Abstract A105: Novel lignin-conjugated PLGA drug delivery system improves efficacy of MEK1/2 inhibitor in triple negative breast cancer
Authors: Byrne Ethan , Astete Carlos E. , Vaithiyanathan Manibarathi , Melvin Adam T , Moradipour Mahsa , Rankin Stephen E. , Knutson Barbara L. , Martin Elizabeth C. , Sabliov Cristina 
Published: March 2020

In 2019, it is predicted that more than a quarter of a million women in the U.S. will be diagnosed with breast cancer (BC). Nearly 15% of those cases will be classified as triple negative breast cancer (TNBC). Patients with TNBC typically have a worse prognosis due to its lack of classically targeted hormone receptors associated with other BC subtypes. Because the more well tolerated targeted endocrine therapies cannot be used to treat TNBC, novel targeted therapies and drug delivery systems must be created. They are needed to assist physicians in battling TNBC while minimizing deleterious effects and comorbidities for the patients associated with chemotherapies that are used as adjuvant therapies. Here we propose a novel lignin-conjugated-PLGA (L-PLGA) biopolymer for a nanoparticle drug delivery system (NPDDS) to improve the efficacy of the targeted therapy GDC-0623, a MEK1/2 inhibitor, to treat the TNBC cell line, MDA-MB-231. We compared our NPDDS to the commonly used PLGA. Our L-PLGA-GDC NPs had an average size of 78 ± 4 nm while PLGA-GDC NPs were 201 ± 2.5 nm making L-PLGA-GDC better suited for passive targeting based on the enhanced permeability and retention effect. Despite having a greater surface-to-volume ratio which favors diffusion, the L-PLGA NPs loaded with drug exhibited a more sustained release over 48 hours than the larger PLGA NPs. QCM-D modeling predicted the ability of our L-PLGA NPs to interact with the lipid bilayer of cells. Cells treated with L-PLGA-GDC NPs had a significant reduction in cell numbers (nearly 50%) compared to free GDC-0623 and PLGA-GDC NPs. Western blot confirmed L-PLGA-GDC was better at inhibiting phosphorylation of GDC-0623 target protein ERK1/2 than free GDC-0623 or PLGA-GDC NPs. We hypothesize that the increase in efficacy was due to the NPs interacting with the cell membrane, being taken up by the cell, and increasing the local drug concentration. This mechanism was predicted by QCM-D and confirmed by fluorescent microscopy of TRITC-conjugated NPs. Cells treated with GDC-0623 presented a different morphology than untreated cells and qPCR confirmed that GDC-0623 reverses EMT in MDA-MB-231 cells. L-PLGA-GDC was more effective at reversing EMT than free GDC-0623 and PLGA-GDC NPs. Our findings indicate that lignin conjugation improves characteristics of PLGA NPDDSs and improves efficacy of GDC-0623 in multiple assays.

Citation Format: Ethan Byrne, Carlos E. Astete, Manibarathi Vaithiyanathan, Adam T Melvin, Mahsa Moradipour, Stephen E. Rankin, Barbara L. Knutson, Elizabeth C. Martin, Cristina Sabliov. Novel lignin-conjugated PLGA drug delivery system improves efficacy of MEK1/2 inhibitor in triple negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A105. doi:10.1158/1535-7163.TARG-19-A105