A versatile theranostic nanomedicine platform based on a non-cytotoxic dendrimer

Objectives: Multifunctional dendrimer with combined diagnostic and drug delivery functions show great promise towards one-step theranostic. However, realizing consistently high in vivo performance of multimodality theranostic in biocompatible platforms remains extremely challenging. Herein, we demonstrate a non-cytotoxic polyacylthiourea dendrimer (PD) can conveniently integrate a broad range of functionalities for cancer theranostic including fluorescence imaging, positron emission tomography (PET), and drug loading. Specifically, small organic fluorescent dyes indocyanine green (ICG) can be loaded into PD for optical imaging. PD also functions as a chelator-free precursor for radiolabeling with ⁶⁴Cu for PET. Furthermore, temozolomide (TMZ) can also be easily incorporated into PD for glioma treatment yet without cytotoxin-induced side effects.

Methods: ICG solution was prepared and mixed with PD for 5 h. PD was diluted in 0.1 M sodium acetate buffer (pH 5.5) and mixed with pH adjusted ⁶⁴Cu for 1 h. TMZ was dissolved in DMSO, diluted in ddH₂O, and mixed with PD overnight. All these resulting products were purified by PD-10 column with PBS as the eluant. Subcutaneous and orthotopic U87MG glioma mice models were established for fluorescence and PET imaging, as well as further treatment. Results In vivo fluorescence image analysis revealed that ICG-PD displayed high accumulation in U87MG xenografts, with tumor-to-background contrast ratio significantly increased to 15.1 at 12 h after tail vein injection (p<0.05). PET imaging showed that ⁶⁴Cu-PD started to accumulate at tumor sites at 1 h after injection, and reached maximum level at 72 h. Biodistribution study indicated that ⁶⁴Cu-PD had high accumulation and retention in both subcutaneous and orthotopic U87MG models, with 12.48 ± 0.75 %ID/g and 12.24 ± 0.87 %ID/g tumor uptake at 72 h post-injection (p.i.), respectively. Tumor/muscle ratios of 28.30 ± 0.30 and 28.2 ± 0.20 were achieved in subcutaneous and orthotopic U87MG models at 72 h p.i., respectively (n=3). On day 14, the TMZ-PD treatment group displayed a relative bioluminescent imaging signal intensity of 6.04 ± 0.88, 41 % less than TMZ treated group in subcutaneous U87MG models (n=8). No cytotoxicity and ultra-low acute and subacute toxicities were found during the 15 days glioma treatment using TMZ-PD in vivo.

Conclusions: PD can be used as a non-cytotoxic platform for multimodality diagnostic imaging with high contrast and achieving high drug-loading efficiency and efficacy. This integrated nanomedicine platform shows great promise as a highly versatile platform to develop multimodal theranostic agents.

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