Tumor targeted, image-guided drug delivery with multifunctional mesoporous silica nanoparticles

Objectives To develop surface functionalized mesoporous silica (mSiO₂) nanoparticles for in vivo tumor (vasculature) targeted, PET image-guided drug delivery.

Methods Uniform mSiO₂ nanoparticles were synthesized via a soft-template method, and conjugated to TRC105 (an antibody that binds to CD105, overexpressed on tumor neovasculature) and NOTA through polyethylene glycol (PEG) linkers, which were labeled with ⁶⁴Cu to form ⁶⁴Cu-NOTA-mSiO₂-PEG-TRC105. In vivo PET imaging, biodistribution, and blocking studies in 4T1 murine breast tumor-bearing mice were performed to evaluate tumor targeting capability and drug delivery efficiency, which was validated by in vitro, in vivo, and ex vivo experiments.

Results Comprehensive characterizations confirmed successful surface modifications of mSiO₂ nanoparticles to NOTA-mSiO₂-PEG-TRC105. Studies in HUVEC (CD105-positive) and MCF-7 human breast cancer cells (CD105-negative) showed strong and specific binding of mSiO₂-PEG-TRC105 to CD105-postive HUVEC cells with negligible non-specific binding. NOTA-mSiO₂-PEG-TRC105 was labeled with ⁶⁴Cu with a radiochemical yield of >50% and purity of >95%, and > 90% of ⁶⁴Cu remained within the mSiO₂ conjugates over 48 h of incubation in mouse serum, indicating superb stability. PET imaging showed CD105-specific uptake of ⁶⁴Cu-NOTA-mSiO₂-PEG-TRC105 in 4T1 mice, with peak tumor uptake of 5.9 ± 0.4 %ID/g (n=3) at 5 h post-injection, significantly higher than that of ⁶⁴Cu-NOTA-mSiO₂-PEG and free ⁶⁴Cu. CD105 specificity of ⁶⁴Cu-NOTA-mSiO₂-PEG-TRC105 was confirmed by blocking and histology studies. As a proof-of-concept, we also demonstrated ~2-fold enhancement of tumor targeted drug delivery in vivo, using TRC105-conjugated mSiO₂ loaded with the drug doxorubicin.

Conclusions Active tumor targeting of uniform mSiO₂ was achieved in vivo, which was specific for vascular CD105 and could be non-invasively quantified by PET. ⁶⁴Cu-NOTA-mSiO₂-PEG-TRC105 had excellent stability and target specificity in vitro and in vivo, with ~2 fold enhancement of tumor uptake and loaded drug when compared to non-targeted control.