Anticancer activity of PEGylated matrix metalloproteinase cleavable peptide-conjugated adriamycin against malignant glioma cells.
Although matrix metalloproteinases (MMPs) play a crucial role in the invasion and growth of malignant gliomas, their increased activity in tumor environment can be used as a specific target for chemotherapy. We investigated whether polymer-drug conjugates formed via MMP-cleavable peptide linkages could provide MMP-responsive tumor targeting and cytotoxicity for malignant glioma cells. One end of an MMP-cleavable peptide was attached to the end of methoxy polyethylene glycol (MPEG) while the other end was attached to adriamycin (ADR). The release of drugs in the presence of conditioned media of U87MG cells was investigated. The cytotoxicities of the MMP-cleavable MPEG-peptide-ADR (PPA) conjugates and non-cleavable MPEG-ADR (PA) conjugates were investigated using U87MG cells. The (1)H nuclear magnetic resonance (NMR) spectra confirmed the conjugation of the two ends of the peptide to the ends of MPEG and ADR, respectively. Gelatin zymography showed that MMP-2 was strongly expressed in the media of U87MG cells. The PA conjugate did not release ADR either in the phosphate buffered saline (PBS) or conditioned media of U87MG cells. The PPA conjugate released ADR in the presence of the conditioned media of U87MG cells, but not in PBS only. In the cytotoxicity test using U87MG cells, ADR and PPA conjugate showed similar anti-proliferative activities, while the cytotoxicity of PA conjugate was lower than that of ADR. Considering that the cytotoxicity of the PPA conjugate was similar to that of ADR, MMP-cleavable polymer-drug conjugates can be used as targeting carriers for the purpose of inhibiting the proliferation of malignant glioma cells.
Lim
Seung-Ho
SH
Department of Neurosurgery, Chonnam National University Hwasun Hospital & Medical School, Republic of Korea.
Jeong
Young-Il
YI
Moon
Kyung-Sub
KS
Ryu
Hyang-Hwa
HH
Jin
Yong-Hao
YH
Jin
Shu-Guang
SG
Jung
Tae-Young
TY
Kim
In-Young
IY
Kang
Sam-Suk
SS
Jung
Shin
S
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D011092:Polyethylene Glycols; D004317:Doxorubicin; D020782:Matrix Metalloproteinases