查找使用阿拉丁产品的科研文献

An iRGD-conjugated prodrug micelle with blood-brain-barrier penetrability for anti-glioma therapy

Lu Lu,Xiaojing Zhao,Tiwei Fu,Ke Li,Ye He,Zhong Luo,Liangliang Dai,Rui Zeng,Kaiyong Cai

Various obstacles impede the chemotherapy efficiency of glioma in clinic, such as blood brain barrier (BBB) and blood brain tumor barrier (BBTB). Ligand-mediated polymeric micelles have shown great potential for improving the efficiency of glioma treatment. Herein, we developed a disulfide bond-conjugated prodrug polymer consisted of camptothecin (CPT) and polyethylene glycol (PEG) with further modification of iRGD peptide. The polymer of CPT-S-S-PEG-COOH could self-assemble into nanosized polymeric micelles with diameter around 100 nm, and loaded with photosensitizer IR780 for combination therapy. The micelles displayed good stability with controlled drug release under physiological environment. Importantly, the iRGD modified polymeric micelles demonstrated favorable ability to cross the BBB and target glioma cells via αv β integrin and neuropilin-1-mediated ligand transportation in vitro and in vivo . The whole synthesis process is simple and the drug loading content of CPT in the [email protected] micelles was higher than 10%. Moreover, [email protected] micelles combined chemotherapy with photodynamic therapy (PDT) displayed more excellent tumor-killing capability than the other groups. Thus, both in vitro and in vivo studies suggested that the targeting prodrug system could not only effectively cross various barriers to reach at glioma site, but also significantly enhance the antitumor effect with laser irradiation . Our findings consequently suggested that [email protected] micelles with laser irradiation are a promising drug delivery system for glioma therapy.

Enhanced tumor targeting and penetration of fluorophores via iRGD peptide conjugation: a strategy for the precision targeting of lung cancer

Yunlong Li,Chenmei Li,Jiamin Li,Dong Han,Gang Xu,Daolong Zhu,Huiming Cai,Yiqing Wang,Dong Wang

Background Accurate real-time tumor delineation is essential for achieving curative resection (R0 resection) during non-small cell lung cancer (NSCLC) surgery. The unique characteristics of lung tissue structure significantly challenge the use of video-assisted thoracoscopic surgery in the identification of lung nodules. This difficulty often results in an inability to discern the margins of lung nodules, necessitating either an expansion of the resection scope, or a transition to open surgery. Due to its high spatial resolution, ease of operation, and capacity for real-time observation, near-infrared fluorescence (NIRF) navigation in oncological surgery has emerged as a focal point of clinical research. Targeted NIRF probes, which accumulate preferentially in tumor tissues and are rapidly cleared from normal tissues, enhance diagnostic sensitivity and surgical outcomes. The imaging effect of the clinically approved NIRF probe indocyanine green (ICG) varies significantly from person to person. Therefore, we hope to develop a new generation of targeted NIRF probes targeting lung tumor-specific targets. Methods First, the peptide iRGD (sequence: CRGDKGPDC) fluorescent tracer was synthesized, and characterized through mass spectrometry (MS), proton nuclear magnetic resonance ( 1 H NMR), and high-performance liquid chromatography (HPLC). Fluorescence properties were tested subsequently. Safety was performed in vitro using both human normal liver cells and human normal breast cells. Second, Metabolism and optimal imaging time were determined by tail vein injection of iRGD fluorescent tracer. Finally, Orthotopic and metastatic lung tumor models were used to evaluate the targeting properties of the iRGD fluorescent tracer. Results We successfully synthesized an iRGD fluorescent tracer specifically designed to target NSCLC. The molecular docking analyses indicated that this tracer has receptor affinity comparable to that of iRGD for αvβ3 integrin, with a purity ≥98%. Additionally, the tracer is highly soluble in water, and its excitation and emission wavelengths are 767 and 799 nm, respectively, positioning it within the near-infrared spectrum. The cellular assays confirmed the tracer’s minimal cytotoxicity, underscoring its excellent biosafety profile. In vivo studies further validated the tracer’s capacity for specific NSCLC detection at the cellular level, alongside a prolonged imaging window of 6 days or more. Notably, the tracer demonstrated superior specificity in localizing very small lung nodules, which are otherwise clinically indiscernible, outperforming non-targeted ICG. Fluorescence intensity analyses across various organs revealed that the tracer is predominantly metabolized by the liver and kidneys, with excretion via bile and urine, and exhibits minimal toxicity to these organs as well as the lungs. Conclusions The iRGD fluorescent tracer selectively accumulates in NSCLC tissues by specifically targeting αvβ3 receptors, which are overexpressed on the surface of tumor cells. This targeted approach facilitates the real-time intraoperative localization of NSCLC, presenting an improved strategy for intraoperative tumor identification with significant potential for clinical application. Click here to view. (86K, pdf)

iRGD-modified lipid–polymer hybrid nanoparticles loaded with isoliquiritigenin to enhance anti-breast cancer effect and tumor-targeting ability

Fei Gao,Jinming Zhang,Chaomei Fu,Xiaoming Xie,Fu Peng,Jieshu You,Hailin Tang,Zhiyu Wang,Peng Li,Jianping Chen

Isoliquiritigenin (ISL), a natural anti-breast cancer dietary compound, has poor delivery characteristics and low bioavailability. In order to promote the therapeutic outcome of ISL, a tumor-targeting lipid–polymer hybrid nanoparticle (NP) system modified by tumor-homing iRGD peptides has been developed. The hybrid NPs were prepared by a modified single-step nanoprecipitation method to encapsulate ISL. iRGD peptides were anchored on the surface by a postinsertion method (ISL-iRGD NPs). The stable lipid–polymer structure of ISL-iRGD NPs, with high encapsulation and loading efficiency, was confirmed. Compared to free ISL and non-iRGD-modified counterparts, ISL-iRGD NPs showed higher cytotoxicity and cell apoptosis against the different type of breast cancer cells. This was attributable to higher cellular accumulation mediated by the iRGD-integrin recognition and the nanoscale effect. More importantly, based on the active tumor-tissue accumulation by iRGD peptides and the prolonged in vivo circulation by the stealth nanostructure, ISL-iRGD NPs displayed higher tumor-growth inhibition efficiency in 4T1-bearing breast-tumor mouse models. Therefore, the constructed iRGD modified lipid–polymer hybrid NPs would provide a promising drug-delivery strategy to improve ISL in anti-breast cancer efficacy.

Hybrid biomaterial hydrogel loading iRGD&PS double modified lipid nanoparticles ameliorates diabetic wound healing through promoting efferocytosis and glycolysis-related macrophage reprogramming

Wenqian Zhang,Shengming Zhang,Samuel Knoedler,Wenhao Han,Kangkang Zha,Hui Li,Adriana Christine Panayi,Michael Alfertshofer,Bong-Sung Kim,Weixian Hu,Yanzhi Zhao,Qian Feng,Yuval Rinkevich,Bobin Mi,Guohui Liu

Efferocytosis is a critical process whereby macrophages residing in the wound area play a key role in the efficient clearing and degradation of apoptotic neutrophils. This process is followed by a phenotypic transition toward an anti-inflammatory state, essential for inflammation resolution and tissue repair. The cystine/glutamate antiporter SLC7A11 has recently been identified as an inhibitor of efferocytosis, and its blockade has been found to enhance wound healing. In this study, we demonstrated that tiliroside, a plant-derived glycoside containing flavones, binds directly to SLC7A11 and pyruvate kinase isozyme M2 (PKM2). This was established by molecular docking predictions and activity-based protein profiling (ABPP). Cytological experiments revealed that tiliroside promoted the process of efferocytosis and led to glycolysis-related macrophage reprogramming. To facilitate targeted drug delivery to macrophages at diabetic wound sites, we designed a novel hybrid biomaterial. This hybrid biomaterial, prepared as Gel@Til iRGD&PS@PLGA NPs is manufactured by loading tiliroside (Til)-conjugated iRGD&PS double modified lipid nanoparticles (iRGD&PS@PLGA NPs) into a pH-responsive hydrogel matrix. The administration of Gel@Til iRGD&PS@PLGA NPs in diabetic cutaneous wound models has been shown to significantly promote tissue regeneration through the promotion of efferocytosis and glycolysis-related macrophage reprogramming. Therefore, this study introduces a novel approach to diabetic wound management by leveraging the promotion of efferocytosis.

Receptor-mediated delivery of therapeutic RNA by peptide functionalized curdlan nanoparticles

Tsogzolmaa Ganbold,Shuqin Han,Agula Hasi,Huricha Baigude

Natural carbohydrate polymer-based nanoparticles have great biocompatibility that is required for the safe delivery of various drugs including nucleic acid therapeutics. Herein, we designed curdlan-based nanoparticles for cancer cell targeted delivery of short interfering RNA (siRNA). iRGD peptide conjugated 6-amino-6-deoxy curdlan specifically delivered siRNA to integrin expressing cancer cells. Incubation of cancer cells with free iRGD peptide competitively blocked cellular uptake of the iRGD functionalized curdlan nanoparticles. Chloroquine but not nystatin inhibited cellular uptake of iRGD functionalized curdlan nanoparticles, indicating that the iRGD peptide conjugated curdlan nanoparticles were internalized through the receptor (clathrin)-mediated endocytosis. Moreover, a disease related gene Plk1 was substantially knocked down by siRNA carried by 6AC-iRGD nanoparticles in HepG2 cells. Our data suggested that iRGD functionalized curdlan may provide a biocompatible carrier for siRNA delivery.

Topical ocular delivery to laser-induced choroidal neovascularization by dual internalizing RGD and TAT peptide-modified nanoparticles

Yongchao Chu,Ning Chen,Huajun Yu,Hongjie Mu,Bin He,Hongchen Hua,Aiping Wang,Kaoxiang Sun

A nanoparticle (NP) was developed to target choroidal neovascularization (CNV) via topical ocular administration. The NPs were prepared through conjugation of internalizing arginine-glycine-aspartic acid RGD (iRGD; Ac-CCRGDKGPDC) and transactivated transcription (TAT) (RKKRRQRRRC) peptide to polymerized ethylene glycol and lactic-co-glycolic acid. The iRGD sequence can specifically bind with integrin αvβ3, while TAT facilitates penetration through the ocular barrier. 1H nuclear magnetic resonance and high-performance liquid chromatography demonstrated that up to 80% of iRGD and TAT were conjugated to poly(ethylene glycol)– poly(lactic-co-glycolic acid). The resulting particle size was 67.0±1.7 nm, and the zeta potential of the particles was −6.63±0.43 mV. The corneal permeation of iRGD and TAT NPs increased by 5.50- and 4.56-fold compared to that of bare and iRGD-modified NPs, respectively. Cellular uptake showed that the red fluorescence intensity of iRGD and TAT NPs was highest among primary NPs and iRGD- or TAT-modified NPs. CNV was fully formed 14 days after photocoagulation in Brown Norway (BN) rats as shown by optical coherence tomography and fundus fluorescein angiography analyses. Choroidal flat mounts in BN rats showed that the red fluorescence intensity of NPs followed the order of iRGD and TAT NPs > TAT-modified NPs > iRGD-modified NPs > primary NPs. iRGD and TAT dual-modified NPs thus displayed significant targeting and penetration ability both in vitro and in vivo, indicating that it is a promising drug delivery system for managing CNV via topical ocular administration.

Virus like nanoparticles of VLP-BSA-iRGD enhanced mucosal immune response by targeting M cells

Huirong Tan,Mingrun Tang,Yufeng Che,Xuanao Li,Zhiwen Tu,Xinghong Zhao,Hongping Wan

In mucosal immunity, targeting microfolds (M)cells of the mucosal epithelium, in combination with suitable adjuvants, is critical for eliciting robust immune response. In the present study, we devised a virus like nanoparticles (VLP)-based nano-delivery platform functionalized with the M cell-targeting peptide iRGD (RGDKGPDC) to enhance the immune responses following intranasal administration. Bovine serum albumin (BSA) was selected as a model antigen, and both BSA and iRGD were conjugated to the VLP surface, forming VLP-BSA-iRGD nanoparticles. Leveraging its M cell-targeting capability, VLP-BSA-iRGD demonstrated enhanced uptake by dendritic cells (DCs) and improved trafficking to lymph nodes compared to BSA alone in a mouse model. VLP-BSA-iRGD enhanced the CCL20 secretion and stimulated the DC activation, as evidenced by an in vitro cell co-culture model. Additionally, it enhanced antigen permeability by disrupting the distribution of the ZO-1 protein in epithelial cells. Importantly, VLP-BSA-iRGD induced stronger humoral and cellular immune responses, accompanied by the upregulation of TLR2/4 expression and activation of the MYD88/NF-κB signaling pathway in DCs. While BSA served as a proof-of-concept antigen, this platform may be broadly applicable to other protein-based subunit vaccines requiring intranasal administration.

Engineering of Bone- and CD44-Dual-Targeting Redox-Sensitive Liposomes for the Treatment of Orthotopic Osteosarcoma

Shuaishuai Feng,Zi-Xin Wu,Ziyan Zhao,Jinhu Liu,Kaoxiang Sun,Chuanyou Guo,Hongbo Wang,Zimei Wu

This study aimed to develop an efficient step-by-step osteosarcoma (OS)-targeting liposome system functionalized with a redox-cleavable, bone- and cluster of differentiation 44 (CD44)-dual-targeting polymer. Furthermore, the effect of coadministration of a tumor-penetrating peptide, internalizing RGD (iRGD), was investigated. First, a bone-targeting moiety, alendronate (ALN), was conjugated with hyaluronic acid (HA), a ligand for CD44. This ALN–HA conjugate was coupled with DSPE–PEG2000–COOH through a bioreducible disulfide linker (−SS−) to obtain a functionalized lipid, ALN–HA–SS–L, to be postinserted into preformed liposomes loaded with doxorubicin (DOX). The roles of ALN, HA, and the redox sensitivity of the ALN–HA–SS–L liposomes (ALN–HA–SS–L–L) in the anti-OS effect were critically evaluated against various reference liposomal formulations (with only ALN, HA, or redox sensitivity). ALN–HA–SS–L–L displayed a zeta potential of −26.07 ± 0.32 mV and selectively disassembled in the presence of a reducing agent, 10 mM glutathione, which can be found in cancer cells. Compared to various reference liposomes, ALN–HA–SS–L–L/DOX had significantly higher cytotoxicity to human OS MG-63 cells alongside high and rapid cellular uptake. In the orthotopic OS nude mouse models, ALN–HA–SS–L–L/DOX showed remarkable tumor growth suppression and prolonged survival time. This result was further improved by the coadministration of iRGD. The antitumor effects of various liposomes were ranked in the same order as the degree of tumor biodistribution shown by in vivo/ex vivo imaging: ALN–HA–SS–L–L coadministered with iRGD > ALN–HA–SS–L–L > HA–SS–L–L > HA–L–L > PEG–L> free drug. ALN–HA–SS–L–L/DOX also reduced the cardiotoxicity of DOX and lung metastases. Overall, this study demonstrated that ALN–HA–SS–L–L/DOX, equipped with bone- and CD44-dual-targeting abilities and redox sensitivity, could be a promising OS-targeted therapy. The efficacy could also be augmented by coadministration of iRGD.

iRGD-NaGd(MoO4)2: A Tumor-Targeted Magnetic Resonance Contrast Agent Activating Immunotherapy via the cGAS-STING Pathway

Ling Yu,Fengkai Qiu,Yumin Hu,Tingting Liao,Mengqian Zhai,Ronghua Wu,Qianhui He,Huilin Hu,Shuiwei Xia,Junguo Hui,Zufei Wang,Yang Yang,Rongfang Qiu,Minjiang Chen,Weiqian Chen,Jianfei Tu,Jiansong Ji,Chenying Lu

Because of the high incidence and mortality of cancer, there is an urgent need for more effective tumor diagnostic imaging and treatment strategies. Single-molecule therapeutics have emerged as a promising strategy to address the limitations of independent imaging and therapeutic modalities, thereby significantly reducing adverse side effects for patients. For the first time, we successfully synthesized NaGd(MoO4)2 nanoparticles via a homogeneous precipitation method in polyol media, which serve as a single-molecule agent for MRI imaging and metallic immunotherapy. With the addition of iRGD, we obtained iRGD-NaGd(MoO4)2. The iRGD-NaGd(MoO4)2 nanoparticles exhibit excellent tumor-targeting capability and significantly enhance T1-weighted MRI contrast with a longitudinal relaxivity of 4.95 mM–1 s–1. In terms of antitumor immunotherapy, iRGD-NaGd(MoO4)2 not only directly activates the cGAS-STING pathway but also induces ferroptosis in tumor cells, resulting in the generation of aberrant dsDNA and thereby indirectly activating the STING pathway. The dual pathway elicits a tumor-specific immune response, plays a significant role in promoting the maturation of DC cells, activates DC and T cells to secrete high levels of TNF-α, IL-6 and other cytokines, and regulates the polarization of macrophages from M2 phenotype to M1 phenotype. This mechanism significantly suppresses tumor growth. Beyond the metallic immunotherapy induced by Mn2+, Zn2+, and Co2+, this study provides robust validation of MoO42– as an effective cGAS-STING agonist. Moreover, this study achieved the synergy of multiple disciplines including biomaterials, tumor immunotherapy and medical imaging. This not only promotes the innovative integration in various fields, but also provides new treatment strategies and imaging tools for cancer treatment, which has important clinical application prospects.

Antitumor activity of iRGD-modified red blood cell membrane nanoparticles loaded with Juglone and Oxaliplatin against colorectal cancer

Jialei Mao,Yinzhu Bian,Qun Zhang,Linghui Kong,Xiao Shi,Jing Hu,Mi Yang,Li Li,Hanqing Qian,Baorui Liu,Xiaoping Qian

A precision-guided MWNT mediated reawakening the sunk synergy in RAS for anti-angiogenesis lung cancer therapy

Yujie Su,Yahui Hu,Yu Wang,Xiangting Xu,Yang Yuan,Yunman Li,Zeyuan Wang,Kerong Chen,Fangrong Zhang,Xuefang Ding,Min Li,Jianping Zhou,Yuan Liu,Wei Wang

Multi-walled carbon nanotube (MWNT) with its versatility has exhibited tremendous superiority in drug delivery. Despite plenty of researches on MWNT based delivery systems, precision-guided assistances to maximize their profitable properties are still lacking in substantive progress. We developed here a dual-targeting and co-delivery system based on MWNT for antiangiogenesis therapy in lung cancer which aimed at renin-angiotensin system (RAS) dysregulation by synergistically conducting angiotensin II type 1 receptor (AT 1 R) and type 2 receptor (AT 2 R) pathway. In this work, iRGD peptide connected to polyethyleneimine (PEI) was linked to MWNT skeleton, accompanying with candesartan (CD) conjugated to MWNT mediated by cystamine (SS). The functionalized MWNT is assembled with plasmid AT 2 (pAT 2 ) to form iRGD-PEI-MWNT-SS-CD/pAT 2 complexes. iRGD and CD act as pilots for complexes to dually target symbolic ανβ3-integrin and AT 1 R both overexpressed on tumor angiogenic endothelium and lung cancer cell. CD as chemotherapy showed synergistic downregulation of VEGF when combining of pAT 2 and efficiently inhibited angiogenesis . iRGD-PEI-MWNT-SS-CD/pAT 2 complexes greatly appreciated drug activities by changing drug distribution and exhibited remarkable tumor growth suppression in A549 xenograft nude mice . Our work presents that such dual-targeting strategy highly improves the delivery performance of MWNT and open a new avenue for RAS related lung cancer therapy.

A novel dual-targeted ultrasound contrast agent provides improvement of gene delivery efficiency in vitro

Xu Jinfeng,Zeng Xinxin,Liu Yingying,Luo Hui,Wei Zhanghong,Liu Huiyu,Zhou Yuli,Zheng Hairong,Zhou Jie,Tan Guanghong,Yan Fei

Ultrasound-targeted microbubble destruction (UTMD) has become a novel gene/drug delivery method in cancer therapeutic application. However, the gene transfection efficiency mediated by UTMD is still unsatisfactory. Here, we introduced iRGD/CCR2 dual-targeted cationic microbubbles (MB iRGD/CCR2 ) which was modified with PEI-600 and coated with iRGD peptides and anti-CCR-2 antibodies. It showed that MB iRGD/CCR2 had a 25.83 ± 1.57 mV surface zeta potential and good stability. The experiments in vitro showed MB iRGD/CCR2 had higher binding efficiency with both bEnd.3 cells and MCF-7 cells than that of iRGD or CCR2 single-targeted cationic microbubbles (MB iRGD or MB CCR2 ) ( P  < 0.05 for both). Agarose gel electrophoresis assay showed that MB iRGD/CCR2 can effectively load pGPU6/GFP/Neo-shAKT2 plasmid DNA. Compared with the plain MBs (MB control ) or single-targeted cationic MBs including MB iRGD and MB CCR2 ( P  < 0.05 for all), the dual-targeted cationic MB iRGD/CCR2 groups had higher gene transfection efficiency under US exposure. It showed that the dual-targeted cationic MB iRGD/CCR2 has a potential value to be used as an ultrasound imaging probe for ultrasound image-guided tumor gene therapy.