PURPOSE: Rapamycin has demonstrated potent anti-tumor activity in preclinical and clinical studies. However, the clinical development of its formulations was hampered due to its poor solubility and undesirable distribution in vivo. Chemical modification of rapamycin presents an opportunity for overcoming the obstacles and improving its therapeutic index. The objective of this study is to develop a drug-polymer conjugate to increase the solubility and cellular uptake of rapamycin. METHODS: We developed the rapamycin-polymer conjugate using a novel, linear, poly(ethylene glycol) (PEG) based multiblock copolymer. Cytotoxicity and cellular uptake of the rapamycin-polymer conjugate were evaluated in various cancer cells. RESULTS: The rapamycin-polymer conjugate provides enhanced solubility in water compared with free rapamycin and shows profound activity against a panel of human cancer cell lines. The rapamycin-polymer conjugate also presents high drug loading capacity (wt% ~ 26%) when GlyGlyGly is used as a linker. Cellular uptake of the conjugate was confirmed by confocal microscopic examination of PC-3 cells that were cultured in the presence of FITC-labled polymer (FITC-polymer). CONCLUSION: This study suggests that the rapamycin-polymer conjugate is a novel anti-cancer agent that may provide an attractive strategy for treatment of a wide variety of tumors.
PURPOSE:Rapamycin has demonstrated potent anti-tumor activity in preclinical and clinical studies. However, the clinical development of its formulations was hampered due to its poor solubility and undesirable distribution in vivo. Chemical modification of rapamycin presents an opportunity for overcoming the obstacles and improving its therapeutic index. The objective of this study is to develop a drug-polymer conjugate to increase the solubility and cellular uptake of rapamycin. METHODS: We developed the rapamycin-polymer conjugate using a novel, linear, poly(ethylene glycol) (PEG) based multiblock copolymer. Cytotoxicity and cellular uptake of the rapamycin-polymer conjugate were evaluated in various cancer cells. RESULTS: The rapamycin-polymer conjugate provides enhanced solubility in water compared with free rapamycin and shows profound activity against a panel of humancancer cell lines. The rapamycin-polymer conjugate also presents high drug loading capacity (wt% ~ 26%) when GlyGlyGly is used as a linker. Cellular uptake of the conjugate was confirmed by confocal microscopic examination of PC-3 cells that were cultured in the presence of FITC-labled polymer (FITC-polymer). CONCLUSION: This study suggests that the rapamycin-polymer conjugate is a novel anti-cancer agent that may provide an attractive strategy for treatment of a wide variety of tumors.
Authors: Christiane J Bruns; Gudrun E Koehl; Markus Guba; Maksim Yezhelyev; Markus Steinbauer; Hendrik Seeliger; Astrid Schwend; Anna Hoehn; Karl-Walter Jauch; Edward K Geissler Journal: Clin Cancer Res Date: 2004-03-15 Impact factor: 12.531