Efficient delivery of anlotinib and radioiodine by long circulating nano-capsules for active enhanced suppression of anaplastic thyroid carcinoma.

¹³¹I therapy is clinically unfeasible for anaplastic thyroid carcinoma (ATC), due to lack of active targets and ATC's resistance to radiation. Novel radionuclide-labeled targeted nano-drug delivery systems have exhibited the potential of prominent tumor imaging and remedy. Capitalizing on recent research achievements in nanotechnology and nuclear medicine, we sought to develop a radiolabeled nano-drug, which could specifically accumulate in ATCs via tumor-selective targeted delivery system and which could treat the tumors with both targeted and radionuclide therapeutics. Epidermal growth factor receptor (EGFR) and mutant P53 expressions were positive in 80% and 60% of patients with ATC, respectively. Herein, core-shell nanoparticles-based poly (ethyleneglycol)-crosslinker (PEG-CL) was fabricated, by encapsulating bovine serum albumin (BSA) inside the core and an enzyme with various tyrosine residues for ¹³¹I radiolabeling, and by loading anlotinib, a multi-kinase inhibitor which can site-selectively target overexpressed EGFR in ATC cells and which also suppresses angiogenesis, onto the PEG-CL shell surface. The Anlotinib-BSA nano-capsule (nBSA) showed a mostly uniform size distribution centering at 21-23 nm, and the nano-drug had a characteristic absorption peak at the wavelength of 325 nm. The Anlotinib-nBSA had a high labeling efficiency with the radiochemical purity being approximately 100%. The cellular uptake efficiency of Anlotinib-nBSA-¹³¹I was much higher than that of free ¹³¹I in both 8305C (3.6% vs 0.0%) and C643 (7.0% vs 0.1%; with a higher EGFR expression level) ATC cell lines. Anlotinib-nBSA-¹³¹I showed the strongest cytotoxicity against ATC cells with different concentrations of anlotinib, and induced the highest rate of apoptosis (C643 cells, 81.7%). The nanoparticles could actively target tumor surface with anlotinib exhibiting enhanced radio-sensitization effects by functionally upregulating P53 and Bax. In vivo SPECT/CT imaging showed that the concentration of Anlotinib-nBSA-¹²⁵I in tumors peaked at 24 h, and the intense signal persisted for at least one week. Anlotinib-nBSA-¹³¹I showed the strongest tumor inhibition effects in tumor-bearing mice, with no evident pathological changes observed. Together, the optimal nanoparticles co-loading anlotinib and ¹³¹I satisfactorily demonstrated efficient drug delivery and prominent antitumor effects both in vitro and in vivo, without obvious in vivo bio-toxicity. Our innovation could offer novel effective strategies for targeted management of ATC, a highly-aggressive disease with dismal prognosis.