Business (w Concentration in Healthcare Management and Consulting), '23
Nano-Talazoparib and Nano-Dinaciclib Combination Therapy for Lung Cancer Cells
Mentor: Srinivas Sridhar, Ph.D. (Northeastern University)
This study examines the combination of Talazoparib (TLZ) and Dinaciclib (DCB) as a strategy to increase inhibition of DNA strand repair in lung cancer cells while simultaneously reducing toxicological effects of both therapies through nanoparticle encapsulation. TLZ is a poly(ADP-ribose) polymerase inhibitor (PARPi) that inhibits PARP1, an enzyme crucial in the regulation of both the homologous recombination repair mechanism and the base excision repair pathway. This mechanism is especially productive in cells with BRCA1/2 mutations and is able to provoke necrosis, as, without PARP, cells are unable to repair DNA double-strand breaks by homologous recombination. DCB is a cyclin-dependent kinase (CDK) inhibitor that blocks CDKs 1, 2, 5 and 9 which contribute to cell cycle regulation during translation, as well as CDK 12, a transcriptional regulator of homologous recombination. Inhibiting the functions of CDKs, which play a vital role throughout the cell cycle, can result in cell cycle arrest. These two therapies can act synergistically in combination to induce a lethal interaction in cells that have developed PARPi resistance. CDK inhibitors are able to sensitize cells to PARPi treatment by downregulating various genes in the DNA damage repair pathway. Delivering these two drugs via biocompatible liposome and lipid nanoparticles offers a drug delivery system that can reduce the compounded hematological toxicities of the treatments while providing increased tissue permeability and extended drug release time to allow the two therapies to effectively work in combination. This therapy is modeled both in vitro using the Calu6 cell line, and subcutaneously in immunodeficient mice.
A nanoparticle assembler is used to combine a lipid mix containing MPEG-PLGA with each drug. Danaciclib (left) is encapsulated inside a lipid monolayer to create a lipid nanoparticle and Talazoparib (right) is encapsulated within a lipid bilayer to create a liposome nanoparticle. The particles exhibited contain surface antibodies. Source: