Theranostic Unimolecular Micelles Based on Brush-Shaped Amphiphilic Block Copolymers for Tumor-Targeted Drug Delivery and Positron Emission Tomography Imaging

• Published in: ACS applied materials & interfaces 2014-12, Vol.6 (24), p.21769-21779
• Main Authors: Guo, Jintang, Hong, Hao, Chen, Guojun, Shi, Sixiang, Nayak, Tapas R, Theuer, Charles P, Barnhart, Todd E, Cai, Weibo, Gong, Shaoqin
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - therapeutic use; Breast Neoplasms - drug therapy; Disease Models, Animal; Doxorubicin - administration & dosage; Doxorubicin - chemistry; Drug Carriers; Female; Forum; Human Umbilical Vein Endothelial Cells; Humans; Lactates - chemistry; MCF-7 Cells; Micelles; Microscopy, Electron, Transmission; Neoplasms - drug therapy; Polyethylene Glycols - chemistry; Polyhydroxyethyl Methacrylate - chemistry; Polymers - chemistry; Positron-Emission Tomography; Pregnancy; Proton Magnetic Resonance Spectroscopy
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/am5002585

Brush-shaped amphiphilic block copolymers were conjugated with a monoclonal antibody against CD105 (i.e., TRC105) and a macrocyclic chelator for 64Cu-labeling to generate multifunctional theranostic unimolecular micelles. The backbone of the brush-shaped amphiphilic block copolymer was poly­(2-hydroxyethyl methacrylate) (PHEMA) and the side chains were poly­(l-lactide)-poly­(ethylene glycol) (PLLA-PEG). The doxorubicin (DOX)-loaded unimolecular micelles showed a pH-dependent drug release profile and a uniform size distribution. A significantly higher cellular uptake of TRC105-conjugated micelles was observed in CD105-positive human umbilical vein endothelial cells (HUVEC) than nontargeted micelles due to CD105-mediated endocytosis. In contrast, similar and extremely low cellular uptake of both targeted and nontargeted micelles was observed in MCF-7 human breast cancer cells (CD105-negative). The difference between the in vivo tumor accumulation of 64Cu-labeled TRC105-conjugated micelles and that of nontargeted micelles was studied in 4T1 murine breast tumor-bearing mice, by serial positron emission tomography (PET) imaging and validated by biodistribution studies. These multifunctional unimolecular micelles offer pH-responsive drug release, noninvasive PET imaging capability, together with both passive and active tumor-targeting abilities, thus making them a desirable nanoplatform for cancer theranostics.