title: Enhancement of the fraction of the active form of an antitumor drug topotecan via an injectable hydrogel.
abstract: Poly(D,L-lactic acid-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(D,L-lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) hydrogels were tried as implants to encapsulate antitumor drug topotecan (TPT), a derivative of camptothecin (CPT). Despite of water solubility of TPT, the in vitro release of this low-molecular-weight drug from hydrogels sustained for 5 days with only a mild initial burst. The antitumor efficacy of the released TPT was further validated in S180-bearing mice. Surprisingly, the fraction of the active lactone form of TPT was increased to above 50% in the hydrogel matrix, while the fraction was just about 10% in phosphate buffer saline under physiological pH at 37°C. This significant effect was interpreted not by the local acidic pH within the hydrogel, but by the increase of pK(a) of the carboxylate group of the open-ring form due to the hydrophobic interaction between the amphiphilic polymer and TPT. Theoretical analysis via a pK(a)-related mechanism was also performed, which was consistent with our experimental measurements. Hence, this study has revealed that an appropriate biomaterial could, via drug-material interactions, enhance the drug efficacy by increasing the active fraction of some drugs which exhibit a reversible conversion between the active and inactive structures.
authors.affiliation: Key Laboratory of Molecular Engineering of Polymers, Ministry of Education, Department of Macromolecular Science, Laboratory of Advanced Materials, Fudan University, Shanghai, China.
authors.forename: Guangtao
authors.initials: G
authors.lastname: Chang
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Ci
authors.forename: Lin
authors.initials: L
authors.lastname: Yu
authors.forename: Jiandong
authors.initials: J
authors.lastname: Ding
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004337:Drug Carriers / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007279:Injections, Subcutaneous; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000737:chemistry*; D011098:Polyglactin 910 / Q000737:chemistry*; D012510:Sarcoma 180 / Q000188:drug therapy; D012995:Solubility; D013499:Surface Properties; D013696:Temperature; D019772:Topotecan / Q000008:administration & dosage* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; C528571:poly(lactic-co-glycolic acid)-polyethylene glycol-poly(lactic-co-glycolic acid); D011098:Polyglactin 910; D011092:Polyethylene Glycols; D019772:Topotecan