Optimizing pH-responsive Polymeric Micelles for Drug Delivery in a Cancer Photodynamic Therapy Model

• Published in: Journal of drug targeting 2002, Vol.10 (5), p.429-437
• Main Authors: Le Garrec, D., Taillefer, J., Van Lier, J.E., Lenaerts, V., Leroux, J.-C.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Division - drug effects; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Drug Carriers - administration & dosage; Drug Carriers - chemistry; Drug Carriers - pharmacokinetics; General pharmacology; Hydrogen-Ion Concentration; Indoles - administration & dosage; Indoles - pharmacokinetics; Indoles - pharmacology; Male; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Mammary Neoplasms, Experimental - therapy; Medical sciences; Mice; Mice, Inbred BALB C; Micelles; N -Vinyl-2-pyrrolidone; Organometallic Compounds - administration & dosage; Organometallic Compounds - pharmacokinetics; Organometallic Compounds - pharmacology; Ph-Sensitivity; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Photochemotherapy - methods; Photosensitizing Agents - administration & dosage; Photosensitizing Agents - pharmacokinetics; Photosensitizing Agents - pharmacology; Phthalocyanine; Poly (N -isopropylacrylamide); Polymeric Micelles; Polymers - administration & dosage; Polymers - chemistry; Polymers - pharmacokinetics; Tissue Distribution
• ISSN: 1061-186X; 1029-2330
• DOI: 10.1080/1061186021000001887

Different pH-sensitive, randomly- and terminally-alkylated N -isopropylacrylamide (NIPAM) copolymers were synthesized and used to prepare pH-responsive polymeric micelles (PM). These copolymers were modified from previously-studied copolymers by incorporating an additional hydrophilic monomer, N- vinyl-2-pyrrolidone (VP) to decrease uptake by the mononuclear phagocyte system (MPS) and improve localization in tumors. VP lowered the phase transition pH of the copolymers but did not affect the onset of micellization. The in vitro cytotoxicity of the copolymers was evaluated on EMT-6 mouse mammary tumor cells in comparison to Cremophor EL (CRM). The anticancer photosensitizer aluminum chloride phthalocyanine (AlClPc) was loaded into the PM with a standard dialysis procedure. Biodistribution and in vivo photodynamic activity were then evaluated in Balb/c mice bearing intradermal EMT-6 tumors. All NIPAM copolymers demonstrated substantially lower cell cytotoxicity than the control surfactant CRM. In vivo, similar AlClPc tumor uptake was observed for the PM and CRM formulations. However, the PM appeared to exhibit greater activity in vivo than CRM formulation at an AlClPc subtherapeutic dose. Therefore, NIPAM-based copolymers containing VP units represent promising alternatives for the formulation of poorly water-soluble phthalocyanines.