Date of Award

4-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Pharmaceutics

Research Advisor

Murali Mohan Yallapu,Ph.D.

Committee

Subhash Chauhan, Ph.D.; Santosh Kumar, Ph.D.; Wei Li, Ph.D.; Bernd Meibohm, FCP, FAAPS, Ph.D.; Ramesh Narayanan, Ph.D.

Abstract

Drug delivery to triple negative breast cancer (TNBC) remains a formidable challenge. Given the lack of expressions of estrogen (ER), progesterone (PR) and human epidermal growth factor receptor (HER2), there is no specific prognostic marker for targeting this aggressive cancer. In spite of rapid advancement in breast cancer with agents such as Trastuzumab in HER2 positive, chemotherapy with cytotoxic agents remains the mainstay treatment for TNBC. Although these cytotoxic agents are potent in managing the tumor progression, yet they pose adverse effects on healthy tissues. Paclitaxel (PTX) has been used as a gold standard chemotherapeutic agent for breast, ovarian, pancreatic and non-small cell lung carcinoma. Till date, PTX has been used as the first line of treatment for metastatic breast cancer. However, being biopharmaceutical classification system (BCS) class IV agent PTX suffers low solubility, poor permeability and remains a major challenge for efficient delivery specific to the tumor sites. Various formulations of PTX have been developed and approved in some countries, however due to serious adverse effects, suffer from poor patient outcomes.In this regard, we choose PTX as our model drug to generate, a safe and efficacious nanoparticle formulation by nanoprecipitation technique. For this, we screened commonly used pharmaceutical excipients and polymers and found the best candidate with built-in chemosensitization motifs (tannic acid: TA) and polyvinyl/pyrrolidone (PVP), given their innate potential to prevent drug efflux and capability to form the structured nanoparticle core due to extensive hydrogen bonding. The optimized formulation of TA and PVP nanoparticles had an average diameter of 102.22 ± 14.05 nm and 140.53 ± 7.08 nm, respectively. A drug encapsulation efficiency of ~ 96% was evaluated by LC-MS/MS. Improved in vitro and in vivo efficacies were achieved with respect to plain drug, attributed to the inhibitory P-gp effects of TA. To expand the scope of the developed formulation for enhanced specificity to TNBC tumors, we screened endogenous cell membranes (Human neutrophil, Mesenchymal s

ORCID

https://orcid.org/0000-0003-0561-3204

DOI

10.21007/etd.cghs.2020.0500

2020-007-Chowdhury-DOA.pdf (630 kB)
Declaration of Authorship

Available for download on Tuesday, April 27, 2021

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