A Biodegradable pH-sensitive Micelle System for Targeting Acidic Solid Tumors

• Published in: Pharmaceutical research Vol. 25; no. 3; pp. 657 - 666
• Main Authors: Sethuraman, Vijay A., Lee, Myung Cheon, Bae, You Han
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-03-2008; Springer; Springer Nature B.V
• Subjects: Acidity; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biochemistry; Biocompatible Materials; Biodegradable materials; Biological and medical sciences; Biological Transport; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Cancer; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Pharmaceutical; Chemotherapy; Doxorubicin - chemistry; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug Carriers; Drug Compounding; General pharmacology; Humans; Hydrogen-Ion Concentration; Lactates - chemistry; Medical Law; Medical sciences; Micelles; Neoplasms - drug therapy; Neoplasms - metabolism; Particle Size; Peptide Fragments - chemistry; Peptides - chemistry; Pharmaceutical technology. Pharmaceutical industry; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Polyethylene Glycols - chemistry; Polymers; Polymers - chemical synthesis; Polymers - chemistry; Polymers - metabolism; Research Paper; Sulfadiazine - chemistry; Trans-Activators - chemistry; degradable pH sensitive polymer; disulfide polymer; tumor pH; pH-sensitive polymer; Solid tumor; Pharmaceutical technology; Targeting; Biodegradability; Controlled release form; Control release polymer; Micelle; Malignant tumor; Target; Dosage form; pH; Cancer
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-007-9480-4

A new pH-sensitive micelle delivery system based on TAT cell penetrating peptide and biodegradable sulfonamide grafted disulfide polymer is presented. The system consists of two components: (1) A polymeric micelle made of Poly(
l
-lactic acid)-
b
-poly(ethylene glycol) (PLLA-
b
-PEG) conjugated to TAT (TAT-micelle), (2) A pH-sensitive diblock copolymer (poly(
l
-cystine bisamide-
g
-sulfadiazine))-
b
-PEG (PCBS-
b
-PEG). The anionic PCBS complexed with cationic TAT of TAT-micelles forms the final carrier. PCBS showed rapid degradation in the presence of cysteine. The TAT-micelles showed increase in particle size between pH 8.0 and 7.0 upon mixing with PCBS-
b
-PEG indicating complexation. As the pH was further decreased (pH 6.8 to 6.0) two populations were observed, one of normal TAT-micelles and the other of aggregated PCBS-
b
-PEG. Flow cytometry showed significantly higher uptake of TAT-micelles at pH 6.6 indicating deshielding compared to pH 7.4. The anticancer drug doxorubicin (DOX) was encapsulated into the TAT-micelles, and the
in vitro
cytotoxicity at different pHs was evaluated. The system was able to distinguish pHs 7.2 and 7.0 in terms of cytotoxicity.