Polymer Nanotechnologies for Rational Combination Therapies against Metastatic Tumors
Drugging solid tumors with combinations of nucleic acids and small molecules can be challenging when cellular colocalization is required for efficient tumor cell killing. These combinations often exhibit vastly differing physiochemical properties and require precise control of both tissue-specific delivery and sequential drug release. My research focuses on the development and translation of engineered polymer technologies that maximize synergistic or synthetic lethal interactions from these combinations while minimizing off-target effects. These include multilayered1 and bottle-brush2 polymer nanoparticles that deliver cocktail chemotherapies3 and chemosensitizing oligodeoxynucleotides4, as well as small interfering RNA that blocks drug efflux5 and combinations of small molecules that dynamically rewire6,7 cell signaling pathways which drive resistance. This work spans polymer design, synthesis, combination development, and in vivo interrogation.
1 Dreaden, E.C., Morton, S.W.; Shopsowitz, K.E., Choi, J.H.; Deng, Z.J.; Cho, N.-J.; Hammond, P.T., Bimodal Tumor-Targeting From Microenvironment Responsive Hyaluronan Layer-by-Layer (LbL) Nanoparticles. ACS Nano, 2014, 8 (8), 8374-8382.
2 Sowers, M.A.; McCombs, J.R.; Wang, Y.; Paletta, J.T.; Morton, S.W.; Dreaden, E.C.; Boska, M.; Ottaviani, F.; Hammond, P.T.; Rajca, A.; Jeremiah, J.A., Redox responsive branched-bottlebrush polymers for in vivo MRI and fluorescence imaging. Nature Communications, 2014, 5, 5460.
3 Liao, L.; Liu, J.; Dreaden, E.C.; Morton, S.; Shopsowitz, K.E.; Hammond, P.T.; Johnson, J.A., A convergent synthetic platform for single-nanoparticle triplex combination cancer therapy: ratiometric loading and release of cisplatin, doxorubicin, and camptothecin. Journal of the American Chemical Society, 2014, 136 (16), 5896–5899.
4 Roh, Y.H.; Lee, J.B.; Shopsowitz, K.E.; Dreaden, E.C.; Morton, S.W.; Poon, Z.; Hong, J.; Yamin, I.; Bonner, D.K.; Hammond, P.T., Layer-by-Layer Assembled Anti-Sense DNA Microsponge Particles for Efficient Delivery of Cancer Therapeutics. ACS Nano, 2014, 8 (10), 9767-9780.
5 Deng, Z.J.; Morton, S.W.; Ben-Akiva, E.; Dreaden, E.C.; Shopsowitz, K.E.; Hammond, P.T., Layer-by-Layer Nanoparticles for Systemic Codelivery of an Anticancer Drug and siRNA for Potential Triple-Negative Breast Cancer Treatment. ACS Nano, 2013, 7 (11), 9571–9584.
6Dreaden, E.C.; Kong, Y.W.; Morton, S.W.; Echevarria, S.C.; Drapkin, R.; Yaffe; M.B.; Hammond, P.T., An Engineered Layer-by-Layer (LbL) Nanoparticle for Tumor-Targeted Synergistic Blockade of MAPK and PI3K, 2015, Clinical Cancer Research, in press.
7 Morton, S.W.; Lee, M.J.; Deng, Z.J.; Dreaden, E.C.; Siouve, E.; Shopsowitz, K.E.; Shah, N.J.; Yaffe, M.B., Hammond, P.T. A Nanoparticle-Based Combination Chemotherapy Delivery System for Enhanced Tumor Killing by Dynamic Rewiring of Signaling Pathways. Science Signaling, 2014, 7 (325), ra44.
Email: edreaden @ mit.edu