In-vitro and in-vivo evaluation of pH-responsive polymeric micelles in a photodynamic cancer therapy model.
pH-sensitive polymeric micelles of randomly and terminally alkylated N-isopropylacrylamide copolymers were prepared and characterized. Aluminium chloride phthalocyanine (AlClPc), a second generation sensitizer for the photodynamic therapy of cancer, was incorporated in the micelles by dialysis. Their photodynamic activities were evaluated in-vitro against EMT-6 mouse mammary tumour cells and in-vivo against EMT-6 tumours implanted intradermally on each hind thigh of Balb/c mice. pH-sensitive polymeric micelles were found to exhibit greater cytotoxicity in-vitro than control Cremophor EL formulations. In the presence of chloroquine, a weak base that raises the internal pH of acidic organelles, in-vitro experiments demonstrated the importance of endosomalllysosomal acidity for the pH-sensitive polymeric micelles to be fully effective. Biodistribution was assessed by fluorescence of tissue extracts after intravenous injection of 2 micromol kg(-1) AlClPc. The results revealed accumulation of AlClPc polymeric micelles in the liver, spleen and lungs, with a lower tumour uptake than AlClPc Cremophor EL formulations. However, polymeric micelles exhibited similar activity in-vivo to the control Cremophor EL formulations, demonstrating the higher potency of AlClPc polymeric micelles when localized in tumour tissue. It was concluded that polymeric micelles represent a good alternative to Cremophor EL preparations for the vectorization of hydrophobic drugs.
Taillefer
J
J
Faculty of Pharmacy, University of Montreal, Qc, Canada.
Brasseur
N
N
van Lier
J E
JE
Lenaerts
V
V
Le Garrec
D
D
Leroux
J C
JC
D000178:Acrylamides / Q000737:chemistry*; D000077410:Aluminum Chloride; D017607:Aluminum Compounds / Q000737:chemistry*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002712:Chlorides / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008325:Mammary Neoplasms, Experimental / Q000628:therapy; D051379:Mice; D008823:Micelles; D009369:Neoplasms / Q000628:therapy*; D010778:Photochemotherapy / Q000379:methods*; D011108:Polymers; D011838:Radiation-Sensitizing Agents / Q000737:chemistry*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000178:Acrylamides; D017607:Aluminum Compounds; D002712:Chlorides; D008823:Micelles; D011108:Polymers; D011838:Radiation-Sensitizing Agents; D000077410:Aluminum Chloride; C067295:N-isopropylacrylamide