When
Location
Sarver Heart Center (SHC), room 4137
Abstracts
Meenu Priya Resmi
"Bio – Templated Nanocluster as Precision Delivery Platforms"
A major challenge in cancer research is delivering drugs that selectively target tumors while preserving therapeutic activity and minimizing off-target effects. Proteins are an excellent delivery platform because of their natural properties, including structural versatility, molecular recognition, and customizability. However, once in the body, proteins become unstable, degrade, and are rapidly cleared from circulation. In recent years, researchers have used protein-coated nanocarriers to deliver therapeutics to tumor sites because their small size and customizability can enhance stability and prolong circulation time in the human body. However, nanocarriers entering the serum interact with proteins, forming a protein corona that can cause aggregation, immunogenicity, and off-target effects that lead to long-term toxicity. These challenges underscore the need for a delivery system that combines nanomaterials' stability and versatility with proteins’ natural targeting ability and biological functions. Metallic nanoclusters offer a promising approach by using proteins as templates around ultrasmall metallic cores. The proteins act as a cage around the core metal atoms, potentially limiting protein adsorption and subsequent corona formation. Unfortunately, current synthesis methods fail to preserve the protein structure and function; moreover, chemical agents can compromise biocompatibility. To address this, we introduced a novel synthesis, cryophotosynthesis, that uses cryochemistry and UV irradiation to synthesize nanoclusters using biologically relevant proteins for cancer targeting, as a proof-of- concept using Lactoferrin. Lactoferrin is an iron-binding glycoprotein that binds to LRP1 receptors overexpressed in cancer, enabling receptor-mediated uptake. Optical, structural, and functional characterization confirmed the successful development of fluorescent, protein-templated metallic nanoclusters with preserved biological functionality. Preliminary studies in colon cancer xenograft models showed considerable tumor accumulation, substantial renal clearance of gold-containing species, and minimal accumulation in the heart and lungs, with no acute toxicity observed within 48 hours. These findings highlight protein-templated metallic nanoclusters as a promising platform for targeted therapeutic delivery in cancer.
Catherine Vasquez
"Z06 Targets cTnT-Tm Overlap Structure and Improves Cardiac Function in Cardiomyopathy Models"
An important component of cardiac myofilament activation is the overlap structure between neighboring tropomyosin (Tm) molecules and the N-terminal extension of cardiac troponin T (cTnT). Previous studies have shown that mutations flanking this region induce structural changes that alter myofilament function. We investigated the effects of the dilated cardiomyopathy-associated mutation D230N-Tm and the hypertrophic cardiomyopathy-associated mutation D219N-Tm on overlap structure using time-resolved fluorescence resonance energy transfer (TR-FRET). D230N-Tm decreased the distance between donor-labeled cTnT (IAEDANS) and acceptor-labeled Tm (DDPM) sites in the absence of calcium compared to WT cardiac thin filaments. Conversely, D219N-Tm exhibits a decrease across cTnT and Tm sites in the presence of saturating calcium. Given these structural changes we investigated the potential for targeting the observed compaction via small molecule, Z06, to improve myofilament function. We treated D230N-Tm, D219N-Tm, and WT reconstituted cardiac thin filaments (CTFs) with 10 μM Z06 and performed TR-FRET. Z06 restored the overlap distance in both D230N-Tm and D219N-Tm CTFs, with minimal effects on WT CTFs. To determine whether alleviating cTnT-Tm overlap compaction improves cardiac function, we administered Z06 to 2-month-old D230N-Tm and D219N-Tm mice and their Non-transgenic (NTg) littermates. At baseline, D230N-Tm mice exhibited decreased fractional shortening (%FS; 18.46 ± 0.462) compared with NTg littermates (28.82 ± 0.606), whereas D219N-Tm mice exhibited increased %FS (38.12 ± 0.743). Following four weeks of treatment, %FS improved in D230N-Tm (25.19 ± 0.812) and D219N-Tm (30.94 ± 0.438) mice, with no significant changes in NTg littermates. These data suggest the potential for targeting structural changes caused by mutations to improve downstream function.