Abstract
1012
Introduction: The morphologies of gold nanoparticles affect their tumor accumulation through EPR effect and thus therapeutic efficacy. However, intrinsic mechanism of shape effect on tumor accumulation through active targeting simultaneously addressing tumor neovesculatures and cells plus EPR effect in tumor region are limited. Herein, we used dopamine coating to fabricate 125I labeling without chelator, αvβ3 integrin-targeted RGD peptide conjugating and cisplatin loaded spherical and rod-shaped gold nano-theranostic probes (RGD-125IPt-AuNPs and RGD-125IPt-AuNRs). With the same sizes, the probes were used to evaluate their tumor accumulation efficiency based on SPECT/CT image and radioactive dosage evaluation and thus the chemo-radio therapeutic performance in vivo, and developed a physiologically based pharmacokinetic (PKPB) model to characterize their intra-tumor pharmaceutical kinetics, trying to understand the mechanism of shape effect of the probes on tumor accumulation through both active targeting and EPR effect in organ level.
Methods: As-prepared AuNPs and AuNRs were first coated with polydopamine. Cisplatin and HS-PEG-NH2 (5000 Da) were immobilized on the surface of PDA-coated AuNPs and AuNRs, and RGD peptide were conjugated cross-linking the amine extremity of PEG with sulfhydryl group in cysteine in the peptide. Subsequently, the RGD peptide-conjugated, cisplatin-loaded AuNPs and AuNRs were further labeled with Idogen reduced 125I radioisotope. The final products (designated as RGD-125IPt-AuNPs and RGD-125IPt-AuNRs) were carefully characterized and its efficacy for tumor imaging (SPECT, photoacoustic) and therapy (chemo, combined chemo-radiosensitization therapy) were evaluated. A PKPB model adjust by experiment result was performed.
Results: The diameter of AuNPs was 56.37 nm, and the size of AuNRs was 22.41 nm in diameter and 56.12 nm in length (aspect ratio of ∼2.5). With a thin dopamine coating, cisplatin was effectively loaded by coordination bonding between catechols in polydopamine and metal ions (NH2Pt2+) and was released in a pH-sensitive manner. Iodine-125 was speculated to label to quinone or indolines via the formation of an irreversible neighboring covalent bond, it was very stable in biological conditions. Both RGD-125IPt-AuNPs and RGD-125IPt-AuNRs could specifically target αvβ3 integrin. SPECT/CT and photoacoustic imaging revealed that rod-shaped probes accumulated in tumor more effectively than spherical ones. The combined chemo-radiosensitization therapy indicated that both probes could inhibit the growth of solid tumor effectively, but the rod-shaped ones performed better. Based on our experiment results, the PKPB model elucidated that the rod-shaped probes with a more pronounced ability than spherical ones by leaking out of the capillary membrane and defusing to distal region of tumor organs and anchored in tumor cells, and thus exhibiting significant tumor accumulation efficiency.
Conclusions: In conclusion, RGD-125IPt-AuNPs and RGD-125IPt-AuNRs were able to target tumor cells and angiogenic vessels. The rod-shaped probe has a higher drug loading efficiency, more rapid diffusion and deeper penetration into tumor interstitials, higher specificity for αvβ3 integrin and thus more efficient tumor accumulation. Therefore, RGD-125IPt-AuNPs has greater tumor inhibition efficiency. Graphical Table Figure 1. A: SPECT/CT imaging.B-C: In vivo kinetics of AuNPs and AuNRs probes.
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