Polypyrrole-based Double Rare Earth Hybrid Nanotheranostic Agents For Multimodal Imaging And Photothermal Therapy

In recent years,the development of nanotechnology has provided a new idea and method for cancer theranostics.Nanomaterials have exhibited great potential for cancer theranostics due to their unique advantages,such as controlled synthesis,easy surface functional modification,and excellent biocompatibility.Currently,X-ray computed tomography（CT）and magnetic resonance imaging（MRI）are widely used for clinical diagnosis.Admittedly,MRI demonstrates superior soft tissue contrast.However,compared with MRI,CT can provide enhanced contrast on bones and calcifications.Therefore,a new nanomaterial realizing MRI/CT bimodal imaging guided cancer treatment has attracted intense attention in the field of biomedical applications.Herein,we designed and synthesized a polypyrrole（PPy）-based theranostic agent containing double rare-earth elements（PPy@BSA-Gd/Dy）for T₁/T₂-weighted MRI/CT trimodal imaging guided photothermal cancer therapy.Gadolinium ion(Gd³⁺)as a paramagnetic ion is the most ideal candidate for T₁-weighted MRI,and dysprosium ion(Dy³⁺)has great advantages in T₂ imaging.At the same time,Dy-based nanoparticles show promise as CT contrast agents because of the high mass X-ray attenuation coefficient（3.36 cm²g^-11 at 100 keV）of Dy³⁺.Based on this,PPy@BSA was prepared using bovine serum albumin（BSA）as a stabilizer via an oxidation polymerization,and then the biomineralization process was triggered by adjusting the pH to 12.The obtained theranostic agent PPy@BSA-Gd/Dy with core-shell structure possessed uniform particle size（59.48?6.12 nm）and superior monodispersibility.Furthermore,the MTT assay,hemolysis assay,and tissue slides analysis demonstrated that PPy@BSA-Gd/Dy exhibited good biocompatibility both in vitro and in vivo.According to the biodistribution investigation and metabolic analysis,this theranostic agent was mainly metabolized through the hepatobiliary system.The PPy@BSA-Gd/Dy had a broad and strong absorption from UV to NIR,and it also exhibited significant photothermal performance with an excellent photothermal conversion efficiency（26.61%）upon irradiation by an 808 nm laser(2.0 W cm^-2).Due to its intrinsic paramagnetic and strong X-ray attenuation ability,the PPy@BSA-Gd/Dy showed excellent longitudinal/transverse relaxivity(r1=6.68 mM^-1 S^-1,r2=38.76 mM^-1 S^-1)and strong X-ray attenuation ability(57.98HU L g^-1).After the intravenous injection of PPy@BSA-Gd/Dy for 24 h,a brightening effect was clearly exhibited in the T₁-weighted image,and the tumor signal intensity increased by52.36%.Concurrently,the obvious dark T₂-weighted signal enhancement occurred at the tumor site,in which the signal intensity reduced by 38.73%within 24 h.At 1 h after intratumoral injection,the HU value of the tumor increased from 119 to 180.The viability of HeLa and 4T1 cells treated with the PPy@BSA-Gd/Dy(0.20 mg mL^-1)under 808 nm laser irradiation was only 29.35%and 33.10%,respectively.After 15 days of photothermal treatment,the tumor growth was significantly inhibited.These results indicated the theranostic agent PPy@BSA-Gd/Dy not only possessed T₁/T₂-weighted MRI/CT imaging effect,but also showed excellent photothermal therapy ability of tumor,exhibiting a potential research prospect in cancer theranostics field.