Background Pancreatic ductal adenocarcinoma (PDAC) is a devastatingly malignant tumor with a high mortality. However, current strategies to treat PDAC generally have low efficacy and high side-effects, therefore, effective treatment against PDAC remains an urgent need. Results We report a semiconducting polymer nano-radiopharmaceutical with intrinsic photothermal capability and labeling with therapeutic radioisotope 177Lu (177Lu-SPN-GIP) for combined radio- and photothermal therapy of pancreatic tumor. 177Lu-SPN-GIP endowed good stability at physiological conditions, high cell uptake, and long retention time in tumor site. By virtue of combined radiotherapy (RT) and photothermal therapy (PTT), 177Lu-SPN-GIP exhibited enhanced therapeutic capability to kill cancer cells and xenograft tumor in living mice compared with RT or PTT alone. More importantly, 177Lu-SPN-GIP could suppress the growth of the tumor stem cells and reverse epithelial mesenchymal transition (EMT), which may greatly reduce the occurrence of metastasis. Conclusion Such strategy we developed could improve therapeutic outcomes over traditional RT as it is able to ablate tumor with relatively lower doses of radiopharmaceuticals to reduce its side effects. Graphical abstract
Background: Beta-2 microglobulin (B2M) and cystatin C are novel glomerular filtration markers that have a stronger association with adverse outcomes than creatinine. The B2Mbased glomerular filtration rate (GFR) estimating equation was built in 2016. Several new creatinine and cystatin C equations were developed in 2019 in China. However, external validation of these new equations remains to be seen. Methods: This is a prospective cohort study. The equations were validated in a population totaling 830 participants (median age 62 years). These equations include the B2M-based equation (built in 2016), three CKD-EPI equations (built in 2009 and 2012), three Yang-Du equations (C-CKD-EPIscr, C-CKD-EPIcys, and C-CKD-EPIscr-cys equations, all of which were Chinese-modified CKD-EPI equations developed by Yang et al. in 2019), and a Xiangya equation (a creatininebased equation built in the Third Xiangya Hospital in 2019).The estimated GFR (eGFR) calculated separately by 8 equations (B2M GFR, CKD-EPIscr, CKD-EPIcys, CKD-EPIscr-cys, C-CKD-EPIscr, C-CKD-EPIcys, C-CKD-EPIscr-cys, and Xiangya equations) was compared with the reference GFR (rGFR) measured by the 99m Tc-DTPA renal dynamic imaging method. Participants were divided into CKD stage 1-5 specific subgroups. The primary outcomes of this study were bias, precision (interquartile range of difference, IQR), and accuracy (the proportion of eGFR within 30% of rGFR [P30] and root mean square error [RMSE]) of eGFR versus rGFR. Results: The B2M-based equation was worse than CKD-EPI equations and Yang-Du equations in most outcomes. CKD-EPIscr and C-CKD-EPIscr equations had a larger area under the receiver operating characteristic curve (ROC AUC ). The CKD-EPIscr equation had the highest sensitivity (83.3%) and the Xiangya equation the highest specificity (89.5%) to diagnose CKD. The bias was the lowest in CKD-EPIcys and C-CKD-EPIscr-cys equations by median and mean difference (1.23 and -1.42, respectively). The Xiangya equation yielded the highest bias by both median and mean difference (8.29 and 6.52, respectively). The C-CKD-EPIscr equation was the most accurate with the highest P30 value (68.1%) and most precise with the lowest IQR (19). The Xiangya equation had the best RMSE (lowest RMSE, 0.56), and gave the best performance in the CKD stage 2 subgroup. The C-CKD-EPIscr-cys equation L.Y. and B.P. contributed equally to this work. achieved the lowest bias in CKD stage 3-5 (p = 0.663, 0.104, and 0.130, respectively, compared with rGFR). Conclusion: The B2M-based equation was worse than CKD-EPI and Yang-Du equations on the whole. CKD-EPIcys and C-CKD-EPIscrcys equations had the lowest bias, whereas the Xiangya equation yielded the highest bias. The Xiangya equation gave the best performance in the CKD stage 2 subgroup, while the C-CKD-EPIscr-cys equation achieved the lowest bias in CKD stage 3-5. Further work to improve the performance of the GFR estimating equation is needed.
Targeted radionuclide therapy (TRT) provides new and safe opportunities for cancer treatment and management with high precision and efficiency. Here we have designed a novel semiconducting polymer nanoparticle (SPN)-based radiopharmaceutical (211At-MeATE-SPN-GIP) for TRT against glucose-dependent insulinotropic polypeptide receptor (GIPR)-positive cancers to further explore the applications of nanoengineered TRT. 211At-MeATE-SPN-GIP was engineered via nanoprecipitation, followed by its functionalization with a glucose-dependent insulinotropic polypeptide (GIP) to target GIPR and deliver 211At for α therapy. The therapeutic effect and biological safety of 211At-MeATE-SPN-GIP were investigated using GIPR-overexpressing human pancreatic cancer CFPAC-1 cells and CFPAC-1-bearing mice. In this work, 211At-MeATE-SPN-GIP was produced with a radiochemical yield of 43% and radiochemical purity of 98%, which exhibited a specifically high uptake in CFPAC-1 cells, inducing cell cycle arrest at the G2/M phase and extensive DNA damage. In the CFPAC-1-bearing tumor model, 211At-MeATE-SPN-GIP exhibited high therapeutic efficiency, with no obvious side effects. The GIPR-specific binding of 211At-MeATE-SPN-GIP combined with effective inhibition of tumor growth and fewer side effects compared to control suggests that 211At-MeATE-SPN-GIP TRT holds great potential as a novel nanoengineered TRT strategy for patients with GIPR-positive cancer.
The theranostics of lymph node metastasis has always been one of the major obstacles to defeating breast cancer and an important decisive factor in the prognosis of patients. Herein, we design NaGdF4:Yb,Tm@NaLuF4 upconversion nanoparticles with PEG and anti-HER2 monoclonal antibody (trastuzumab, Herceptin) (NP-mAb) conjugation for targeting lymphatic metastasis. Radionuclides 177Lu could be chelated by the bisphosphate groups of NP-mAb. The obtained 177Lu-NP-mAb exhibited excellent radiolabeling stability and show high accumulation and prolong retention in the lymph node metastasis after intratumoral injection into the footpad by SPECT/CT imaging. Utilizing the β rays released by 177Lu, 177Lu-NP-mAb could not only decrease the number of lymph node metastasis, but also significantly improve therapeutic efficiency of lymph node metastasis. Additionally, 177Lu-NP-mAb induce no obvious toxicity to treated mice through blood routine, live and spleen function assay. Therefore, 177Lu-NP-mAb we designed could be acted as excellent theranostics agents for lymph node metastasis, providing a potential alternative treatment option for lymph node metastasis therapy.
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