title: Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells.
abstract: Tumor cells disseminate into compartments that are poorly accessible from circulation, which necessitates high doses of systemic chemotherapy. However, the effectiveness of many drugs, such as the potent topoisomerase I poison SN-38, is hampered by poor pharmacokinetics. To deliver SN-38 to lymphoma tumors in vivo, we took advantage of the fact that healthy lymphocytes can be programmed to phenocopy the biodistribution of the tumor cells. In a murine model of disseminated lymphoma, we expanded autologous polyclonal T cells ex vivo under conditions that retained homing receptors mirroring lymphoma cells, and functionalized these T cells to carry SN-38-loaded nanocapsules on their surfaces. Nanocapsule-functionalized T cells were resistant to SN-38 but mediated efficient killing of lymphoma cells in vitro. Upon adoptive transfer into tumor-bearing mice, these T cells served as active vectors to deliver the chemotherapeutic into tumor-bearing lymphoid organs. Cell-mediated delivery concentrated SN-38 in lymph nodes at levels 90-fold greater than free drug systemically administered at 10-fold higher doses. The live T cell delivery approach reduced tumor burden significantly after 2 weeks of treatment and enhanced survival under conditions where free SN-38 and SN-38-loaded nanocapsules alone were ineffective. These results suggest that tissue-homing lymphocytes can serve as specific targeting agents to deliver nanoparticles into sites difficult to access from the circulation, and thus improve the therapeutic index of chemotherapeutic drugs with unfavorable pharmacokinetics.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Huang
authors.affiliation: Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA. Department of Materials Science and Engineering, MIT, Cambridge, MA 02139, USA.
authors.forename: Wuhbet D
authors.initials: WD
authors.lastname: Abraham
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA. Department of Materials Science and Engineering, MIT, Cambridge, MA 02139, USA.
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Bustamante López
authors.affiliation: Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA. Department of Materials Science and Engineering, MIT, Cambridge, MA 02139, USA.
authors.forename: Samantha S
authors.initials: SS
authors.lastname: Luo
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA. Department of Materials Science and Engineering, MIT, Cambridge, MA 02139, USA. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. djirvine@mit.edu.
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Irvine
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D024201:Bystander Effect / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D000077146:Irinotecan; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D053769:Nanocapsules / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry*; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007376:Interleukin-2; D053769:Nanocapsules; D016201:Receptors, Lymphocyte Homing; D000077146:Irinotecan; D020123:Sirolimus; D002166:Camptothecin