Applying nanotechnology towards developing an integrative drug delivery system for inhibiting antibiotic-resistant bacteria and restoring mitochondrial genetic expression In eukaryotic host cells

Abstract

Numerous medical incentives are critical factors in the output of clinically relevant deliverables, including state-of-the-art medications, implants, or diagnostic tools, that are handled in accordance with principles of nanotechnology. One area that requires immediate attention is the pathogenesis of bacterial infections, especially, as the result of a diminution in the available treatments for countering the disease progression. Following the discovery of penicillin almost one century ago, the problem of bacterial infection has been largely digressed from until recently, since it has been determined that pathogens have acquired mechanisms through which to avoid susceptibility to antibiotics. These bacteria are termed antibiotic-resistant, and nanomedicine has been proffered as a dynamic field for bypassing the evolutionary functions of these antagonists. Strategies to suppress bacterial overgrowth include inorganic and organic nanosystems of metal particles and drug delivery materials, often, delivered in tandem. Other drugs, biomolecules, and natural substances may be integrated within these systems to fabricate a multi-modular method, that, upon administration to sites of bacterial colonization is absolutely suppressive. Concurrently, the nano-antibacterial must be biocompatible and non-cytotoxic towards eukaryotic host cells, with potential benefits. This latter criterion, of aiding host cell functions, may be necessary following certain bacterial infections that occur. Many bacteria are proficient in permanently damaging eukaryotic cells by consuming cellular ATP and releasing toxins that perturb normal functions of homeostasis, respiration, apoptosis, and necrosis. The dysregulation of intracellular reactive oxygen species (ROS) levels and mitochondrial impairment are common modes by which pathogens leverage long-term secondary diseases. There are numerous reports linking accelerated cellular senescence, irritable bowel disorders, and certain cancers, among other conditions, to previous bacterial infections. A method for conjointly remediating the primary and secondary syndromes caused by bacteria is recommended in this dissertation. A sequential approach is described for countering the growth processes of antibiotic-resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Escherichia coli (MDR E. coli); to help reconstruct genetically impaired mitochondria; and for modulating ROS production and apoptosis onset by intracellular caspase-3/7 activation. Finally, a recommendation for conserving the long-term viability of isolated mitochondria by polymeric encapsulation and cryopreservation is made. Briefly, 100-nm polymer nanocapsules of poly (D,L-lactide) and polyethylene glycol were mechanically and chemically modified to transport silver nanospheres (AgNP, 11.6 μg/ml) and peptides of the porcine innate immune system (PR-39, 14.3 μM). These demonstrated complete inhibitory effects on MRSA bacteria over a 23-hour examination period in vitro, and this outcome was corroborated by standard plating and microbial kinetic growth assays. The potent AgNP and PR-39 antibacterial is proposed to be clinically followed by the administration of antioxidant nanoparticles, specifically of yttrium-doped ceria nano fluorite crystals (Y-doped CNPs), in cooperation with isolated viable mitochondria (isoM) for repairing defects in the native host cell mitochondria that could originate from bacterial toxins or interactions. Indeed, compared to human umbilical veins that had been depleted of their mitochondria (ρ_0-HUVECS), those in the (+) Y-doped CNP and (+) isoM treatment category demonstrated a 4.5-fold upregulation of mtDNA-encoded genes. Moreover, the antioxidant nanoparticles, independently, contributed to an up to 47.6% reduction in the intracellular ROS and a 63.5% decrease in caspase-3/7, besides demonstrating significant anti-MRSA and anti-MDR E. coli effects. The outcomes of the research presented within this dissertation are a nanoparticle suite with implications in bacterial pathogenesis aversion and a unique approach to offsetting the cascade of pernicious events leading to host cell impairment caused by bacteria.--Author's abstract