie et al. (2015) Biomaterials for mRNA delivery. Biomater Sci 3:1519-33
Gadde, Suresh; Even-Or, Orli; Kamaly, Nazila et al. (2014) Development of therapeutic polymeric nanoparticles for the resolution of inflammation. Adv Healthc Mater 3:1448-56

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