Tumor targeted drug delivery with hollow mesoporous silica nanoparticles

Objectives To functionalize hollow mesoporous silica nanoparticle (HMSN) for tumor (vascular) targeted, PET image-guided drug delivery.

Methods HMSNs of ~150 nm in size were synthesized via a hard-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-HMSN-PEG-TRC105. Both hydrophobic (e.g. sunitinib [SUN]) and hydrophilic (e.g. doxorubicin [DOX]) anti-cancer drugs were loaded inside HMSNs. 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 studies.

Results Systematic characterizations confirmed the synthesis of NOTA-HMSN-PEG-TRC105. The loading capacity for SUN and DOX were found to be 482 and 1129 mg/g, respectively, significantly higher than that of regular mesoporous silica nanoparticle (without a hollow cavity inside). Studies in HUVEC (CD105-positive) and MCF-7 human breast cancer cells (CD105-negative) showed strong and specific binding of NOTA-HMSN-PEG-TRC105 to CD105-postive HUVEC cells with negligible non-specific binding. In vivo tumor targeting and PET imaging demonstrated CD105-specific accumulation of ⁶⁴Cu-NOTA-HMSN-PEG-TRC105 in 4T1 tumor-bearing mice, with peak tumor uptake of 5.5 ± 0.4 %ID/g (n=3) at 3 h post-injection, significantly higher than that of non-targeted group. CD105 specificity of ⁶⁴Cu-NOTA-HMSN-PEG-TRC105 was confirmed by blocking and histology studies. Enhanced drug delivery in vivo was also achieved.

Conclusions We report the first in vivo tumor targeting of HMSN, which was specific for tumor vascular CD105 and could be non-invasively quantified by PET. ⁶⁴Cu-NOTA-HMSN-PEG-TRC105 had excellent stability and target specificity, as evidenced by various in vitro/in vivo/ex vivo experiments. With very high loading capacity for multiple drugs, HMSN is a desirable nanoplatform for future image-guided drug delivery and cancer therapy.