Intelligent nanogels with self-adaptive responsiveness for improved tumor drug delivery and augmented chemotherapy

For cancer nanomedicine,the main goal is to deliver therapeutic agents effectively to solid tumors.Here,we report the unique design of self-adaptive ultrafast charge-reversible chitosan-polypyrrole nanogels(CH-PPy NGs)for enhanced tumor delivery and augmented chemotherapy.CH was first grafted with PPy to form CH-PPy polymers that were used to form CH-PPy NGs through glutaraldehyde cross-linking via a miniemulsion method.The CH-PPy NGs could be finely treated with an alkaline solution to generate ultrafast charge-reversible CH-PPy-OH-4 NGs(R-NGs)with a negative charge at a physiological pH and a positive charge at a slightly acidic pH.The R-NGs display good cytocompatibility,excellent protein resistance,and high doxorubicin(DOX)loading efficiency.Encouragingly,the prepared R-NGs/DOX have prolonged blood circulation time,enhanced tumor accumulation,penetration and tumor cell uptake due to their self-adaptive charge switching to be positively charged,and responsive drug delivery for augmented chemotherapy of ovarian carcinoma in vivo.Notably,the tumor accumulation of R-NGs/DOX(around 4.7%)is much higher than the average tumor accumulation of other nanocarriers(less than 1%)reported elsewhere.The developed self-adaptive PPy-grafted CH NGs represent one of the advanced designs of nanomedicine that could be used for augmented antitumor therapy with low side effects.

点击反应在糖聚肽及其类似物合成中的应用

糖聚肽是一类由聚肽/聚氨基酸与糖类化合物共价相连构成的高分子化合物,因其良好的生物相容性及独特的生物学性能,在自组装、组织工程、药物输送等领域均显示出广泛的应用前景,成为近年来蓬勃发展的热点领域.高效合成结构规整可控的糖聚肽是该领域的热点和难点.点击化学的快速发展为糖聚肽的合成提供了高效便捷的途径.系统综述了点击反应在糖聚肽两种合成策略中的应用——通过聚合后修饰法将糖分子引入到聚氨基酸前体侧链上以及对糖苷化的α-氨基酸-N-羧酸酐(glyco-NCA)"可点击"化学单体的开环聚合反应,同时也总结了通过点击反应将含糖功能基元化学偶联到聚氨基酸链末端合成糖聚肽类似物的策略,并对其优缺点和发展方向进行了简要讨论.

Construction of Electrospun Organic/Inorganic Hybrid Nanofibers for Drug Delivery and Tissue Engineering Applications

Electrospun nanofibers hold a great potential in biomedical applications due to their advantages of large specific surface area,good biocompatibility,easy fabrication and surface modification.In particular,organic/inorganic hybrid nanofibers exhibit enhanced mechanical properties and long-term sustained release or controlled release profile of encapsulated drugs,which enables hybrid nanofibers to serve as desired platform for drug delivery and tissue engineering applications.This review summarizes the recent progresses in the preparation,performances and applications of hybrid nanofibers as drug delivery vectors for antibacterial and antitumor therapy,and as nanofibrous scaffolds for bone tissue engineering or other types of tissue engineering applications.Nanofibers doped with various types of inorganic nanoparticles(e.g.,halloysite,laponite®,nano-hydroxyapatite,attapulgite,carbon nanotubes,and graphene,etc.)are introduced and summarized in detail.Future perspectives are also briefly discussed.

Gene silencing-mediated immune checkpoint blockade for tumor therapy boosted by dendrimer-entrapped gold nanoparticles

Immune checkpoint blockade(ICB) has been regarded as one promising approach for tumor immunotherapy. Here, we report a functional nanoplatform based on generation 5(G5) poly(amidoamine)(PAMAM)dendrimer-entrapped gold nanoparticles(Au DENPs) as a nonviral vector to deliver programmed death-ligand 1(PDL1) small interfering RNA(siPD-L1) for subsequent PD-L1 gene silencing-mediated tumor immunotherapy. In this work,G5 dendrimers with amine termini were partially decorated with methoxy polyethylene glycol(m PEG) on their periphery,entrapped Au NPs within their interiors, and were eventually labeled with fluorescamine. The generated functional Au DENPs possess desired dispersibility in water and colloidal stability, satisfactory cytocompatibility after complexation with siPD-L1, and efficient gene delivery performance. Strikingly, the functional Au DENPs enabled the delivery of siPDL1 to cancer cells to efficiently knock down the PD-L1 protein expression, thus boosting the ICB-based immunotherapy of a xenografted melanoma mouse tumor model with a tumor inhibition efficiency much higher than the PD-L1 antibody.The immune responses were also well demonstrated by downregulation of PD-L1 protein on the tumor cell surface and abundant distribution of CD8+and CD4+T cells in the infiltrating tumor tissue and spleen organ. The developed functional dendrimer-based nanoplatform may be promising to boost ICB-based immunotherapy of other tumor types.

Dendrimer-decorated nanogels:Efficient nanocarriers for biodistribution in vivo and chemotherapy of ovarian carcinoma

Nanomedicine has revolutionized disease theranostics by the accurate diagnosis and efficient therapy.Here,the PAMAM dendrimer decorated PVCL-GMA nanogels(NGs)were developed for favorable biodistribution in vivo and enhanced antitumor efficacy of ovarian carcinoma.By an ingenious design,the NGs with a unique structure that GMA-rich domains were localized on the surface were synthesized via precipitation polymerization.After G2 dendrimer decoration,the overall charge is changed from neutral to positive,and the NGs-G2 display the whole charge nature of positively charged corona and neutral core.Importantly,the unique architecture and charge conversion of NGs-G2 have a profound impact on the biodistribution and drug delivery in vivo.As a consequence of this alteration,the NGs-G2 as nanocarriers emerge the highly sought biodistribution of reduced liver accumulation,enhanced tumor uptake,and promoted drug release,resulting in the significantly augmented antitumor efficacy with low side effects.Remarkably,this finding is contrary to some reported work that the nanocarriers with positive charge have preferential liver uptake.Moreover,the NGs-G2 also displayed thermal/pH dual-responsive behaviors,excellent biocompatibility,improved cellular uptake,and stimuli-responsive drug release.Encouragingly,this work demonstrates a novel insight into the strategy for optimizing design,improving biodistribution and enhancing theranostic efficacy of nanocarriers.

Brain delivery of fibronectin through bioactive phosphorous dendrimers for Parkinson’s disease treatment via cooperative modulation of microglia

Effective treatment of Parkinson’s disease(PD),a prevalent central neurodegenerative disorder particularly affecting the elderly population,still remains a huge challenge.We present here a novel nanomedicine formulation based on bioactive hydroxyl-terminated phosphorous dendrimers(termed as AK123)complexed with fibronectin(FN)with anti-inflammatory and antioxidative activities.The created optimized AK123/FN nanocomplexes(NCs)with a size of 223 nm display good colloidal stability in aqueous solution and can be specifically taken up by microglia through FN-mediated targeting.We show that the AK123/FN NCs are able to consume excessive reactive oxygen species,promote microglia M2 polarization and inhibit the nuclear factor-kappa B signaling pathway to downregulate inflammatory factors.With the abundant dendrimer surface hydroxyl terminal groups,the developed NCs are able to cross blood-brain barrier(BBB)to exert targeted therapy of a PD mouse model through the AK123-mediated anti-inflammation for M2 polarization of microglia and FN-mediated antioxidant and anti-inflammatory effects,thus reducing the aggregation ofα-synuclein and restoring the contents of dopamine and tyrosine hydroxylase to normal levels in vivo.The developed dendrimer/FN NCs combine the advantages of BBB-crossing hydroxyl-terminated bioactive per se phosphorus dendrimers and FN,which is expected to be extended for the treatment of different neurodegenerative diseases.