Date of Degree

9-2018

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Krishnaswami Raja

Committee Members

Nan-Loh Yang

William L’Amoreaux

Michal Kruk

George John

Subject Categories

Chemicals and Drugs

Abstract

This dissertation describes the novel synthetic methodologies towards: a) protein/polysaccharide intercalated sponge-mimetic scaffolds for 3D cell culture, b) peptide-mimetic cationic amphiphilic antibacterial polymers, and c) bioactive Poly(DL-lactide-co-glycolide) (PLGA) nanofibers by solution blow spinning for the treatment of cancer and traumatic wound care.

The classic “chemical garden” experiment is reconstructed to produce protein/polysaccharide (ingredients of cyanobacterial origin) intercalated silicate-phosphate tubules that resemble tubular sponges. The constructs were synthesized by seeding calcium chloride into a solution of sodium silicate-potassium phosphate and gelatin/polysaccharides. The morphology and composition of sponge-mimetic tubules were analyzed by a battery of techniques. Bioconjugation and coating protocols were developed to program the scaffolds with cues for cell adhesion and the resulting constructs were employed for 3D cell culture of marine and mammalian cell lines. The cytocompatibility of the constructs was established by live cell-imaging and confocal laser scanning microscopy. We have successfully shown that these biomimetic materials can indeed support life by serving as scaffolds that facilitate the attachment and assembly of individual cells to form multicellular entities. Hybrid chemical garden biomaterials, which are programmable and readily fabricated, could be employed in tissue engineering, biomolecular materials development, 3D mammalian cell culture, and by researchers investigating the origins of multicellular life.

Global increase in infections involving antibiotic resistant bacteria has now become a severe threat to human health. As compared to target specific conventional antibiotics, natural antimicrobial peptides (AMPs) have been shown to attack the bacterial cell surface through non-specific electrostatic and lipophilic interactions. We investigated the bactericidal activities of a random amphiphilic cationic terpolymer architecture with a combination of 6-carbon and 2-carbon spacer arms (distance from polymer backbone to the cationic center) interspersed with hydrophobic side groups. Substantial increase in antibacterial activities without detrimental effects on hemolytic activities was observed by controlled replacement of 2-carbon spacer arm unit with hydrophobic alkyl comonomer. This strategy led to polymers with highly selective antibacterial activities towards bacteria over red blood corpuscles (RBCs). These results indicate the potential of these amphiphilic polymers to contribute toward the widespread therapeutic applications for fighting infections caused by drug resistant bacteria.

Drug releasing nanofiber mats have recently gained attention for localized drug delivery applications. The non-toxic FDA GRAS (Generally Regarded as Safe) nutraceuticals, like curcumin and rosmarinic acid have promising anti-cancer, anti-bacterial and wound healing properties. In this report, we have synthesized nutraceuticals loaded bioactive PLGA nanofibers via solution blow spinning, using a commercial air brush and compressed CO2. The time-dependent drug release studied by monitoring the degradation of nanofiber mat over 30 days shows the sustained release of drugs over extended period of time. The inhibition of bacterial cell growth by the drug loaded nanofibers was assessed by agar diffusion assay. It was observed that all the tested nutraceuticals loaded nanofibers inhibited cancer cell growth and induced cancer cell apoptosis even at the lowest concentration tested. Preliminary experiments to evaluate the application of the nanofibers in traumatic wound treatment was evaluated in vivo in the mouse model. The facile fabrication of these drug loaded nanofibers and results of our experiments indicate that they are promising candidates for bioactive sealing of wounds after the removal of tumors, and in rapid traumatic wound care.

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