Preclinical Evaluation of Promitil, a Radiation-Responsive Liposomal Formulation of Mitomycin C Prodrug, in Chemoradiotherapy.
To examine the effect of radiation on in vitro drug activation and release of Promitil, a pegylated liposomal formulation of a mitomycin C (MMC) lipid-based prodrug; and examine the efficacy and toxicity of Promitil with concurrent radiation in colorectal cancer models.



Promitil was obtained from Lipomedix Pharmaceuticals (Jerusalem, Israel). We tested the effects of radiation on release of active MMC from Promitil in vitro. We next examined the radiosensitization effect of Promitil in vitro. We further evaluated the toxicity of a single injection of free MMC or Promitil when combined with radiation by assessing the effects on blood counts and in-field skin and hair toxicity. Finally, we compared the efficacy of MMC and Promitil in chemoradiotherapy using mouse xenograft models.



Mitomycin C was activated and released from Promitil in a controlled-release profile, and the rate of release was significantly increased in medium from previously irradiated cells. Both Promitil and MMC potently radiosensitized HT-29 cells in vitro. Toxicity of MMC (8.4 mg/kg) was substantially greater than with equivalent doses of Promitil (30 mg/kg). Mice treated with human-equivalent doses of MMC (3.3 mg/kg) experienced comparable levels of toxicity as Promitil-treated mice at 30 mg/kg. Promitil improved the antitumor efficacy of 5-fluorouracil-based chemoradiotherapy in mouse xenograft models of colorectal cancer, while equitoxic doses of MMC did not.



We demonstrated that Promitil is an attractive agent for chemoradiotherapy because it demonstrates a radiation-triggered release of active drug. We further demonstrated that Promitil is a well-tolerated and potent radiosensitizer at doses not achievable with free MMC. These results support clinical investigations using Promitil in chemoradiotherapy.
Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Xi
X
Tian
Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Samuel B
SB
Warner
Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Kyle T
KT
Wagner
Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Joseph M
JM
Caster
Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
Tian
T
Zhang
Lipomedix Pharmaceuticals, Jerusalem, Israel.
Patricia
P
Ohana
Lipomedix Pharmaceuticals, Jerusalem, Israel; Shaare Zedek Medical Center, Jerusalem, Israel.
Alberto A
AA
Gabizon
Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Electronic address: zawang@med.unc.edu.
Andrew Z
AZ
Wang
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy / Q000379:methods*; D015179:Colorectal Neoplasms / Q000473:pathology* / Q000628:therapy*; D003692:Delayed-Action Preparations / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005260:Female; D019073:HT29 Cells; D006801:Humans; D008081:Liposomes / Q000528:radiation effects; D051379:Mice; D008819:Mice, Nude; D016685:Mitomycin / Q000008:administration & dosage*; D011355:Prodrugs / Q000008:administration & dosage*; D011879:Radiotherapy Dosage; D016896:Treatment Outcome
D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D008081:Liposomes; D011355:Prodrugs; D016685:Mitomycin