Lung cancer accounts for more deaths than any other types of cancer in both men and women, with an estimated 226,160 new cases and 160,770 deaths in 2012, in the United States. Although platinum drugs have played a very important role in the chemotherapy of lung cancer, their major limitations are systemic toxicity and the rapid acquisition of resistance. As such, there is an urgent need to develop alternative strategies to effectively treat refractory lung cancer in a clinically-meaningful way without the associated toxicity burden. RNA interference therapy can be a powerful approach to down-regulate specific genes involved in platinum resistance and, therefore, can work synergistically with cytotoxic chemotherapy in refractory lung cancer patients. The main objective of this R21 proposal is to evaluate the therapeutic potential for combination lung cancer therapy using lipophilic (lipid-tailed) platinate derivatives and small interfering RNAs (siRNAs) delivered in CD44- and epidermal growth factor receptor (EGFR)-targeted biocompatible hyaluronic acid (HA) based self-assembling nano-systems. As part of the preliminary studies, we have developed a series of modified HA derivatives, using """"""""click"""""""" chemical conjugation that allow for combinatorial- designed formulation development approach for encapsulation of hydrophobic (e.g., lipid-tailed platinates) and hydrophilic/charged (e.g., siRNA) molecules. Additionally, the modular nano-platform allows for incorporation of additional functionalities, including EGFR specific peptide, for dual targeting in lung cancer.
The specific aims of the proposal are as follows: (1) synthesis and characterization of """"""""lipid tailed"""""""" platinate derivatives and encapsulation, along with siRNA duplexes, in HA-based self-assembling nano- systems, (2) evaluation of in vitro gene silencing and cell-kill efficacy using single (lipid-tailed platinate alone) and combination (siRNA+platinate therapy in sensitive A549 and cisplatin-resistant A549DDP human non-small cell lung cancer cells, and (3) establish A549 and A549DDP tumor xenografts in athymic (nu/nu) mice and in vivo evaluation of anti-tumor efficacy and safety of single and combination siRNA/platinate therapy using dual targeting HA-based self-assembled nano-systems. This study is highly significant in evaluating gene silencing strategy in vivo for overcoming tumor drug resistance using a safe and effective delivery system. Following successful completion, future studies in the R01 phase will focus on evaluation of multiple gene silencing and combination therapy delivered with dual targeted HA nanoparticles in a transgenic human lung cancer model.

Public Health Relevance

With more than 220,000 individuals diagnosed and over 150,000 patients dying each year, lung cancer is the second-most common malignancy in both men and women and the leading cause of cancer-related deaths in the United States. Although platinum-based drugs are first-line choice for lung cancer treatment, they cause significant systemic toxicity and are susceptible to acquisition of resistance. In this study, we will use a combination of lipid-modified platinate drug and therapeutic siRNA delivered using hyaluronic acid-based self- assembling nano-systems for effective treatment of platinum-resistant human lung cancer models in mice.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1-RPRB-J (J1))
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Arya, Suresh
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Northeastern University
Schools of Pharmacy
United States
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Ahmad, Gulzar; El Sadda, Rana; Botchkina, Galina et al. (2017) Nanoemulsion formulation of a novel taxoid DHA-SBT-1214 inhibits prostate cancer stem cell-induced tumor growth. Cancer Lett 406:71-80
Wickens, Jennifer M; Alsaab, Hashem O; Kesharwani, Prashant et al. (2017) Recent advances in hyaluronic acid-decorated nanocarriers for targeted cancer therapy. Drug Discov Today 22:665-680
Nascimento, Ana Vanessa; Singh, Amit; Bousbaa, Hassan et al. (2017) Overcoming cisplatin resistance in non-small cell lung cancer with Mad2 silencing siRNA delivered systemically using EGFR-targeted chitosan nanoparticles. Acta Biomater 47:71-80
Bhise, Ketki; Kashaw, Sushil Kumar; Sau, Samaresh et al. (2017) Nanostructured lipid carriers employing polyphenols as promising anticancer agents: Quality by design (QbD) approach. Int J Pharm 526:506-515
Luong, Duy; Kesharwani, Prashant; Alsaab, Hashem O et al. (2017) Folic acid conjugated polymeric micelles loaded with a curcumin difluorinated analog for targeting cervical and ovarian cancers. Colloids Surf B Biointerfaces 157:490-502
Trivedi, Malav; Singh, Amit; Talekar, Meghna et al. (2017) MicroRNA-34a Encapsulated in Hyaluronic Acid Nanoparticles Induces Epigenetic Changes with Altered Mitochondrial Bioenergetics and Apoptosis in Non-Small-Cell Lung Cancer Cells. Sci Rep 7:3636
Tatiparti, Katyayani; Sau, Samaresh; Kashaw, Sushil Kumar et al. (2017) siRNA Delivery Strategies: A Comprehensive Review of Recent Developments. Nanomaterials (Basel) 7:
Luong, Duy; Sau, Samaresh; Kesharwani, Prashant et al. (2017) Polyvalent Folate-Dendrimer-Coated Iron Oxide Theranostic Nanoparticles for Simultaneous Magnetic Resonance Imaging and Precise Cancer Cell Targeting. Biomacromolecules 18:1197-1209
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
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

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