Engineering Biomimetic Anticancer Therapies
Open Access
- Author:
- Aronson, Matthew
- Area of Honors:
- Biomedical Engineering
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Scott H Medina, Thesis Supervisor
Jian Yang, Thesis Honors Advisor
Deb Kelly, Faculty Reader - Keywords:
- De novo design
anticancer peptides
supramolecular assembly
nanostructures
combinatorial therapy
de novo design
anticancer peptides
supramolecular assembly
nanostructures
combinatorial therapy
drug delivery
nanomedicine - Abstract:
- Antimicrobial peptides (AMPs) are short, cationic amphiphiles, ubiquitous in nature as a part of organisms’ immune systems, that preferentially kill bacterial pathogens through folding-dependent membrane disruption. Briefly, this antibacterial activity is initiated by electrostatic interactions between the cationic peptide and anionic bacterial surface, followed by subsequent interpolation of the sequence into the hydrophobic cell envelope of the cell. Interestingly, bacteria and cancer cells share a common trait – both possess an electronegative exterior that distinguishes them from healthy mammalian counterparts. This opens opportunities to re-design antimicrobial peptides (AMPs) into anticancer peptides (ACPs). To test this assertion, I investigate the ability of a pathogen-specific AMP named MAD1, originally designed to kill bacterial tuberculosis, to potentiate the lytic destruction of drug-resistant cancers and synergistically enhance the efficacy of chemotherapeutics. Structure-activity relationships (SAR)-driven de novo design reveals spatial sequestration of amphiphilic regions increases ACP potency, but at the cost of specificity. Biophysical and biochemical studies demonstrate that MAD1 binds to the outer membrane of cancer cells to rapidly form pore-like supramolecular assemblies, leading to rapid cell death through both lytic and apoptotic mechanisms. This diverse anticancer activity enables MAD1 to synergize broadly with chemotherapeutics, particularly against drug-resistant ovarian cancer cells and patient-derived tumor models, leading to remarkable combinatorial potency. Yet, despite the attractive therapeutic properties of synergistic ACPs, like MAD1, their successful translation into clinical practice has gone unrealized due to the poor bioavailability, serum instability and, most importantly, severe hemolytic toxicity of membranolytic sequences. Therefore, in a parallel project, I exploit the membrane-specific interactions of ACPs to prepare a new class of peptide-lipid particle, I term a lipopeptisome (LP). This design sequesters loaded ACPs within a lipid lamellar corona to avoid contact with red blood cells and healthy tissues, while affording potent lytic destruction of cancer cells following LP-membrane fusion. Biophysical studies show ACPs rapidly fold at, and integrate into, liposomal membranes to form stable LPs with high loading efficiencies (>80%). Rational design of the particles to possess lipid combinations mimicking that of the aberrant cancer cell outer leaflet allows LPs to rapidly fuse with tumor cell membranes and afford localized assembly of loaded ACPs within the bilayer. This leads to preferential fusolytic killing of cancer cells with minimal collateral toxicity towards non-cancerous cells and erythrocytes, thereby imparting clinically relevant therapeutic indices to otherwise toxic ACPs. Together, I show cancer-specific ACPs can be rationally engineered using nature’s AMP tool-box as templates, demonstrate the potential of this strategy to open a wealth of synthetic biotherapies that offer new, combinatorial opportunities against drug resistant tumors, and offer the Lipopeptisomes design as a novel drug delivery platform to improve ACP potency and specificity. Future studies will combine this delivery technology with bioinspired ACPs to develop targeted, combinatorial therapies that are effective against multidrug resistant cancers.