Antitumor activity of EGFR targeted pH-sensitive immunoliposomes encapsulating gemcitabine in A549 xenograft nude mice.
Immunoliposomes directed by monoclonal antibodies are promising vehicles for tumor targeted drug delivery. Development of a long-circulating formulation of pH-sensitive liposomes (PSLs) with epidermal growth factor receptor (EGFR) antibody attached was designed and tested using A549 cells and BALB/c-nu/nu mouse tumor model. PSL formulation was prepared using small unilamellar vesicles of DOPE and CHEMS (6:4 molar ratio) by REV method. The average size and zeta-potential of the formulation measured by dynamic laser-light scattering were approximately 146+/-43.9 nm (PDI=0.09+/-0.02) and -1.77+/-0.03 mV, respectively. A549 cells were xenotransplanted into BALB/c-nu/nu mice and various formulations of gemcitabine (gem), such as in its free form, PSLs or Ab-PSLs, were injected intravenously via a tail vein. The rate of tumor volume increment in Ab-PSLs with gem-treated group was remarkably slower than that of other drug-treated group. The tumor from Ab-PSLs with gem 160 mg/kg-injected group exhibited a markedly lowest account of PCNA labeled cells and had highest TUNEL-positive cells among tested. This suggests that treatment of Ab-PSLs with gem resulted in an increased apoptosis of tumor cells, leading to tumor growth inhibition. These results demonstrate that PSLs provide an efficient and targeted delivery of gemcitabine and may represent a useful new treatment approach for tumors which overexpress the EGFR.
Kim
In-Young
IY
College of Pharmacy, Sookmyung Women's University Chungpa-Dong 2-Ga, Yongsan-Gu, Seoul, 140-742, Republic of Korea.
Kang
Young-Sook
YS
Lee
Doo Sung
DS
Park
Heon-Joo
HJ
Choi
Eun-Kyung
EK
Oh
Yu-Kyoung
YK
Son
Hye-Jung
HJ
Kim
Jin-Seok
JS
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling / Q000379:methods; D008081:Liposomes / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010316:Particle Size; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011897:Random Allocation; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D008081:Liposomes; D018809:Proliferating Cell Nuclear Antigen; D003841:Deoxycytidine; D066246:ErbB Receptors; D000093542:Gemcitabine