Antitumor activity of EGFR targeted pH-sensitive immunoliposomes encapsulating gemcitabine in A549 xenograft nude mice

• Published in: Journal of controlled release Vol. 140; no. 1; pp. 55 - 60
• Main Authors: Kim, In-Young, Kang, Young-Sook, Lee, Doo Sung, Park, Heon-Joo, Choi, Eun-Kyung, Oh, Yu-Kyoung, Son, Hye-Jung, Kim, Jin-Seok
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 16-11-2009; Elsevier
• Subjects: A549; Animal models; Animals; Antimetabolites, Antineoplastic - pharmacology; Antitumor activity; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Cancer therapy; Carcinoma, Non-Small-Cell Lung - drug therapy; Cell Line, Tumor; Controlled release; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Drug delivery; Drug Evaluation, Preclinical; EGFR; Epidermal growth factor receptors; Gemcitabine; General pharmacology; Humans; Hydrogen-Ion Concentration; Immunohistochemistry; In Situ Nick-End Labeling - methods; Liposomes; Liposomes - pharmacology; Lung Neoplasms - drug therapy; Medical sciences; Mice; Mice, Nude; Monoclonal antibodies; Neoplasm Transplantation; Particle Size; pH effects; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Proliferating cell nuclear antigen; Proliferating Cell Nuclear Antigen - metabolism; PSL; Random Allocation; Receptor, Epidermal Growth Factor - immunology; Receptor, Epidermal Growth Factor - metabolism; Tumor Burden - drug effects; Tumor cells; Tumors; Veins; Vesicles; Xenograft Model Antitumor Assays - methods; Xenografts; DOPE; PBS; PDP-PEG-DOPE; PCNA; NSCLC; Gemcitabine; DTT; A549; PSL; SMPB; EGFR; gem; TUNEL; Cancer therapy; CHEMS; Ab-PSL; Antineoplastic agent; Targeting; Heterograft; Epidermal growth factor receptor; Target; Immunoliposome; pH; Pyrimidine nucleoside; Pharmaceutical technology; Rodentia; Malignant tumor; Vertebrata; Mammalia; Treatment; Antimetabolic; Mouse; Animal; Pyrimidine derivatives; Fluorine Organic compounds; Cancer
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2009.07.005

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.
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