Evaluation of the effect of SMA-pirarubicin micelles on colorectal cancer liver metastases and of hyperbaric oxygen in CBA mice.
Tetrahydropyranyladriamycin (THP or pirarubicin) destroys tumors via several mechanisms; one of which involves the production of ROS that requires molecular oxygen for its generation. SMA forms stable self-assembled associated micelles with pirarubicin (SMA-pirarubicin), and confers macromolecular characteristics to pirarubicin. This micellar macromolecular drug is selectively delivered to solid tumors via the EPR effect and its preferential tumor accumulation suppresses the systemic toxicity whilst its prolonged high concentration at the site of tumor enhances its efficacy much higher compared to free pirarubicin. Administration of SMA-pirarubicin micelle under HBO can further enhance the delivery of molecular oxygen that facilitates tumor selective generation of ROS, thus augmenting its antitumor potency. In this study, we evaluated the efficacy of SMA-pirarubicin micelles either as single drug or in combination with HBO in a mouse metastatic colorectal cancer model. At or below the maximum tolerated dose, SMA-pirarubicin remarkably reduced metastatic tumor nodules and it was far more effective than free pirarubicin. The data also suggests a potential benefit of combined therapy of HBO with micellar anthracyclins.
Department of Surgery, Austin Health Hospital, University of Melbourne, Heidelberg, Vic., Australia.
Jurstine
J
Daruwalla
Khaled
K
Greish
Mehrdad
M
Nikfarjam
Ian
I
Millar
Cathy
C
Malcontenti-Wilson
Arun K
AK
Iyer
Chris
C
Christophi
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000473:pathology*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D016503:Drug Delivery Systems; D006931:Hyperbaric Oxygenation; D008113:Liver Neoplasms / Q000556:secondary / Q000628:therapy*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008823:Micelles; D008855:Microscopy, Electron, Scanning; D010539:Permeability; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D008823:Micelles; D017382:Reactive Oxygen Species; D004317:Doxorubicin; C027260:pirarubicin