A homogenous nanoporous pulmonary drug delivery system based on metal-organic frameworks with fine aerosolization performance and good compatibility

Pulmonary drug delivery has attracted increasing attention in biomedicine,and porous particles can effectively enhance the aerosolization performance and bioavailability of drugs.However,the existing methods for preparing porous particles using porogens have several drawbacks,such as the inhomogeneous and uncontrollable pores,drug leakage,and high risk of fragmentation.In this study,a series of cyclodextrin-based metal-organic framework(CD-MOF)particles containing homogenous nanopores were delicately engineered without porogens.Compared with commercial inhalation carrier,CDMOF showed excellent aerosolization performance because of the homogenous nanoporous structure.The great biocompatibility of CD-MOF in pulmonary delivery was also confirmed by a series of experiments,including cytotoxicity assay,hemolysis ratio test,lung function evaluation,in vivo lung injury markers measurement,and histological analysis.The results of ex vivo fluorescence imaging showed the high deposition rate of CD-MOF in lungs.Therefore,all results demonstrated that CD-MOF was a promising carrier for pulmonary drug delivery.This study may throw light on the nanoporous particles for effective pulmonary administration.

The crystal structure of Ac-AChBP in complex with α-conotoxin LvlA reveals the mechanism of its selectivity towards different nAChR subtypes

The a3＊ nAChRs, which are considered to be promising drug targets for problems such as pain, addiction, cardiovascular function, cognitive disorders etc., are found throughout the central and peripheral nervous system. The α-conotoxin （α-CTx） LvlA has been identified as the most selective inhibitor of α3β2 nAChRs known to date, and it can distinguish the α3132 nAChR subtype from the α6/α3β2β3 and α3β4 nAChR subtypes. However, the mechanism of its selectivity towards α3132, α6/α3β2β3, and α3β4 nAChRs remains elusive. Here we report the co-crystal structure of LvlA in complex with Aplysia californica acetylcholine binding protein （Ac-AChBP） at a resolution of 3.4 A. Based on the structure of this complex, together with homology modeling based on other nAChR subtypes and binding affinity assays, we conclude that Asp-11 of LvlA plays an important role in the selectivity of LvlA towards α3132 and α31o6132133 nAChRs by making a salt bridge with Lys-155 of the rat α3 subunit. Asn-9 lies within a hydrophobic pocket that is formed by Met-36, Thr-59, and Phe-119 of the rat β2 subunit in the α3β2 nAChR model, revealing the reason for its more potent selectivity towards the a3β2 nAChR subtype. These results provide molecular insights that can be used to design ligands that selectively target α3β2 nAChRs, with significant implications for the design of new therapeutic a-CTxs.

Tailored core-shell dual metal-eorganic frameworks as a versatile nanomotor for effective synergistic antitumor therapy

Malignant tumor has become an urgent threat to global public healthcare.Because of the heterogeneity of tumor,single therapy presents great limitations while synergistic therapy is arousing much attention,which shows desperate need of intelligent carrier for co-delivery.A core-shell dual metaleorganic frameworks(MOFs)system was delicately designed in this study,which not only possessed the unique properties of both materials,but also provided two individual specific functional zones for co-drug delivery.Photosensitizer indocyanine green(ICG)and chemotherapeutic agent doxorubicin(DOX)were stepwisely encapsulated into the nanopores of MIL-88 core and ZIF-8 shell to construct a synergistic photothermal/photodynamic/chemotherapy nanoplatform.Except for efficient drug delivery,the MIL-88 could be functioned as a nanomotor to convert the excessive hydrogen peroxide at tumor microenvironment into adequate oxygen for photodynamic therapy.The DOX release from MIL-88-ICG@ZIF-8-DOX nanoparticles was triggered at tumor acidic microenvironment and further accelerated by near-infrared(NIR)light irradiation.The in vivo antitumor study showed superior synergistic antitumor effect by concentrating the nanoparticles into dissolving microneedles as compared to intravenous and intratumoral injection of nanoparticles,with a significantly higher inhibition rate.It is anticipated that the multi-model synergistic system based on dual-MOFs was promising for further biomedical application.