ReGel polymer-based delivery of interleukin-2 as a cancer treatment.
ReGel is an aqueous, filter sterilizable ABA tri-block polymer consisting of poly-(lactide-co-glycolide) and polyethylene glycol. We tested the suitability of this polymer to provide sustained interleukin-2 (IL-2) delivery for cancer immunotherapy. ReGel/IL-2 is liquid at or below room temperature, and is easily injectable through narrow gauge needles, but undergoes a reversible thermal transition into a bioerodible depot at body temperature. We demonstrated that ReGel/IL-2 releases IL-2 over 72 to 96 hours in vitro, without loss of bioactivity. Pharmacokinetic studies after peritumoral injection of 0.1 mL ReGel/IL-2 in mice demonstrated an early burst of IL-2 release, followed by more sustained release kinetics over 96 hours (T(1/2)beta 48 h). Less than 1.5% of the injected dose was detectable in blood or kidneys during the first 48 hours. A single peritumoral dose of ReGel/IL-2 [1 to 4 million international units (MIU) ReGel/IL-2, split into 4 quadrant injections] was administered to mice bearing subcutaneous RD-995 spindle cell carcinoma. Only the highest dose of ReGel/IL-2 tested (4.0 MIU) resulted in significant hypotension on day 3 after injection. Weekly treatment of Meth A fibrosarcoma and RENCA renal carcinoma with ReGel/IL-2 (2 MIU/dose) induced a significant reduction in tumor growth and improved survival. Reduction in tumor growth at implants remote from treated lesions was also observed, suggesting systemic activation of antitumor immunity. These findings establish that peritumoral injection of ReGel/IL-2 is an effective delivery system for cancer immunotherapy, while decreasing IL-2 toxicity. This polymer delivery system is likely to be broadly applicable for sustained delivery of other cytokines and peptides.
Samlowski
Wolfram E
WE
Multidisciplinary Melanoma Program, Huntsman Cancer Institute, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USA. wolfram.samlowski@hci.utah.edu
McGregor
John R
JR
Jurek
Maria
M
Baudys
Miroslav
M
Zentner
Gaylen M
GM
Fowers
Kirk D
KD
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002292:Carcinoma, Renal Cell; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005354:Fibrosarcoma; D007022:Hypotension / Q000139:chemically induced; D015552:Injections, Intralesional; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols; D011098:Polyglactin 910; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000970:Antineoplastic Agents; D004337:Drug Carriers; D007376:Interleukin-2; D011098:Polyglactin 910; D011092:Polyethylene Glycols