Systemic delivery and preclinical evaluation of Au nanoparticle containing beta-lapachone for radiosensitization.
Effective delivery of radiosensitizer to target tumor cells, causing preferentially increased tumor cytotoxicity, while simultaneously minimizing damage to healthy cells around the tumor, is an ideal strategy for the improvement of radiotherapeutic efficacy against human cancer. We aimed to enhance radiotherapeutic efficacy by using biocompatible gold nanoparticles (AuNP) as a vehicle for systemic delivery of ss-lapachone (lap). Lap is a novel anticancer agent displaying potent cytotoxicity against cancer cells expressing NAD(P)H:quinone oxidoreductase-1 enzyme (NQO1). Although lap is expected to be a very promising radiosensitizer, its poor solubility and non-specific distribution obstruct preclinical evaluation and clinical application. In this study, the property of AuNPs carrying lap (AuNPs/lap) for active-targeting tumor cells and improving in vivo radiotherapeutic efficacy was evaluated. Murine monoclonal anti-EGFR antibody was conjugated to the AuNPs/lap as a ligand for active targeting. The active tumor-targeting property of AuNPs/lap conjugating anti-EGFR antibody was validated in vitro experiments using cell lines expressing EGFR at different levels. In mice bearing xenograft human tumors, the intravenous injection of AuNPs/lap exhibited highly enhanced radiotherapeutic efficacy. AuNPs/lap offers a new modality for improvement of radiotherapeutic efficacy and feasibility of further clinical application for human cancer treatment.
Jeong
Seong-Yun
SY
Institute for Innovative Cancer Research, Asan Medical Center, Seoul, 138-736, Republic of Korea.
Park
Sung-Jin
SJ
Yoon
Sang Min
SM
Jung
Joohee
J
Woo
Ha Na
HN
Yi
So Lyoung
SL
Song
Si Yeol
SY
Park
Heon Joo
HJ
Kim
Chulhee
C
Lee
Jin Seong
JS
Lee
Jung Shin
JS
Choi
Eun Kyung
EK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism; D001692:Biological Transport; D045744:Cell Line, Tumor; D002470:Cell Survival; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D004339:Drug Compounding; D004353:Drug Evaluation, Preclinical; D066246:ErbB Receptors / Q000378:metabolism; D006046:Gold / Q000737:chemistry*; D006801:Humans; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D053768:Metal Nanoparticles; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009285:Naphthoquinones / Q000008:administration & dosage* / Q000737:chemistry; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000737:chemistry; D015203:Reproducibility of Results; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D004337:Drug Carriers; D009285:Naphthoquinones; D011838:Radiation-Sensitizing Agents; C014638:beta-lapachone; D006046:Gold; C512478:EGFR protein, human; D066246:ErbB Receptors