PLGA-PEG-NHS/PLGA-PEG-COOH from PolySciTech used in development of nanoparticles for pancreatic cancer treatment

In the early stages of development, pancreatic cancer presents relatively little in terms of symptoms which unfortunately makes it very difficult to detect until later stages when it may be too late to effectively treat. This means pancreatic cancer treatment requires aggressive interventions and targeting in order to be effective. Recently, researchers at Queen's University Belfast, Dublin City University (Ireland), State University of New York, and Roswell Park Comprehensive Cancer Center (USA) used PLGA-PEG-NHS (AI064) and PLGA-PEG-COOH (AI034) from PolySciTech (www.polyscitech.com) to produce targeted nanoparticles against pancreatic cancer. This research holds promise to provide for improved therapies against this often fatal form of cancer in the future. Read more: Johnston, M.C., Nicoll, J.A., Redmond, K.M., Smyth, P., Greene, M.K., McDaid, W.J., Chan, D.K.W., Crawford, N., Stott, K.J., Fox, J.P. and Straubinger, N.L., 2020. DR5-targeted, chemotherapeutic drug-loaded nanoparticles induce apoptosis and tumor regression in pancreatic cancer in vivo models. Journal of Controlled Release. https://www.sciencedirect.com/science/article/pii/S0168365920303230 

“Highlights: The death receptor 5 pathway is upregulated in pancreatic cancer and correlates with poorer prognosis. Conjugation of AMG 655 to the nanoparticle surface renders it capable of inducing apoptosis via death receptor 5 in pancreatic cancer cell lines. FLIP downregulation increases response to TRAIL and nanoparticle conjugated AMG 655. Camptothecin entrapment causes downregulation of FLIP. CRISPR targeting shows conjugated AMG 655 efficacy is FADD and caspase 8 dependent. Abstract: Pancreatic cancer is usually advanced and drug resistant at diagnosis. A potential therapeutic approach outlined here uses nanoparticle (NP)-based drug carriers, which have unique properties that enhance intra-tumor drug exposure and reduce systemic toxicity of encapsulated drugs. Here we report that patients whose pancreatic cancers express elevated levels of Death Receptor 5 (DR5) and its downstream regulators/effectors FLIP, Caspase-8, and FADD had particularly poor prognoses. To take advantage of elevated expression of this pathway, we designed drug-loaded NPs with a surface-conjugated αDR5 antibody (AMG 655). Binding and clustering of the DR5 is a prerequisite for efficient apoptosis initiation, and the αDR5-NPs were indeed found to activate apoptosis in multiple pancreatic cancer models, whereas the free antibody did not. The extent of apoptosis induced by αDR5-NPs was enhanced by down-regulating FLIP, a key modulator of death receptor-mediated activation of caspase-8. Moreover, the DNA topoisomerase-1 inhibitor camptothecin (CPT) down-regulated FLIP in pancreatic cancer models and enhanced apoptosis induced by αDR5-NPs. CPT-loaded αDR5-NPs significantly increased apoptosis and decreased cell viability in vitro in a caspase-8- and FADD-dependent manner consistent with their expected mechanism-of-action. Importantly, CPT-loaded αDR5-NPs markedly reduced tumor growth rates in vivo in established pancreatic tumor models, inducing regressions in one model. These proof-of-concept studies indicate that αDR5-NPs loaded with agents that downregulate or inhibit FLIP are promising candidate agents for the treatment of pancreatic cancer.”