PDF(Pubmed)
Abstract：
Rationale: Although surgery, radioiodine therapy, and thyroid hormone therapy are the primary clinical treatments for differentiated thyroid carcinoma (DTC), effective therapy for locally advanced or progressive DTC remains challenging. BRAF V600E, the most common BRAF mutation subtype, is highly related to DTC. Previous studies prove that combination of kinase inhibitors and chemotherapeutic drugs may be a potential approach for DTC treatment. In this study, a supramolecular peptide nanofiber (SPNs) co-loaded with dabrafenib (Da) and doxorubicin (Dox) was constructed for targeted and synergistic therapy with BRAF V600E+ DTC. Methods: A self-assembling peptide nanofiber (Biotin-GDFDFDYGRGD, termed SPNs) bearing biotin at the N-terminus and a cancer-targeting ligand RGD at the C-terminus was used as a carrier for co-loading Da and Dox. D-phenylalanine and D-tyrosine (DFDFDY) are used to improve the stability of peptides in vivo. Under multiple non-covalent interactions, SPNs/Da/Dox assembled into longer and denser nanofibers. RGD ligand endows self-assembled nanofibers with targeting cancer cells and co-delivery, thereby improving cellular uptake of payloads. Results: Both Da and Dox indicated decreased IC50 values upon encapsulation in SPNs. Co-delivery of Da and Dox by SPNs exhibited the strongest therapeutic effect in vitro and in vivo by inhibiting ERK phosphorylation in BRAF V600E mutant thyroid cancer cells. Moreover, SPNs enable efficient drug delivery and lower Dox dosage, thereby significantly reducing its side effects. Conclusion: This study proposes a promising paradigm for the synergistic treatment of DTC with Da and Dox using supramolecular self-assembled peptides as carriers.
摘要：
理由：虽然手术，放射性碘治疗,甲状腺激素治疗是分化型甲状腺癌（DTC）的主要临床治疗方法，对于局部晚期或进行性DTC的有效治疗仍然具有挑战性。BRAFV600E,最常见的BRAF突变亚型，与DTC高度相关。先前的研究证明，激酶抑制剂和化疗药物的组合可能是DTC治疗的潜在方法。在这项研究中,构建了共负载达拉非尼（Da）和多柔比星（Dox）的超分子肽纳米纤维（SPNs），用于BRAFV600EDTC的靶向和协同治疗。方法：一种自组装肽纳米纤维(生物素-GDFDFDYGRGD，称为SPN），在N端带有生物素，在C端带有癌症靶向配体RGD，用作共负载Da和Dox的载体。D-苯丙氨酸和D-酪氨酸(DFDFDY)用于提高肽在体内的稳定性。在多重非共价相互作用下,SPNs/Da/Dox组装成更长且更致密的纳米纤维。RGD配体赋予自组装纳米纤维靶向癌细胞和共同递送，从而改善细胞对有效载荷的摄取。结果:Da和Dox均表明在包封在SPN中时IC50值降低。通过SPN共同递送Da和Dox通过抑制BRAFV600E突变甲状腺癌细胞中的ERK磷酸化在体外和体内表现出最强的治疗效果。此外，SPNs能够实现高效的药物输送和较低的Dox剂量，从而显著减少其副作用。结论：本研究提出了以超分子自组装肽为载体，用Da和Dox协同治疗DTC的有希望的范例。
