Evaluation of doxorubicin-loaded pH-sensitive polymeric micelle release from tumor blood vessels and anticancer efficacy using a dorsal skin-fold window chamber model
Abstract
Zhe-hu JIN1, 2, #, Ming-ji JIN1, #, Chang-gao JIANG2, Xue-zhe YIN2, Shuai-xing JIN2, Xiu-quan QUAN2, Zhong-gao GAO1, 2, *
1State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Chinese Academy of Medical Sciences, Beijing 100050, China; 2Yanbian University Hospital, Yanji 133000, China
Aim: To evaluation the doxorubicin (DOX)-loaded pH-sensitive polymeric micelle release from tumor blood vessels into tumor interstitium using an animal vessel visibility model, the so-called dorsal skin-fold window chamber model.
Methods: DOX-loaded pH-sensitive polyHis-b-PEG micelles and DOX-loaded pH-insensitive PLLA-b-PEG micelles were prepared. The uptake of the micelles by MDA-MB-231 breast cancer cells in vitro and in vivo was examined using flow cytometry. The pharmacokinetic parameters of the micelles were determined in SD rats after intravenous injection of a DOX dose (6 mg/kg). The release of the micelles from tumor vasculature and the antitumor efficacy were evaluated in MDA-MB-231 breast cancer xenografted in nude mice using a dorsal skin-fold window chamber.
Results: The effective elimination half-life t1/2 of the pH-sensitive, pH-insensitive polymeric micelles and DOX-PBS in rats were 11.3 h, 9.4 h, and 2.1 h, respectively. Intravital microscopy in MDA-MB-231 breast cancer xenografted in nude mice showed that the pH-sensitive polymeric micelles rapidly extravasated from the tumor blood vessels, and DOX carried by the pH-sensitive micelles was preferentially released at the tumor site as compared to the pH-insensitive polymeric micelles. Furthermore, the pH-sensitive polymeric micelles exhibited significant greater efficacy in inhibition of tumor growth in the nude mice.
Conclusion: When DOX is loaded into pH-sensitive polymeric micelles, the acidity in tumor interstitium causes the destabilization of the micelles and triggers drug release, resulting in high local concentrations within the tumor, thus more effectively inhibiting the tumor growth in vivo.
Keywords: anticancer drug; doxorubicin; nanoparticle; polymeric micelle; drug release; pharmacokinetics; pH; dorsal skin-fold window chamber model
This research was supported by the National Natural Science Foundation of China (No 81373342), and the Natural Science Foundation of Beijing (No 2141004 and 7142114).
# These authors contributed equally to this study.
* To whom correspondence should be addressed.
E-mail zggao@imm.ac.cn
Received 2013-10-12 Accepted 2014-01-13
Keywords:
1State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Chinese Academy of Medical Sciences, Beijing 100050, China; 2Yanbian University Hospital, Yanji 133000, China
Aim: To evaluation the doxorubicin (DOX)-loaded pH-sensitive polymeric micelle release from tumor blood vessels into tumor interstitium using an animal vessel visibility model, the so-called dorsal skin-fold window chamber model.
Methods: DOX-loaded pH-sensitive polyHis-b-PEG micelles and DOX-loaded pH-insensitive PLLA-b-PEG micelles were prepared. The uptake of the micelles by MDA-MB-231 breast cancer cells in vitro and in vivo was examined using flow cytometry. The pharmacokinetic parameters of the micelles were determined in SD rats after intravenous injection of a DOX dose (6 mg/kg). The release of the micelles from tumor vasculature and the antitumor efficacy were evaluated in MDA-MB-231 breast cancer xenografted in nude mice using a dorsal skin-fold window chamber.
Results: The effective elimination half-life t1/2 of the pH-sensitive, pH-insensitive polymeric micelles and DOX-PBS in rats were 11.3 h, 9.4 h, and 2.1 h, respectively. Intravital microscopy in MDA-MB-231 breast cancer xenografted in nude mice showed that the pH-sensitive polymeric micelles rapidly extravasated from the tumor blood vessels, and DOX carried by the pH-sensitive micelles was preferentially released at the tumor site as compared to the pH-insensitive polymeric micelles. Furthermore, the pH-sensitive polymeric micelles exhibited significant greater efficacy in inhibition of tumor growth in the nude mice.
Conclusion: When DOX is loaded into pH-sensitive polymeric micelles, the acidity in tumor interstitium causes the destabilization of the micelles and triggers drug release, resulting in high local concentrations within the tumor, thus more effectively inhibiting the tumor growth in vivo.
Keywords: anticancer drug; doxorubicin; nanoparticle; polymeric micelle; drug release; pharmacokinetics; pH; dorsal skin-fold window chamber model
This research was supported by the National Natural Science Foundation of China (No 81373342), and the Natural Science Foundation of Beijing (No 2141004 and 7142114).
# These authors contributed equally to this study.
* To whom correspondence should be addressed.
E-mail zggao@imm.ac.cn
Received 2013-10-12 Accepted 2014-01-13