Over the past two decades, polymeric micelles have been investigated as carriers to provide increased solubility and improved in vivo circulation for anticancer drugs with poor distribution, such as paclitaxel (PTX) and doxorubicin. Furthermore, micelles approximately 10–100nm take advantage of the enhanced permeability and retention (EPR) effect for preferential localization to tumors. However, these micelles are thermo-dynamic systems constantly dissociating and associating into their monomers, thereby posing a challenge whereby these micelles fall below critical micelle concentration (CMC). To address this, hafnium (Hf), demonstrated as a radio-enhancer in metal- organic frameworks (MOFs), was utilized to cross-link linear-dendritic amphiphilic polymers (telodendrimers) to develop a self-assembling polymeric nanoparticle (NP) with enhanced stability. The dendrimer portion was synthesized via solution-phase condensation reactions beginning with MeO-PEG5000-NH2 utilizing stepwise peptide chemistry of branched lysine residues. The resulting amphiphilic dendrimer contained 8 terminal amines which were then coupled with 4 cholic acid (CA) moieties and 4 carboxylic acid (COOH) functional groups to yield a PEG5000-CA4/COOH4 telodendrimer. The resulting hybrid telodendrimers self-assembled into ~30 nm nanoparticles, as measured by dynamic light scattering (DLS), and upon addition of HfCl4, cross-linking chelation occurred to stabilize the nanoparticles up to 20 mg/mL of sodium dodecyl sulfate (SDS). Furthermore, this Hf-NP shows efficient drug loading and uptake by a number of cancer cell lines, as observed under confocal microscopy. Development of this novel hafnium cross-linked drug-delivery nanoparticle not only boasts increased in vivo stability during circulation, but also serves as a potent radio-enhancer for more efficacious radiotherapy.

All living cells are enclosed by biological membranes, comprising of lipid bilayers formed by self-assembly of phospholipids, membrane proteins, cholesterol etc. Membrane active peptides (MAPs) are peptides that interact with the lipid bilayer, perturbing the structure and function of the biological membranes, impacting the function of the living cells. Antimicrobial peptides (AMPs), are a subset of MAPs that interact with pathogenic microbial membranes, disrupting the integrity of the lipid bilayer, using mechanisms such as pore formation, resulting in membrane leakage and cell death. Since MAPs interact directly with cell membranes, they are becoming increasingly important as a possible solution to multi-drug resistant pathogens. Multi-drug resistant fungal infections due to opportunistic and pathogenic fungi are one of the most common infections in the world. Millions of people across the globe are affected by these infections and about 1.5 million people each year succumb to this disease. Amphotericin B and azole drugs such as fluconazole and ketoconazole are common anti-fungal agents that have been used for many years but have a variety of short-term and long-term side effects and have induced widespread resistance in fungi. Therefore, there is dire need for the discovery of novel membrane active peptides with antimicrobial activities, and understanding how they interact with cell membranes. By applying this knowledge, we hope to develop highly selective antifungal membrane active peptides.In this dissertation, we report on the successful use of one-bead one-compound (OBOC) combinatorial library method to discover new MAPs with antifungal properties. To better understand the mechanism of action of these MAPs, we have used various methods to biochemically and biologically characterize these peptides.

Non-small cell lung cancer (NSCLC) is the largest contributor to cancer mortality in the United States. Traditional chemotherapies are toxic and prone to the development of drug resistance. Recently, several drug candidates were shown to induce lysosomal membrane permeabilization (LMP) in aggressive cancers. This has led to increased interest in lysosome dysregulation as a therapeutic target. However, approaches are needed to overcome two limitations of current lysosomal inhibitors: low specificity and potency. Here, we report the development of a transformable nanomaterial that is triggered to induce LMP of lysosomes in NSCLC. The nanomaterial consists of peptide amphiphiles, which self-assemble into nanoparticles, colocalize with the lysosome, and change conformation to nanofibrils due to lysosomal pH shift, leading to the disruption of the disruption of the lysosome, cell death, and cisplatin sensitization. We have found that this cell-penetrating transformable peptide nanoparticle (CPTNP) was cytotoxic to NSCLC cells in the low-micromolar range, synergizing cisplatin cytotoxicity four-fold. Moreover, we demonstrate CPTNP's promising antitumor effect in mouse xenograft models with limited toxicity when given in combination with low-dose cisplatin chemotherapy. CPTNPs the first example of enhanced LMP via transformable peptide nanomaterial and offers a promising new strategy for cancer therapy. Crispr-Cas genome editing promises to revolutionize medicine as it is currently conceived; if it can overcome the challenge of target tissue delivery. Several CRISPR-Cas delivery systems have been developed which can systemically edit somatic tissue in vivo if IV delivered. However, no system currently exists which can edit somatic cells after the oral delivery of CRISPR-Cas. Hepatitis E virus like nanoparticles, were originally developed by the Cheng group and have previously been used to deliver plasmid-based vaccines orally, and are a promising platform for the oral delivery of nucleic acid and protein cargos. Herein we develop Cas9 ribonucleoprotein -loaded Hepatitis E virus-like nanoparticles capable of delivering CRISPR-Cas editing systems in vivo via the oral route. We demonstrate 39% editing efficiency in vitro and up to 10% editing efficiency in the crypts of small intestinal tissue. This is the first example of orally available Crispr-Cas gene editing. Together these systems represent two novel nano-systems which make major advancements in self-assembling cancer therapeutics and orally available gene editing.

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