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Enhanced efficacy against cervical carcinomas through polymeric micelles physically incorporating the proteasome inhibitor MG 132
Ist Teil von
Cancer science, 2016-06, Vol.107 (6), p.773-781
Ort / Verlag
Tokyo: John Wiley & Sons, Inc
Erscheinungsjahr
2016
Quelle
Wiley Online Library All Journals
Beschreibungen/Notizen
Treatment of recurrent or advanced cervical cancer is still limited, and new therapeutic choices are needed for improving prognosis and quality of life of patients. Because human papilloma virus (
HPV
) infection is critical in cervical carcinogenesis, with the
E6
and
E7
oncogenes of
HPV
degrading tumor suppressor proteins through the ubiquitin proteasome system, the inhibition of the ubiquitin proteasome system appears to be an ideal target to suppress the growth of cervical tumors. Herein, we focused on the ubiquitin proteasome inhibitor
MG
132 (carbobenzoxy‐Leu‐Leu‐leucinal) as an anticancer agent against cervical cancer cells, and physically incorporated it into micellar nanomedicines for achieving selective delivery to solid tumors and improving its
in vivo
efficacy. These
MG
132‐loaded polymeric micelles (
MG
132/m) showed strong tumor inhibitory
in vivo
effect against
HPV
‐positive tumors from HeLa and CaSki cells, and even in
HPV
‐negative tumors from C33A cells. Repeated injection of
MG
132/m showed no significant toxicity to mice under analysis by weight change or histopathology. Moreover, the tumors treated with
MG
132/m showed higher levels of tumor suppressing proteins,
hS
crib and p53, as well as apoptotic degree, than tumors treated with free
MG
132. This enhanced efficacy of
MG
132/m was attributed to their prolonged circulation in the bloodstream, which allowed their gradual extravasation and penetration within the tumor tissue, as determined by intravital microscopy. These results support the use of
MG
132 incorporated into polymeric micelles as a safe and effective therapeutic strategy against cervical tumors.