Microneedle-array patch with pH-sensitive formulation for glucoseresponsive insulin delivery

Glucose-responsive insulin delivery systems show great promise to improve therapeutic outcomes and quality of life for people with diabetes.Herein,a new microneedle-array patch containing pH-sensitive insulin-loaded nanoparticles(NPs)(SNP(I))together with glucose oxidase(GOx)-and catalase(CAT)-loaded pH-insensitive NPs(iSNP(G+C))is constructed for transcutaneous glucose-responsive insulin delivery.SNP(I)are prepared via double emulsion from a pH-sensitive amphiphilic block copolymer,and undergo rapid dissociation to promote insulin release at a mild acidic environment induced by GOx in iSNP(G+C)under hyperglycemic conditions.CAT in iSNP(G+C)can further consume excess H_(2)O_(2) generated during GOx oxidation,and thus reduce the risk of inflammation toward the normal skin.The in vivo study on type 1 diabetic mice demonstrates that the platform can effectively regulate blood glucose levels within normal ranges for a prolonged period.

A polyamidoamine(PAMAM)derivative dendrimer with high loading capacity of TLR7/8 agonist for improved cancer immunotherapy

Tumor associated macrophages(TAMs)tend to exhibit tumor-promoting M2 phenotype and contribute to the development of immunosuppressive microenvironment of solid tumors.Reprograming TAMs from M2 into tumoricidal M1 phenotype is robust for stimulating tumor immunosuppressive microenvironment(TIME).In this study,we developed a poly(amidoamine)(PAMAM)derivative dendrimer(denoted as fourth generation-N,N-diethylaminoethyl(G4-DEEA))for efficient loading of Toll-like receptor 7 and 8(TLR7/8)agonist(R848)to remodel the TIME for potent cancer immunotherapy,G4-DEEA exhibited a high loading capacity of R848 up to 35.9 wt%by taking advantage of its dendritic structure.The resulting formulation(designated as G4-DEEA@R848)effectively polarized M2 macrophages into M1 phenotype in vitro,and improved the maturation and activation of antigen-presenting cells.In the 4T1 orthotopic breast cancer model,G4-DEEA@R848 showed a stronger tumor inhibitory effect than free drug.The mechanistic studies suggested that G4-DEEA@R848 could significantly stimulate the TIME by repolarizing TAMs into M1 phenotype,reducing the presence of immunosuppressive myeloid cells and increasing the infiltration of tumor cytotoxic T cells.This study provides a simple but effective dendrimer-based strategy to improve the formulation of R848 for improved cancer immunotherapy.

基于TACMAA化学的肿瘤微酸性环境响应高分子纳米药物载体

过去几十年,纳米技术在药物递送、分子影像、肿瘤治疗等领域获得了广泛的应用.相比小分子药物,纳米药物具有提高药物成药性、改善药物分布、降低毒副作用等特点,但是,纳米药物需面临复杂的体内递送过程,才能最终到达靶部位发挥药效.有针对性地设计高分子载体材料的结构,使其对体内微环境产生特异性的响应以改变纳米载体性能,适应体内药物递送复杂环境,是提高纳米药物递送效率的重要策略.本文系统介绍了我们如何思考归纳纳米药物体内递送的复杂过程,并进一步提出基于肿瘤组织酸性微环境调控纳米载体性能以提高药物递送效率这一核心思想.详细回顾了基本设想的提出、验证到体内效果的系统性评估,以及基于这一思想发展的多种药物递送策略,从多个层面解决体内药物输送面临的难题,并对此领域未来的发展进行了展望.

An Intracellular pH-Actuated Polymer for Robust Cytosolic Protein Delivery

Robust cytosolic protein delivery requires both efficient protein binding with delivery vehicles and effective protein release after cell internalization.Although a variety of stimuli-responsive carriers have been designed,simultaneously integrating these two functions in one versatile carrier is challenging.Herein,we developed a polyamidoamine(PAMAM)-based polymer with an intracellular pHactuated hydrophobic-to-hydrophilic transition for this purpose.

A Redox-responsive Prodrug Nanogel of TLR7/8 Agonist for Improved Cancer Immunotherapy

The existence of tumor immunosuppressive microenvironment(TIME)is the major determinant for the poor efficacy of current tumor immunotherapy.Tumor-associated macrophages(TAMs)tend to become tumor-promoting M2-like phenotype and hinder immune response in solid tumors.Repolarization of TAMs from M2 to anti-tumor M1 phenotype is robust for remodeling the TIME.Herein,we developed a redox-responsive nanogel as the delivery system of Toll-like receptor 7 and 8(TLR7/8)agonist(R848)prodrug for potent cancer immunotherapy.The nanogel(denoted as R848-Gel)was obtained by emulsion polymerization of HSEMA and R848 prodrug(R848-HSEMA),whose size was appropriate 100 nm.R848-Gel could be internalized by macrophages and dendritic cells in vitro,and effectively repolarized M2 into M1 macrophages and promoted the maturation of antigen-presenting cells.In vivo study indicated that the R848-Gel showed a stronger tumor inhibitory effect and no drastic body weight change compared with free drug.Immune cell analysis after the treatment indicated that R848-Gel was helpful to activating the TIME.In summary,this study provides a simple but effective vehicle for R848 to improve cancer immunotherapy.

A New Lower Bound on the Potential-Ramsey Number of Two Graphs

A nonincreasing sequenceπ=(d1,…,dn)of nonnegative integers is a graphic sequence if it is realizable by a simple graph G on n vertices.In this case,G is referred to as a realization ofπ.Given a graph H,a graphic sequenceπis potentially H-graphic ifπhas a realization containing H as a subgraph.For graphs G1 and G2,the potential-Ramsey number rpot(G1,G2)is the smallest integer k such that for every k-term graphic sequenceπ,eitherπis potentially G1-graphic or the complementary sequenceπ=(k-1-dk,…,k-1-d1)is potentially G2-graphic.For 0≤k≤[t/2],denote Kt-k to be the graph obtained from Kt by deleting k independent edges.If k=0,Busch et al.(Graphs Combin.,30(2014)847-859)present a lower bound on rpot(G,Kt)by using the 1-dependence number of G.In this paper,we utilize i-dependence number of G for i≥1 to give a new lower bound on rpot(G,Kt-k)for any k with 0≤k≤[T/2].Moreover,we also determine the exact values of rpot(Kn,Kt-k)for 1≤k≤2.