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: αvβ3 integrin-targeted, cisplatin-loaded and radioisotope iodine-125 labeled spherical and rod-shaped gold nano theranostic probes (RGD- 125 IPt-AuNPs and RGD- 125 IPt-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- 125 IPt-AuNPs and RGD- 125 IPt-AuNRs exhibited high specificity for αvβ3 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- 125 IPt-AuNRs was higher in short term (1 h post injection), but not pronounced and similar to that of non-targeted spherical RAD- 125 IPt-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- 125 IPt-AuNRs also had a much higher tumor maximum uptake rate constant than RGD- 125 IPt-AuNPs, indicating both the shape and active targeting ligands affected the tumor uptake of rod-shaped NPs. As a result, RGD- 125 IPt-AuNRs had a more effective inhibition of tumor growth than RGD- 125 IPt-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.

Delivery of polymeric nanostars for molecular imaging and endoradiotherapy through the enhanced permeability and retention (EPR) effect

“…Considerably lower tumour uptake values have been reported for the current generation of nanoparticles, emphasising the remarkably high tumour accumulation observed for the star polymers in this study 10. This could be explained by the size, composition and flexibility of the nanostars 44, 45. First, the large size of the nanostars prevents their renal clearance, but enables their accumulation at the tumour site through the leaky vasculature associated with the EPR effect.…”

Gold Nanoparticles and Nanorods in Nuclear Medicine: A Mini Review

“…The 131 I-Au-PE-NPs-CTX were tested for targeted SPECT imaging and radionuclide therapy in glioma C6 cells. Overall, the results show high viabilities without 131 I, suggesting good cellular compatibility. On the contrary, after treatment with 131 I, the C6 viability decreases in a dose-dependent manner.…”

“…The results show a high cell uptake of the AuNRs with respect to AuNPs, indicating that the shape could influence the uptake into cells. Furthermore, the study shows a greater therapeutic efficacy of NRs compared to NPs assessed in terms of cell viability in vitro and the γ-H2AX induction ex vivo, which is probably due to their rapid spread in the tumor interstitial [131].…”

“…Zhang et al conjugated 131 I-labeled AuNRs with cyclic arginine-glycine-aspartic acid (RGD) and investigated its biological characteristics for the targeted imaging of integrin α V β 3 -expressing tumors [91]. The 131 I-labeled AuNRs-PEG-cRGD probe targeted selectively and could be taken up by tumor cells mainly via integrin α-receptor-mediated endocytosis.…”

Enhanced Cancer Therapy by Combining Radiation and Chemical Effects Mediated by Nanocarriers

“…Zhang et al. investigated whether the morphology of gold nanocarriers and the presence of a targeting agent such as RGD (αvβ3 integrin) would affect tumor uptake . For this purpose, spherical and rod‐shaped gold nanocarriers were covered with a thin layer of polydopamine in which iodine‐125 was encapsulated and subsequently cisplatin was added.…”