Date of Award

2014

Degree Type

Thesis

Degree Name

Master of Science in Chemical Engineering (MSChE)

Department

Chemical Engineering

First Advisor

Samantha Meenach

Abstract

The overall survival rate for patients diagnosed with lung cancer is still extremely low and many affected patients are not eligible for first-line treatments such as surgery, chemotherapy, and radiation for the treatment due to the severe side effects associated with these therapies. Paclitaxel (PTX) along with imatinib mesylate are currently first-line therapies for many types of cancer (Kelly 2001, Schiller 2002). However, the successful delivery of paclitaxel faces many challenges due to its lipophilic nature and high protein affinity, which often results in low bioavailability. Solubilization of drugs such as PTX, enhanced tumor accumulation, and toxicity attenuation of such therapeutics can be enhanced via targeted delivery to tumors using nanoparticles (NPs). For example, chemotherapeutic drugs such as PTX and doxorubicin have been encapsulated singularly in micelles (Jinhyang 2012) and nanoliposomes (Zhang 2011), thereby increasing the efficacy of radiation therapy against in vitro lung cancer cells and in animals, demonstrating the success of nanoparticle-mediated treatment of cancer. Current cancer treatment, however, revolves around the tandem delivery of PTX and therapeutics such as imatinib, doxorubicin, and carboplatin. Unfortunately, multi-drug delivery is not easily achieved with single-agent delivery systems demonstrating the need for a nanoparticle system capable of delivering multiple drugs in tandem directly to the tumor site(s). While the enhanced permeability and retention (EPR) effect has served as a key rationale for using nanoparticles to treat solid tumors, as it allows for increased uptake of NPs at the tumor site, it often does not enable uniform delivery of these particles to all regions of tumors. Tumor-penetrating peptides show great promise in overcoming the relevant physiological barriers preventing accumulation and penetrating into the avascular region of tumors. iRGD (internalizing RGD, CRGDKDPDC), has been shown to effectively target and penetrate both in vitro multicellular spheroids (MCS) and in vivo animal model tumors when conjugated to drugs or nanoparticles (Sugahara 2010). For the described research, I hypothesize that iRGD-conjugated nanoparticles containing PTX and imatinib will more effectively home to and penetrate lung cancer tumor spheroids for more effective treatment of this dismal disease. In particular, acetalated dextran (Ac-Dex) nanoparticles were synthesized to contain PTX and/or imatinib. These particles were shown to have sizes appropriate for systemic delivery (approximately 250 nm) and exhibited smooth, round morphology. All particle systems exhibited favorable homogeneity as evidenced by low polydispersity index values (less than 0.20) and were nearly neutral in charge with zeta potentials near zero. Both PTX and imatinib were successfully loaded into the nanoparticles with 50 and 14 weight % loading, respectively. 80% of iRGD was conjugated to the nanoparticles and the peptide showed affinity for A549 lung adenocarcinoma cells in vitro. A549 multicellular spheroids were generated to allow for evaluation of the newly developed therapeutics. Finally, in vitro analysis using A549 cells showed that the drug-loaded nanoparticles were more effective at killing cells than pure drugs. Overall, this work shows the promise of Ac-Dex drug-loaded nanoparticles conjugated with iRGD to enhance the treatment of lung cancer.

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