A nanoparticle-based combination chemotherapy delivery system for enhanced tumor killing by dynamic rewiring of signaling pathways.
Exposure to the EGFR (epidermal growth factor receptor) inhibitor erlotinib promotes the dynamic rewiring of apoptotic pathways, which sensitizes cells within a specific period to subsequent exposure to the DNA-damaging agent doxorubicin. A critical challenge for translating this therapeutic network rewiring into clinical practice is the design of optimal drug delivery systems. We report the generation of a nanoparticle delivery vehicle that contained more than one therapeutic agent and produced a controlled sequence of drug release. Liposomes, representing the first clinically approved nanomedicine systems, are well-characterized, simple, and versatile platforms for the manufacture of functional and tunable drug carriers. Using the hydrophobic and hydrophilic compartments of liposomes, we effectively incorporated both hydrophobic (erlotinib) and hydrophilic (doxorubicin) small molecules, through which we achieved the desired time sequence of drug release. We also coated the liposomes with folate to facilitate targeting to cancer cells. When compared to the time-staggered application of individual drugs, staggered release from tumor-targeted single liposomal particles enhanced dynamic rewiring of apoptotic signaling pathways, resulting in improved tumor cell killing in culture and tumor shrinkage in animal models.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA.
Stephen W
SW
Morton
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Department of Biology and Biological Engineering, MIT, Cambridge, MA 02139, USA.
Michael J
MJ
Lee
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
Zhou J
ZJ
Deng
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
Erik C
EC
Dreaden
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
Elise
E
Siouve
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
Kevin E
KE
Shopsowitz
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
Nisarg J
NJ
Shah
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Department of Biology and Biological Engineering, MIT, Cambridge, MA 02139, USA. Division of Acute Care Surgery, Trauma, and Critical Care, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. myaffe@mit.edu hammond@mit.edu.
Michael B
MB
Yaffe
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA. Institute for Soldier Nanotechnologies, MIT, Cambridge, MA 02139, USA. myaffe@mit.edu hammond@mit.edu.
Paula T
PT
Hammond
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000493:pharmacokinetics / Q000494:pharmacology; D000069347:Erlotinib Hydrochloride; D005260:Female; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology
D004337:Drug Carriers; D008081:Liposomes; D011799:Quinazolines; D004317:Doxorubicin; D000069347:Erlotinib Hydrochloride