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A common bottleneck challenge for many therapeutic proteins lies in their short plasma half-lives, which often makes the treatment far less compliant or even disables achieving sufficient therapeutic efficacy. To address this problem, we introduce a novel drug delivery strategy based on the genetic fusion of an albumin binding domain (ABD) and an anti-neonatal Fc receptor (FcRn) affibody (AFF) to therapeutic proteins. This ABD-AFF fusion strategy can provide a synergistic effect on extending the plasma residence time by, on one hand, preventing the rapid glomerular filtration via ABD-mediated albumin binding and, on the other hand, increasing the efficiency of FcRn-mediated recycling by AFF-mediated high-affinity binding to the FcRn. In this research, we explored the feasibility of applying the ABD-AFF fusion strategy to exendin-4 (EX), a clinically available anti-diabetic peptide possessing a short plasma half-life. The EX-ABD-AFF produced from the E. coli displayed a remarkably (241-fold) longer plasma half-life than the SUMO tagged-EX (SUMO-EX) (0.7 h) in mice. Furthermore, in high-fat diet (HFD)-fed obese mice model, the EX-ABD-AFF could provide significant hypoglycemic effects for over 12 days, accompanied by a reduction of body weight. In the long-term study, the EX-ABD-AFF could significantly reverse the obesity-related metabolic complications (hyperglycemia, hyperlipidemia, and hepatic steatosis) and, moreover, improve cognitive deficits. Overall, this study demonstrated that the ABD-AFF fusion could be an effective strategy to greatly increase the plasma half-lives of therapeutic proteins and thus markedly improve their druggability.Sonodynamic therapy (SDT) utilizing semiconductors or organic sonosensitizers has attracted increasing attention as a noninvasive treatment for deep-seated tumors, but its practical applications are still limited due to unsatisfactory therapeutical effects. To address the issue, we reported a metal-organic nanosonosensitizer by assembling clinical drug hematoporphyrin monomethyl ether (HMME) with Fe(III) ions through covalently coordination. The Fe-HMME coordination particles (FeCPs) had the average size of ~70 nm, and they were surface-modified with phospholipids to confer high hydrophilicity and stability. Upon ultrasound irradiation, they efficiently produced 1O2 to destroy cancer cells coated without or with tissue-barriers (1-3 cm). Importantly, the porous structure of FeCPs facilitated high loading capacity (31.3%) of anticancer drug doxorubicin (DOX), and the DOX@FeCPs exhibited pH-sensitive and ultrasound-enhanced releasing behavior that was favorable to the acidic microenvironment of tumors. When the lipids-coated FeCPs were intravenously injected into tumor-bearing mouse, they could passively accumulate within tumors, leading to the magnetic resonance imaging of tumors. Importantly, as deep-seated tumor model, tumors covered with barrier were exposed to ultrasound and thereafter their growth was significantly inhibited by SDT of FeCPs. The inhibition effects could be further enhanced by DOX@FeCPs due to the SDT-chemo combined therapy. Therefore, the DOX@FeCPs have achieved good therapeutical performances on deep-seated tumor and would supply some insights on the design of other metal-organic nanoplatforms.The clinical application of cancer radiotherapy is critically impeded by hypoxia-induced radioresistance, insufficient DNA damage, and multiple DNA repair mechanisms. Herein we demonstrate a dual-hyperthermia strategy to potentiate radiotherapy by relieving tumor hypoxia and preventing irradiation-induced DNA damage repair. The tumor hyperthermia temperature was well-controlled by a near infrared laser with minimal side effects using PEGylated nanobipyramids (PNBys) as the photo-transducer. PNBys have narrow longitudinal localized surface plasmon resonance peak in NIR-II window with a high extinction coefficient (2.0 × 1011 M-1 cm-1) and an excellent photothermal conversion efficiency (44.2%). PNBys-induced mild hyperthermia (MHt) prior to radiotherapy enables vessel dilation, blood perfusion, and hypoxia relief, resulting in an increased susceptibility of tumor cells response to radiotherapy. On the other hand, MHt after radiotherapy inhibits the repair of DNA damage generated by irradiation. The PNBys exert hierarchically superior antitumor effects by the combination of MHt pre- and post-radiotherapy in murine mammary tumor EMT-6 model. Consequently, different from the simple combination of RT and MHt, the coupling of pre- and post-MHt with RT by PNBys open intriguing avenues towards new promising antitumor efficacy.Gadolinium-based contrast agents (GBCAs) are the most widely used T1 contrast agents for magnetic resonance imaging (MRI) and have achieved remarkable success in clinical cancer diagnosis. However, GBCAs could cause severe nephrogenic systemic fibrosis to patients with renal insufficiency. Nevertheless, GBCAs are quickly excreted from the kidneys, which shortens their imaging window and prevents long-term monitoring of the disease per injection. Herein, a nephrotoxicity-free T1 MRI contrast agent is developed by coordinating ferric iron into a telodendritic, micellar nanostructure. This new nano-enabled, iron-based contrast agent (nIBCA) not only can reduce the renal accumulation and relieve the kidney burden, but also exhibit a significantly higher tumor to noise ratio (TNR) for cancer diagnosis. In comparison with Magnevist (a clinical-used GBCA), Magnevist induces obvious nephrotoxicity while nIBCA does not, indicating that such a novel contrast agent may be applicable to renally compromised patients requiring a contrast-enhanced MRI. The nIBCA could precisely image subcutaneous brain tumors in a mouse model and the effective imaging window lasted for at least 24 h. The nIBCA also precisely highlights the intracranial brain tumor with high TNR. The nIBCA presents a potential alternative to GBCAs as it has superior biocompatibility, high TNR and effective imaging window.Photodynamic therapy (PDT) has been successfully demonstrated for anticancer treatment in vivo. However, tumor metastasis during PDT are still inevitable due to the activation of the epidermal growth factor receptor (EGFR). selleck chemicals The current work describes the synthesis of a photosensitizer (PS)-EGFR inhibitor conjugate for PDT with simultaneous tumor metastasis inhibition. The conjugate efficiently internalized into cancer cells and generated reactive oxygen species (ROS) under light, indicating strong cytotoxicity even in hypoxic tumor environment. The presence of an EGFR inhibitor significantly inhibited cell migration and invasion. Accordingly, photoactivation of the conjugate resulted in efficient tumor growth inhibition in a 4T1 tumor-bearing mouse model and suppressed angiogenesis and tumor metastasis during PDT. Therefore, combined PDT and EGFR inhibition strategy provides a new platform for future anticancer treatment with high safety.
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