Targeting chemotherapy induced adaptive resistance using hybrid nanoparticles (LB577)

Abstract

Chemotherapy is still a standard of care in adjuvant treatment of breast cancer, but it often leads to incomplete tumor response resulting in acquisition of chemoresistance and relapse, primarily due to upregulation of survival signals in tumor cells. To overcome this, chemotherapeutic agent and signaling inhibitor need to be delivered to the same cell sequentially with a precise spatial and temporal control. We designed a hybrid nanoparticle platform that synergistically integrates a cytotoxic agent with an ‘Oncogenic Signaling Inhibitor’ into a single nanovector thereby overcomes adaptive resistance to cytotoxics, increase efficacy & minimize significant off‐target toxicities. As traditional approaches for nanoformulation were incompatible with cytotoxic molecules such as Paclitaxel (PTX) and PI3K inhibitors (PI103), we rationally re‐engineered these molecules by conjugating it to cholesterol to enable supramolecular nanoassembly. Hybrid supramolecular nanoparticles were synthesized by lipid film hydration method. In vitro cytotoxicity studies in multiple cell lines including Breast Cancer (4T1, MDA‐MB‐231), Ovarian Cancer (4306) and Lung Cancer (A549, LLC) showed that hybrid nanoparticles were as effective as free drug combinations and more potent that individual drug nanoparticles. In both 4T1 breast cancer and in a K‐RasLSL/+/Ptenfl/fl ovarian cancer model in vivo, hybrid nanoparticles exerted superior antitumor efficacy as compared with free drugs & individual drug combination (p<0.01, one way ANOVA). Immunohistochemistry staining of tumor tissues for p‐AKT showed that the hybrid nanoparticles had significantly higher inhibition of p‐AKT as compared to individual drug nanoparticles (p<0.01, Student t‐test). These results posit supramolecular nanochemistry as a powerful approach that can potentially impact clinical translation of cytotoxic agents and PI3K inhibitors, and could be extended to enhance the efficacy of molecularly targeted therapeutics. Additionally, rational optimization of the chemical structures to facilitate supramolecular assembly can overcome existing limitations associated with parent molecules, thereby opening up possibility of resuscitating promising drug candidates that had failed to translate to clinics, rejuvenating drug pipelines.Grant Funding Source: National Institute of Health, Department of Defense, BCRP Collaborative Innovator award