Development of multidrug resistance (MDR) to conventional and newer generations of anticancer therapeutics is a significant challenge in cancer therapy. MDR is presented clinically as a consequence of many factors that include poor systemic drug delivery efficiency, short residence time, poor permeability in tumor mass and intracellular availability, as well as microenvironmental selection pressures that give rise to resistant phenotype. As such, our innovative strategy to overcome MDR is based on development of combinatorial designed nano-formulation libraries with encapsulated small interference RNA (against mdr-1 and mrp-1 efflux transporter and Bcl-2 and survivin anti-apoptotic genes) and cytotoxic therapeutic agents (paclitaxel and doxorubicin). Our preliminary studies show that this multimodal therapeutic approach has significant potential in the treatment of refractory tumors.
The specific aims of this project are: (1) to synthesize and characterize dextran-based macrostructures with fatty acids, thiol groups, poly(ethylene glycol) (PEG), and epidermal growth factor receptor (EGFR)- targeting peptide for combinatorial self-assembly in aqueous media into nanostructures that can encapsulate siRNA duplexes, paclitaxel, and doxorubicin;(2) high-throughput evaluation of cellular delivery and vesicular stability of siRNA duplexes and drugs, quantitative and qualitative gene silencing efficacy, cytotoxicity and apoptotic activity in wild-type (SK0V3) mdr-1 positive (SKOVSTR) human ovarian adenocarcinoma and wild- type (NIH-H69) and mrp-1 positive (NIH-H69AR) small cell lung adenocarcinoma cells;(3) selection of """"""""hits"""""""" for in vivo evaluation of tumor targeting efficacy, residence, biodistribution profiles, and evaluation of non- compartmental pharmacokinetics in SK0V3TR and NIH-H69AR tumor xenograft models after systemic administration;(4) further refinement of """"""""hits"""""""" and evaluation of in vivo gene silencing efficacy, tumor suppression, and inhibition of metastasis resistant tumor xenograft models after systemic administration of single and combination sIRNA/drug co-therapy;and (5) determination of acute safety profiles by measuring changes in body weight, blood cell counts, liver enzymes, and liver tissue histopathology with single and combination siRNA/drug co-therapy in resistant tumor models. The proposed clinically-translatable strategy holds tremendous promise in the treatment of refractory ovarian and small cell lung cancers, which continue to have very high mortality rates in the United States.

Public Health Relevance

Tumor multidrug resistance (MDR) is a serious challenge in clinical cancer therapy. A multimodal approach that enhances drug delivery efficiency as well as overcomes cellular resistance is necessary to successfully treat MDR in cancer patients. In this study, we will develop a novel class of biocompatible dextran-based polymeric nano-assembled structures for encapsulation and delivery of small interfering RNA that can silence specific genes in resistant cells. and cytotoxic drugs for maximum cell-kill effect.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA151452-03
Application #
8308696
Study Section
Special Emphasis Panel (ZCA1-SRLB-X (M1))
Program Officer
Grodzinski, Piotr
Project Start
2010-09-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$413,032
Indirect Cost
$104,079
Name
Northeastern University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Ye, Shunan; Shen, Jacson; Choy, Edwin et al. (2016) p53 overexpression increases chemosensitivity in multidrug-resistant osteosarcoma cell lines. Cancer Chemother Pharmacol 77:349-56
Liu, Xianzhe; Gao, Yan; Shen, Jacson et al. (2016) Cyclin-Dependent Kinase 11 (CDK11) Is Required for Ovarian Cancer Cell Growth In Vitro and In Vivo, and Its Inhibition Causes Apoptosis and Sensitizes Cells to Paclitaxel. Mol Cancer Ther 15:1691-701
Min, Li; Shen, Jacson; Tu, Chongqi et al. (2016) The roles and implications of exosomes in sarcoma. Cancer Metastasis Rev 35:377-90
Chen, Hua; Shen, Jacson; Choy, Edwin et al. (2016) Targeting protein kinases to reverse multidrug resistance in sarcoma. Cancer Treat Rev 43:8-18
Nascimento, Ana Vanessa; Gattacceca, Florence; Singh, Amit et al. (2016) Biodistribution and pharmacokinetics of Mad2 siRNA-loaded EGFR-targeted chitosan nanoparticles in cisplatin sensitive and resistant lung cancer models. Nanomedicine (Lond) 11:767-81
Mattheolabakis, George; Ling, Dandan; Ahmad, Gulzar et al. (2016) Enhanced Anti-Tumor Efficacy of Lipid-Modified Platinum Derivatives in Combination with Survivin Silencing siRNA in Resistant Non-Small Cell Lung Cancer. Pharm Res 33:2943-2953
Trivedi, M; Talekar, M; Shah, P et al. (2016) Modification of tumor cell exosome content by transfection with wt-p53 and microRNA-125b expressing plasmid DNA and its effect on macrophage polarization. Oncogenesis 5:e250
Shen, Jacson K; Cote, Gregory M; Gao, Yan et al. (2016) Targeting EZH2-mediated methylation of H3K27 inhibits proliferation and migration of Synovial Sarcoma in vitro. Sci Rep 6:25239
Liu, Tang; Shen, Jacson K; Li, Zhihong et al. (2016) Development and potential applications of CRISPR-Cas9 genome editing technology in sarcoma. Cancer Lett 373:109-18
Talekar, Meghna; Trivedi, Malav; Shah, Parin et al. (2016) Combination wt-p53 and MicroRNA-125b Transfection in a Genetically Engineered Lung Cancer Model Using Dual CD44/EGFR-targeting Nanoparticles. Mol Ther 24:759-69

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