Despite recent advances in cancer treatment, the clinical outcome among NSCLC patients is not impressive. Our laboratory has been working with the use of inhalation and oral delivery of anticancer agents for treatment of lung cancer. Active targeting of chemotherapeutic drugs containing nanoparticles may effectively treat adenocarcinomas by achieving higher concentration at target sites. EphA2, an Eph family receptor tyrosine kinase is overexpressed in 90% of NSCLC tumors; high levels of EphA2 predicted poorer overall patient survival. Studies conducted in our laboratory have shown that H460 and A549 tumors express EphA2 receptors. Recently, the peptide, YSAYPDSVPMMS (YSA) has demonstrated to selectively bind to EphA2 receptors on lung and prostate cancer cells. Taking advantage of YSA peptide selective binding and overexpressed status of EphA2 receptors in lung cancer cells, we propose an YSA peptide conjugated NCs system to simultaneously and selectively deliver anticancer drugs to lung cancer tumors. However, irrespective of the targeting nature of the nanoparticles, their intratumoral distribution is hindeed by dense collagen network and highly fibrous interstitium. Use of antifibrotic agents has reported to decrease tumor interstitial fibrosis and promote nanoparticle intratumoral distribution. Recent studies have demonstrated that Losartan through transforming growth factor beta 1 (TGF-1) inhibition improved the penetration and therapeutic efficacy of drug loaded nanoparticles. Preliminary studies from our laboratory suggest that Telmisartan (AT1 blocker) produced 3 fold higher fibrolysis than Losartan. Therefore, it is expected that prior treatment with Telmisartan will make tumors lose their dense collagen network and will promote better intratumoral distribution of nanotherapeutics. We intend to treat the lung tumors with Telmisartan by inhalation and oral route prior to administering the NCs- Ds (Docetaxel containing nanoparticles) to solid lung tumors. We hypothesize that YSA conjugated targeted nanoparticles (NCs-D-Y) will selectively distribute, bind and actively internalize into the EphA2 over expressing lung cancer and tumor neovascular cells. This distribution will be facilitated by Telmisartan by its antifibrotc effects.
Our specific Aims are:
Specific Aim 1 : To prepare and evaluate various NC-D-Y formulations. In this aim we will prepare NCs-D conjugated with YSA peptide (NCs-D-Y) which shows evidence of specific targeting to the EphA2 receptors and inhibiting the growth of tumor cells in vitro.
Specific Aim 2 : In vivo Pharmacokinetic and Pharmacodynamic evaluation of NCs-F-Y and NCs-D-Y in orthotopic and metastatic tumors. In this aim, following Telmisartan treatment, the NCs-D-Y will be administered intravenously to lung tumor bearing animals for EphA2 specific targeted delivery. Telmisartan will make difficulty penetrable solid tumors into easily nanoparticle penetrable loose interstitial networks The results emanating from these studies will allow us to assess the role of Telmisartan in enhancing intratumoral delivery of targeted nanoparticles with their payloads of various chemotherapeutic drugs. The long term objectives of this proposal are to use the current approach to other fibrotic tumors and also with other nanoparticle payloads like siRNA, shRNA or small molecule anticancer drugs.

Public Health Relevance

Cancer is a major global health problem, and each year in the US, approximately 571,950 people are diagnosed. The complex nature of tumors represents a significant challenge to the health care system. Development of target specific nanotherapeutics have offered new hope for cancer treatment, However, Poor penetration and heterogeneous distribution of therapeutics into tumors can be an important factor limiting their efficacy. The dense collagen network in tumors significantly reduces the penetration and efficacy of nanotherapeutics. The combinatorial approach for improved drug efficacy with tumor homing nanotherapeutics and anti-fibrotic drugs is likely to have a profound impact on cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA175618-02
Application #
8791884
Study Section
Special Emphasis Panel (ZCA1-SRLB-2 (O1))
Program Officer
Fu, Yali
Project Start
2014-04-01
Project End
2016-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
2
Fiscal Year
2015
Total Cost
$158,775
Indirect Cost
$50,025
Name
Florida Agricultural and Mechanical University
Department
Type
Schools of Pharmacy
DUNS #
623751831
City
Tallahassee
State
FL
Country
United States
Zip Code
32307
Cheriyan, Vino T; Alsaab, Hashem; Sekhar, Sreeja et al. (2018) A CARP-1 functional mimetic compound is synergistic with BRAF-targeting in non-small cell lung cancers. Oncotarget 9:29680-29697
Chowdhury, Nusrat; Vhora, Imran; Patel, Ketan et al. (2017) Liposomes co-Loaded with 6-Phosphofructo-2-Kinase/Fructose-2, 6-Biphosphatase 3 (PFKFB3) shRNA Plasmid and Docetaxel for the Treatment of non-small Cell Lung Cancer. Pharm Res 34:2371-2384
Boakye, Cedar H A; Patel, Ketan; Doddapaneni, Ravi et al. (2016) Ultra-flexible nanocarriers for enhanced topical delivery of a highly lipophilic antioxidative molecule for skin cancer chemoprevention. Colloids Surf B Biointerfaces 143:156-167
Patel, Ketan; Doddapaneni, Ravi; Sekar, Vasanthakumar et al. (2016) Combination Approach of YSA Peptide Anchored Docetaxel Stealth Liposomes with Oral Antifibrotic Agent for the Treatment of Lung Cancer. Mol Pharm 13:2049-58
Patel, Ketan; Doddapaneni, Ravi; Chowdhury, Nusrat et al. (2016) Tumor stromal disrupting agent enhances the anticancer efficacy of docetaxel loaded PEGylated liposomes in lung cancer. Nanomedicine (Lond) 11:1377-92
Patel, Ketan; Chowdhury, Nusrat; Doddapaneni, Ravi et al. (2015) Piperlongumine for Enhancing Oral Bioavailability and Cytotoxicity of Docetaxel in Triple-Negative Breast Cancer. J Pharm Sci 104:4417-4426
Boakye, Cedar H A; Patel, Ketan; Singh, Mandip (2015) Doxorubicin liposomes as an investigative model to study the skin permeation of nanocarriers. Int J Pharm 489:106-16
Patel, Apurva R; Doddapaneni, Ravi; Andey, Terrick et al. (2015) Evaluation of self-emulsified DIM-14 in dogs for oral bioavailability and in Nu/nu mice bearing stem cell lung tumor models for anticancer activity. J Control Release 213:18-26
Patel, Apurva R; Chougule, Mahavir; Singh, Mandip (2014) EphA2 targeting pegylated nanocarrier drug delivery system for treatment of lung cancer. Pharm Res 31:2796-809
Andey, Terrick; Marepally, Srujan; Patel, Apurva et al. (2014) Cationic lipid guided short-hairpin RNA interference of annexin A2 attenuates tumor growth and metastasis in a mouse lung cancer stem cell model. J Control Release 184:67-78