Abstract
116
Objectives Unimolecular micelles (UMM) are much more stable in vivo than conventional micelles since there is no self-assembly process for UMM and each molecule is a single UMM. Our goal is to design, synthesize, and characterize multifunctional UMM for cancer-targeted drug delivery and non-invasive PET imaging in tumor-bearing mice.
Methods Multifunctional UMM based on the amphiphilic block copolymer, poly(amidoamine) (PAMAM) and poly(L-lactide)-b-poly(ethylene glycol) (PLA-PEG), was synthesized and conjugated with an anti-CD105 monoclonal antibody (i.e. TRC105, for tumor targeting) and NOTA (for 64Cu labeling). Doxorubicin, a model anti-cancer drug, was loaded into the hydrophobic core of the UMM by physical encapsulation. Nontargeted UMM (without TRC105) was synthesized as the control. Flow cytometry and fluorescence microscopy studies were carried out to measure CD105-targeting characteristics of the UMM in vitro. PET imaging, biodistribution and blocking studies were performed to evaluate the tumor targeting efficacy of 64Cu-labeled UMM in vivo, which was validated by ex vivo studies.
Results The UMM exhibited a uniform size distribution (~86 nm on average) and pH-sensitive drug release behavior. Targeted UMM had much higher cellular uptake in CD105-positive HUVEC cells than nontargeted UMM, whereas the difference in cellular uptake was minimal in CD105-negative MCF-7 cells. In 4T1 tumor-bearing mice, 64Cu-labeled targeted UMM had significantly higher tumor uptake (5.5±0.3, 4.5±0.3, and 3.0±0.1 %ID/g at 2, 16, and 48 h post-injection, n=4) than nontargeted UMM, which was confirmed by biodistribution studies. Similar findings were also observed for UMM synthesized based on another polymeric core, poly(2-hydroxyethyl methacrylate) (PHEMA), demonstrating that this is a generally applicable approach to generate UMM for drug delivery.
Conclusions The UMM that synergistically integrated passive and active tumor-targeting abilities, pH-controlled drug release, PET imaging capabilities, and suitable size range, are promising nanoplatforms for image-guided drug delivery and cancer theranostics.