Tumor Chemo-Radiotherapy with Rod-Shaped and Spherical Gold Nano Probes: Shape and Active Targeting Both Matter.

ABSTRACT: The morphologies of gold nanoparticles (NPs) affect their tumor accumulation through enhanced permeability and retention effect. However, detailed information and mechanisms of NPs' characteristics affecting tumor accumulation are limited. The aim of this study is to evaluate the effects of shape and active targeting ligands of theranostic NPs on tumor accumulation and therapeutic efficacy, and to elucidate the underlying mechanism. Methods: ?v?3 integrin-targeted, cisplatin-loaded and radioisotope iodine-125 labeled spherical and rod-shaped gold nano theranostic probes (RGD-¹²⁵IPt-AuNPs and RGD-¹²⁵IPt-AuNRs) with similar sizes were fabricated and characterized. The in vivo distribution and chemo-radio therapeutic efficacy against tumors of these newly developed probes were subsequently evaluated. Moreover, a physiologically based pharmacokinetic (PBPK) model was developed to characterize the in vivo kinetics of these probes at the sub-organ level, and to reveal the mechanism of NPs' shape and active targeting ligands effects on tumor accumulation. Result: Cisplatin and iodine-125 were loaded sequentially onto the NPs through a thin polydopamine coating layer on the NPs. Both RGD-¹²⁵IPt-AuNPs and RGD-¹²⁵IPt-AuNRs exhibited high specificity for ?v?3 in vitro, with the rod-shaped probe being more efficient. The PBPK model revealed that rod-shaped gold NPs diffused more rapidly in tumor interstitial than the spherical ones. Tumor accumulations of non-targeted and rod-shaped RAD-¹²⁵IPt-AuNRs was higher in short term (1 h post injection), but not pronounced and similar to that of non-targeted spherical RAD-¹²⁵IPt-AuNPs in 24 h after intravenous injection, revealing that the NPs' shape did not have a significant impact on tumor accumulations through enhanced permeability and retention (EPR) effect in long-term. While for actively targeted NPs, in addition to a higher distribution coefficient, RGD-¹²⁵IPt-AuNRs also had a much higher tumor maximum uptake rate constant than RGD-¹²⁵IPt-AuNPs, indicating both the shape and active targeting ligands affected the tumor uptake of rod-shaped NPs. As a result, RGD-¹²⁵IPt-AuNRs had a more effective inhibition of tumor growth than RGD-¹²⁵IPt-AuNPs by chemo-radiationtherapy. Conclusion: Our study suggests that both the shape and active targeting ligands of gold NPs play important roles on tumor accumulation and chemo-radio therapeutic effect.

SUBMITTER: Zhang L 

PROVIDER: S-EPMC6485290 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature