Breast cancer continues to remain a major health care concern in the U.S. The triple-negative breast cancer (TNBC) subtype tends to be particularly aggressive with poor prognosis. Triple combination therapy by encapsulating a chemotherapeutic agent, immunotherapeutic agent and interfering RNA (RNAi) may enhance treatment response in TNBC. First-line treatment of TNBC currently includes docetaxel, or pegylated liposomal doxorubicin followed by docetaxel. These drugs are toxic to healthy normal cells in addition to cancer tissues. Furthermore, metastatic tumor treatment can fail due to multi-drug resistance (MDR) to standard therapies. We aim to mitigate MDR through combination treatment and reduce peripheral toxicity by drug encapsulation and active targetting.
Co-delivery of cytotoxic agent docetaxel, tyrosine kinase inhibitor sunitinib, and anti-VEGF RNAi is a promising alternative that may mitigate the pro-survival tumor response to chemotherapy. Solid lipid nanoparticles will be synthesized by encapsulating docetaxel within PLGA nanoparticles (NPs). The NPs will be surrounded with a lipid bilayer while embedding sunitinib and anti-VEGF oligonucleotides at the interface of the PLGA polymers and the lipid bilayer to create liposomal chemo- immunotherapeutic nanocarriers (LICHINs, see Figure 1). Furthermore, we will coat LICHINs with folic acid, actively targeting folate receptor alpha, commonly overexpressed in TNBC cells.
NPs will be characterized based on particle size, polydispersity, and zeta potential. Carrier production will be optimized for uniformity based on these characteristics, as well as encapsulation efficiency and surface morphology. Treatment efficacy will be evaluated for cytotoxicity in MDA-MB-231 cells. The impact of RNAi delivery on down-regulation of VEGF will also be evaluated by assay. If successful, LICHINs will represent a novel delivery platform for targeting tumor cell proteins and mRNA via chemo, immuno and gene therapy while minimizing treatment toxicity.