A novel 131I-labeled nanoprobe for tumor multimodal imaging and combination therapy

Introduction: Radionuclide therapy（RNT）is one of the effective methods of precision treatment of tumors, but the effective killing of tumors is often limited by uneven dose distribution of radionuclides. Combination therapy can overcome the limitations of single nuclide therapy and further improve the treatment of tumors. As a "star nuclide", radionuclide ¹³¹I not only performs intratumoral radiation therapy (RNT) by releasing β rays to destroy the double strands of tumor DNA, but also can significantly improve the problem of uneven radiation distribution by labeling it on the nanoprobe and can also collect the nuclides at the tumor site for SPECT functional imaging under the passive targeting of the nanoprobe. In addition, sonodynamic therapy (SDT) uses ultrasound (US) to activate sonosensitizer to produce a large amount of reactive oxygen species (ROS) to destroy tumor cells, which can overcome tumor depth limitations. The sonosensitizer manganese porphyrin (MnTPP) not only has an ultrasound-activated porphyrin ring, but Mn²⁺ can be used as a T1 contrast agent for MRI imaging, which can pinpoint the location of the tumor. Based on this, we developed a novel ¹³¹I-labeled nanoprobe ¹³¹I-MnP@D for tumor multimodal imaging and combination therapy in this study.

Methods: Polylactic acid-glycolic acid copolymer (PLGA) is an FDA-approved controlled-release vehicle. MnTPP was loaded into PLGA microspheres by emulsion/solvent evaporation method, followed by chloramine T method to label radionuclide ¹³¹I on the surface of the extragranular dopamine coating. Finally, the integrated probe ¹³¹I-MnP@D was successfully prepared. The probes were characterized, and the colloidal stability and nuclide stability of the probes were detected in PBS and FBS for 7 consecutive days. In the BxPC3 cell experiment, not only was the cytotoxicity of 131I-MnP@D assessed, but the peak probe uptake of the cells was assessed using a γ counter over a 24-hour period. After combined with 1.5W·cm^-2 US treatment, the cell viability of BxPC3 cells was detected at 450 nm. In mouse imaging detection, the tumor metabolism and distribution of the probe were evaluated by intratumoral injection of ¹³¹I-MnP@D to clarify the tumor location on MRI and SPECT, respectively.

Results: The particle size of the ¹³¹I-MnP@D is 108±2 nm, and there is a significant absorption peak at 474.5 nm at the ultraviolet wave. ¹³¹I-MnP@D has a high radiolabeling rate (65-70%) and radiochemical purity (>90%), and has good PDI stability (0.4775±0.02) in serum. The stability of the nuclides was investigated by simulating the entry of ¹³¹I-MnP@D into the bloodstream using 1640 medium containing 10% FBS, and the results showed that the stability was > 60% after 7 days. In cell uptake experiments, ¹³¹I-MP@D could be taken up by BxPC3 cells, and the peak uptake was about 60 min. After combined with 1.5W·cm^-2 US treatment, CCK-8 showed that the cell survival rate was 33.54±3.625%, showing significant tumor killing ability compared with monotherapy. In addition, SPECT imaging results showed that ¹³¹I-MnP@D could significantly accumulate at the tumor site for up to 24 hours in tumor-bearing mice compared with free ¹³¹I and showed good biosafety. And as the probes are distributed at the tumor site, MRI shows a more pronounced signal difference between the tumor and the surrounding normal tissue.

Conclusions: In this study, a novel ¹³¹I-labeled nanoprobe was successfully synthesized, and in vitro and in vivo experiments suggest that ¹³¹I-MnP@D may be a promising integrated nanoprobe for pancreatic tumor diagnosis and treatment.