Yin Dou

Cyclodextrin-derived pH-responsive nanoparticles for delivery of paclitaxel.

Engineering of pH-responsive nanoplatforms can be facilely achieved from acetalated α-cyclodextrin materials. The hydrolysis period of nanoparticles can be precisely tailored by using materials with various acetal types that can be easily controlled by acetalation time. These nanomaterials with pH-modulated hydrolysis and pH-triggered drug delivery capability show good biocompatibility in vitro and in vivo. Incorporation of anticancer drug paclitaxel (PTX) into newly developed pH-sensitive nanosystems leads to nanotherapeutics with significantly improved cytotoxic activity against various tumor cells. Importantly, thus formulated nanomedicines can reverse the multidrug resistance of PTX-resistant cancer cells. In vivo antitumor studies also reveal the superior of pH-sensitive nanosystems over pristine PTX and pH-insensitive PLGA nanoformulations. Moreover, comparison with other two acid-labile materials evidenced the advantages of cyclodextrin-based nanovehicles with respect to drug loading capacity, in vitro and in vivo activity as well as alleviated adverse effects. These pH-responsive nanoparticles may serve as new generation nanocarriers for drug delivery.

Nanostructured poly(L-lactide) matrix as novel platform for drug delivery.

With the aim to establish new strategies for fabricating bioactive nanostructured matrices for controlled drug delivery or potential tissue engineering, a facile and one-pot protocol was developed in this study to produce drug-loaded poly(l-lactide) (PLLA) nanostructures by thermally induced phase separation. Using both steroidal and nonsteroidal anti-inflammatory drugs, we demonstrated that lipophilic drugs can be efficiently incorporated in either nanosheet-like or nanofibrous PLLA matrices. Thus entrapped drug was randomly distributed in the interconnected nanostructures in the form of nanoscaled crystals. In vitro release study revealed that drug release kinetics may be modulated, on the one hand, by the nanostructure of matrices, while on the other hand by the polymer concentration utilized for fabrication. As for hydrophilic compounds, they could be conveniently loaded into nanofibrous structure by post-fabrication absorption. In addition to the conceptual proof of potential applications of nanostructured PLLA matrices for controlled drug delivery, the strategy employed herein offers a new way to construct bioactive scaffolds, such as antibacterial or anti-inflammatory scaffolds, which may find broad applications for tissue regeneration and stem cells-based biotherapy.

Sustained delivery by a cyclodextrin material-based nanocarrier potentiates antiatherosclerotic activity of rapamycin via selectively inhibiting mTORC1 in mice.

Increasing evidence has demonstrated special advantages of the nanomedicinal approach for the management of cardiovascular disease. We hypothesize that sustained delivery of rapamycin (RAP) may provide more desirable therapeutic effects than traditional oral administration by selectively inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling. To evidence this assumption and develop an effective, safe, and translational nanotherapy for atherosclerosis, this study was designed to examine antiatherosclerotic efficacy of a RAP nanotherapy based on an acetalated β-cyclodextrin (Ac-bCD) material in apolipoprotein E-deficient (ApoE(-/-)) mice. First, biodegradable and biocompatible materials of Ac-bCDs were synthesized by kinetically controlled acetalation, giving rise to carrier materials that may not generate acidic byproducts after hydrolysis. Then RAP-loaded nanoparticles base on various Ac-bCDs were prepared by a nanoemulsion technique, which can sustain drug release for different periods of time, depending on the composition of Ac-bCDs. For a RAP/Ac-bCD180-derived nanotherapy (RAP-NP) that may continue RAP release for up to 20days in vitro, it afforded constant drug levels in both the blood and aortic tissue after subcutaneous injection, while orally administered free RAP showed typical peak-valley profiles with remarkably high peak concentrations. Therapeutic studies conducted in an experimental model of atherosclerosis established in ApoE(-/-) mice revealed that RAP-NP significantly reduced the formation of atherosclerotic lesions and dramatically enhanced the stability of plaques, which was more efficacious than orally delivered free RAP. Moreover, rupture-prone proinflammatory factors in both serum and aortas were significantly decreased after treatment. Whereas oral administration of RAP simultaneously inhibited mTORC1 and mTORC2 in the aorta, sustained delivery by RAP-NP selectively suppressed mTORC1, agreeing with in vitro results in smooth muscle cells. These findings demonstrated that antiatherosclerotic activity of RAP may be considerably improved by sustained release via the Ac-bCD material-derived nanocarrier, which was achieved through selectively inhibiting mTORC1.

A facile route to diverse assemblies by host–guest recognition

Self-assembly provides a powerful approach for generating complex materials with advanced functionalities. Currently it remains a great challenge to create hierarchically structured assemblies from materials with simple molecular structure. Further, successful clinical translation of polymer assemblies-based therapeutics requires facile yet effective strategies for their fabrication and cargo loading based on structurally simple and cost-effective starting materials. Herein we partly addressed these issues by an all-in-one strategy involving host–guest assembly via molecular recognition, in which carboxyl-bearing compounds serve as guest molecules, while N-substituted acrylamide homopolymers or their various copolymers are host materials. Assembly and therapeutic loading can be simultaneously realized by this one-pot approach, leading to superstructures across length scales and with multiple morphologies, such as micelle-like nanoparticles, vesicles, nano- and microspheres, microtubes, and onion-like multilayer structures. In addition to biomedical applications, superstructures generated by this simple and robust strategy have potential uses in templated synthesis, catalysis, optics, and microelectronics.

Facile route to versatile nanoplatforms for drug delivery by one-pot self-assembly.

There is still unmet demand for developing powerful approaches to produce polymeric nanoplatforms with versatile functions and broad applications, which are essential for the successful bench-to-bedside translation of polymeric nanotherapeutics developed in the laboratory. We have discovered a facile, convenient, cost-effective and easily scalable one-pot strategy to assemble various lipophilic therapeutics bearing carboxyl groups into nanomedicines, through which highly effective cargo loading and nanoparticle formation can be achieved simultaneously. Besides dramatically improving water solubility, the assembled nanopharmaceuticals showed significantly higher bioavailability and much better therapeutic activity. These one-pot assemblies may also serve as nanocontainers to effectively accommodate other highly hydrophobic drugs such as paclitaxel (PTX). PTX nanomedicines thus formulated display strikingly enhanced in vitro antitumor activity and can reverse the multidrug resistance of tumor cells to PTX therapy. The special surface chemistry offers these assembled entities the additional capability of efficiently packaging and efficaciously transfecting plasmid DNA, with a transfection efficiency markedly higher than that of commonly used positive controls. Consequently, this one-pot assembly approach provides a facile route to multifunctional nanoplatforms for simultaneous delivery of multiple therapeutics with improved therapeutic significance.

Compound K Attenuates the Development of Atherosclerosis in ApoE−/− Mice via LXRα Activation

Background: Atherosclerosis is a fundamental pathological process responded to some serious cardiovascular events. Although the cholesterol-lowering drugs are widely prescribed for atherosclerosis therapy, it is still the leading cause of death in the developed world. Here we measured the effects of compound K in atherosclerosis formation and investigated the probably mechanisms of the anti-antherosclerosis roles of compound K. Methods: We treated the atherosclerotic model animals (apoE−/− mice on western diet) with compound K and measured the size of atherosclerotic lesions, inflammatory cytokine levels and serum lipid profile. Peritoneal macrophages were collected in vitro for the foam cell and inflammasome experiments. Results: Our results show that treatment with compound K dose-dependently attenuates the formation of atherosclerotic plaques by 55% through activation of reverse cholesterol transport pathway, reduction of systemic inflammatory cytokines and inhibition of local inflammasome activity. Compound K increases the cholesterol efflux of macrophage-derived foam cells, and reduces the inflammasome activity in cholesterol crystal stimulated macrophages. The activation of LXRα may contribute to the athero-protective effects of compound K. Conclusion: These observations provide evidence for an athero-protective effect of compound K via LXRα activation, and support its further evaluation as a potential effective modulator for the prevention and treatment of atherosclerosis.

Nanoassemblies from homostructured polypeptides as efficient nanoplatforms for oral drug delivery

UNLABELLED The assembly of homostructured polypeptides bearing various side groups into well-defined nanostructures was presented, with their size and topology mainly dominated by the chemical structure and molecular weight of peptides. Pharmacokinetic and pharmacodynamic studies based on rat models suggested these newly constructed nanoassemblies with low cytotoxicity may function as novel nanoplatforms to efficiently and safely deliver therapeutics to achieve better efficacy but lower side effects. Other applications in biomedical fields, such as biotechnology, medical imaging, and tissue engineering, may also be expected. FROM THE CLINICAL EDITOR This research team investigated the assembly of homostructured polypeptides bearing various side groups into well-defined nanostructures, and demonstrated low cytotoxicity in rat disease models, suggesting that these novel nanoplatforms may safely and efficiently deliver therapeutics with low side effects.

Multiple noncovalent interactions mediated one-pot therapeutic assemblies for the effective treatment of atherosclerosis

Atherosclerosis may cause life-threatening coronary artery disease, carotid artery disease, stroke, and peripheral vascular disease, while its effective therapy remains challenging thus far. With the aim of facilely constructing efficacious and translational oral delivery systems for an anti-atherosclerotic drug of rapamycin (RAP), an all-in-one approach was created. This strategy involves a carboxyl-bearing compound (serves as a guest molecule) mediated self-assembly of a structurally simple host polymer of poly(N-isopropylacrylamide) (PNIPAm). The formation of microspheres and highly efficient packaging of RAP could be simultaneously achieved by this host-guest self-assembly, affording cost-effective therapeutic assemblies with particularly robust drug loading capacity, desirable drug dissolution, relative manufacturing simplicity, good lyophilization-reconstitution character, and facile scalability. Besides these pharmaceutical characteristics superior over control microspheres based on poly(lactide-co-glycolide) or a enteric coating material, therapeutic RAP microspheres fabricated by this assembly approach had high oral bioavailability. More importantly, assembled RAP microspheres displayed significant therapeutic advantages upon treatment of atherosclerosis in an apolipoprotein E-deficient mouse model. In addition, a long-term treatment with either RAP-containing assemblies or the carrier material PNIPAm revealed a good safety profile in mice post oral delivery. Accordingly, RAP microspheres developed herein are promising and translational therapeutics for atherosclerotic diseases. This study also provides new insights into the design of effective carrier materials for various lipophilic therapeutics.

Targeted Therapy of Atherosclerosis by a Broad-Spectrum Reactive Oxygen Species Scavenging Nanoparticle with Intrinsic Anti-inflammatory Activity

Atherosclerosis is a leading cause of vascular diseases worldwide. Whereas antioxidative therapy has been considered promising for the treatment of atherosclerosis in view of a critical role of reactive oxygen species (ROS) in the pathogenesis of atherosclerosis, currently available antioxidants showed considerably limited clinical outcomes. Herein, we hypothesize that a broad-spectrum ROS-scavenging nanoparticle can serve as an effective therapy for atherosclerosis, taking advantage of its antioxidative stress activity and targeting effects. As a proof of concept, a broad-spectrum ROS-eliminating material was synthesized by covalently conjugating a superoxide dismutase mimetic agent Tempol and a hydrogen-peroxide-eliminating compound of phenylboronic acid pinacol ester onto a cyclic polysaccharide β-cyclodextrin (abbreviated as TPCD). TPCD could be easily processed into a nanoparticle (TPCD NP). The obtained nanotherapy TPCD NP could be efficiently and rapidly internalized by macrophages and vascular smooth muscle cells (VSMCs). TPCD NPs significantly attenuated ROS-induced inflammation and cell apoptosis in macrophages, by eliminating overproduced intracellular ROS. Also, TPCD NPs effectively inhibited foam cell formation in macrophages and VSMCs by decreasing internalization of oxidized low-density lipoprotein. After intravenous (i.v.) administration, TPCD NPs accumulated in atherosclerotic lesions of apolipoprotein E-deficient (ApoE-/-) mice by passive targeting through the dysfunctional endothelium and translocation via inflammatory cells. TPCD NPs significantly inhibited the development of atherosclerosis in ApoE-/- mice after i.v. delivery. More importantly, therapy with TPCD NPs afforded stabilized plaques with less cholesterol crystals, a smaller necrotic core, thicker fibrous cap, and lower macrophages and matrix metalloproteinase-9, compared with those treated with control drugs previously developed for antiatherosclerosis. The therapeutic benefits of TPCD NPs mainly resulted from reduced systemic and local oxidative stress and inflammation as well as decreased inflammatory cell infiltration in atherosclerotic plaques. Preliminary in vivo tests implied that TPCD NPs were safe after long-term treatment via i.v. injection. Consequently, TPCD NPs can be developed as a potential antiatherosclerotic nanotherapy.