BIOMATERIALS
·
2020
·
IF 10.317
Jing Yan,Qinghua Wu,Ziyin Zhao,Jianhua Wu,Huan Ye,Qiujun Liang,Zhuchao Zhou,Mengying Hou,Xudong Li,Yong Liu,Lichen Yin
The anticancer performance of nanomedicine is largely impeded by insufficient intratumoral penetration. Herein, tumor microenvironment (TME)-amendatory and self-adaptive nanoclusters (NCs) capable of cancer-associated fibroblasts (CAFs) depletion and size/charge conversion were engineered to mediate light-assisted, hierarchical intratumoral penetration. Particularly, large-sized NCs (~50 nm) were prepared via self-assembly of FAP-α-targeting peptide-modified, 1 O 2 -sensitive polymers, which were further used to envelope small-sized dendrimer (~5 nm) conjugated with Ce6 and loaded with DOX (DC/D). After systemic administration, the NCs efficiently targeted CAFs and generated lethal levels of 1 O 2 upon light irradiation, which depleted CAFs and concomitantly dissociated the NCs to liberate small-sized, positively charged DC/D. Such stroma attenuation and NCs transformation collectively facilitated the delivery of DC/D into deeper regions of CAF-rich tumors, where DOX and 1 O 2 provoked synergistic anti-cancer efficacies. This study provides an effective approach to facilitate the tumor penetration of nanomedicine by concurrently and spatiotemporally reconfiguring the nano-properties and remodeling the TME.
研究领域:
纳米技术
·
癌症治疗
·
药学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2021
·
IF 4.749
Chuhang Zhou,Xinping Hu,Qi Liu,Leqi Wang,Yuanhang Zhou,Yao Jin,Yining Ma,Yan Liu
Cancer-associated fibroblasts (CAFs) were believed to establish a tight physical barrier and a dense scaffold for tumor cells to make them maintain immunosuppression and drug resistance, strongly hindering nanoparticles to penetrate into the core of tumor tissues and limiting the performance of tumor cell-targeted nanoparticles. Here, we fabricated the substrate Z-Gly-Pro of fibroblast activation protein α (FAPα) and folic acid-codecorated pH-responsive polymeric micelles (dual ligand-modified PEOz-PLA polymeric micelles, DL-PP-PMs) that possessed nanodrill and tumor cell-targeted functions based on Z-Gly-pro-conjugated poly(2-ethyl-2-oxazoline)-poly(D,l-lactide) (ZGP-PEOz-PLA), folic acid (FA)-conjugated PEOz-PLA (FA-PEOz-PLA), and PEOz-PLA for cancer therapy. The micelles with about 40 nm particle size and a narrow distribution exhibited favorable pH-activated endo/lysosome escape induced by their pH responsibility. In addition, the enhancement of in vitro cellular uptake and cytotoxicity to folate receptors or FAPα-positive cells for doxorubicin (DOX)/DL-PP-PMs compared with DOX/PP-PMs evidenced the dual target ability of DOX/DL-PP-PMs, which was further supported by in vivo biodistribution results. As expected, in the human oral epidermal carcinoma (KB) cells xenograft nude mice model, the remarkable enhancement of antitumor efficacy for DOX/DL-PP-PMs with low toxicity was observed compared with DOX/FA-PP-PMs and DOX/ZGP-PP-PMs. The possible mechanism was elucidated to be the dismantling of the stromal barrier by nanodrill-like DOX/DL-PP-PMs via the deletion of CAFs evidenced by the downregulation of α-SMA and inhibition of their functions proved by the decrease in the microvascular density labeled with CD31 and the reduction in the extracellular matrix detected by the collagen content, thereby promoting tumor penetration and enhancing their uptake by tumor cells. The present research offered an alternative approach integrating anticancer and antifibrosis effects in one delivery system to enhance the delivery efficiency and therapeutic efficacy of anticancer drugs.
研究领域:
药学
·
纳米技术
·
肿瘤学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-14
·
IF 10.6
Shen Wenqi,Li Yecheng,Yang Ziyi,Li Wenjing,Cao Yi,Liu Yilin,Wang Zheng,Pei Renjun,Xing Chungen
The combination of immune checkpoint inhibitors and immunogenic cell death (ICD) inducers has become a promising strategy for the treatment of various cancers. However, its efficacy remains unmet because of the dense stroma and defective vasculatures in the tumor microenvironment (TME) that restricts the intratumoral infiltration of cytotoxic T lymphocytes (CTLs). Herein, cancer-associated fibroblasts (CAFs)-targeted nanoemulsions are tailored to combine the ICD induction and the TME reprogramming to sensitize checkpoint blockade immunotherapy. Melittin, as an ICD inducer and an antifibrotic agent, is efficiently encapsulated into the nanoemulsion accompanied by a nitric oxide donor to improve its bioavailability and tumor targeting. The nanoemulsions exhibited dual functionality by directly inducing direct cancer cell death and enhancing the tumoral immunogenicity, while also synergistically reprogramming the TME through reversing the activated CAFs, decreasing collagen deposition and restoring tumor vessels. Consequently, these nanemulsions successfully facilitated the CTLs infiltration and suppressing the recruitment of immunosuppressive cells. A combination of AE-MGNPs and anti-CTLA-4 antibody greatly elicited a striking level of antitumor T-cell response to suppress tumor growth in CAFs-rich colorectal tumor models. Our work emphasized the integration of the ICD induction with simultaneous modulation of the TME to enhance the sensitivity of patients to checkpoint blockade immunotherapy.
研究领域:
癌症免疫治疗
·
纳米技术
·
肿瘤微环境
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Yuxin Zhang,Jie Zhou,Xiaoting Chen,Zhiqian Li,Lei Gu,Dayi Pan,Xiuli Zheng,Qianfeng Zhang,Rongjun Chen,Hu Zhang,Qiyong Gong,Zhongwei Gu,Kui Luo
Interaction between carcinoma-associated fibroblasts (CAFs) and tumor cells leads to the invasion and metastasis of breast cancer. Herein, we prepared a redox-responsive chondroitin sulfate (CS)-based nanomedicine , in which hydrophobic cabazitaxel (CTX) was conjugated to the backbone of CS via glutathione (GSH)-sensitive dithiomaleimide (DTM) to form an amphipathic CS-DTM-CTX (CDC) conjugate, and dasatinib (DAS) co-assembled with the CDC conjugate to obtain [email protected] After CD44 receptor-mediated internalization by CAFs, the nanomedicine could reverse CAFs to normal fibroblasts, blocking their crosstalk with tumor cells and reducing synthesis of major tumor extracellular matrix proteins , including collagen and fibronectin . Meanwhile, the nanomedicine internalized by tumor cells could effectively inhibit tumor proliferation and metastasis, leading to shrinkage of the tumor volume and inhibition of lung metastasis in a subcutaneous 4T1 tumor model with low side effects. Collectively, the nanomedicine showed a remarkably synergistic therapy effect against breast cancer by modulating tumor-stromal crosstalk.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2022
·
IF 11.467
Meirong Huo,Jiyuan Zhou,Honglan Wang,Yuzhao Zheng,Yuqing Tong,Jianping Zhou,Jiyong Liu,Tingjie Yin
Current chemotherapies for metastatic tumors are seriously restricted by limited drug infiltration and deficient disturbance of metastasis-associated complex pathways involving tumor cell autocrine as well as paracrine loops in the microenvironment (TME). Of note, cancer-associated fibroblasts (CAFs) play a predominant role in shaping TME favoring drug resistance and metastasis. Herein, we constructed a tumor extracellular pH (pH e ) sensitive methotrexate-chitosan conjugate (MTX-GC-DEAP) and co-assembled it with quercetin (QUE) to achieve co-delivered nanodrugs (MTX-GC-DEAP/QUE). The pH e sensitive protonation and disassembly enabled MTX-GC-DEAP/QUE for stroma-specific delivery of QUE and positive-charged MTX-GC-DEAP molecular conjugates, thereby achieving deep tumor penetration via the combination of QUE-mediated CAF inactivation and adsorption-mediated transcytosis . On the basis of significantly promoted drug availability, a strengthened “omnidirectional” inhibition of pre-metastatic initiation was generated both in vitro and in vivo from the CAF inactivation-mediated reversion of metastasis-promoting environments as well as the inhibition of epithelial-mesenchymal transition, local and blood vessel invasion via QUE-mediated direct regulation on tumor cells. Our tailor-designed versatile nanodrug provides a deep insight into potentiating multi-faceted penetration of multi-mechanism-based regulating agents for intensive metastasis inhibition .
研究领域:
药学
·
肿瘤学
·
纳米技术
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanomedicine-Nanotechnology Biology and Medicine
·
2024
·
IF 4.2
Lisha Liu,Beiyuan Zhang,Xianggui Wu,Gang Cheng,Xiaopeng Han,Xiaofei Xin,Chao Qin,Lei Yang,Meirong Huo,Lifang Yin
Cancer-associated fibroblasts (CAFs) play a crucial role in creating an immunosuppressive environment and remodeling the extracellular matrix within tumors, leading to chemotherapy resistance and limited immune cell infiltration. To address these challenges, integrating CAFs deactivation into immunogenic chemotherapy may represent a promising approach to the reversal of immune-excluded tumor. We developed a tumor-targeted nanomedicine called the glutathione-responsive nanocomplex (GNC). The GNC co-loaded dasatinib, a CAF inhibitor, and paclitaxel, a chemotherapeutic agent, to deactivate CAFs and enhance the effects of immunogenic chemotherapy. Due to the modification with hyaluronic acid, the GNC preferentially accumulated in the tumor periphery and responsively released cargos, mitigating the tumor stroma as well as overcoming chemoresistance. Moreover, GNC treatment exhibited remarkable immunostimulatory efficacy, including CD8+ T cell expansion and PD-L1 downregulation, facilitating immune checkpoint blockade therapy. In summary, the integration of CAF deactivation and immunogenic chemotherapy using the GNC nanoplatform holds promise for rebuilding immune-excluded tumors.
研究领域:
肿瘤学
·
纳米技术
·
免疫疗法
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2023
·
IF 29.4
Daoxia Guo,Xiaoyuan Ji,Hui Xie,Jia Ma,Chunchen Xu,Yanfeng Zhou,Nan Chen,Hui Wang,Chunhai Fan,Haiyun Song
Cancer-associated fibroblasts (CAFs) promote cancer stem cell (CSC)-mediated chemoresistance and immunosuppressive tumor microenvironment. However, direct depletion of CAFs may increase cancer invasiveness and metastasis. As a generalized strategy against chemoresistant cancers, we design Gemini-like homotypic targeting nanoparticles (NPs) for two-pronged CAF transformation and cancer cell elimination. The CAF-targeted NPs couple vitamin B 3 metabolic reprogramming to epigenetic modulation of secreted pro-stemness and immunosuppressive factors, thereby diminishing CSC and suppressive immune cell populations to enhance cancer cell drug susceptibility and cytotoxic T cell infiltration. In mouse models of breast, liver, pancreatic and colorectal cancers that are resistant to their respective first-line chemotherapeutics, a single dose of hydrogel co-delivering the Gemini-like NPs can rehabilitate chemosensitivity, induce immune activation, and achieve tumor regression. Moreover, it stimulates robust T cell memory for long-term protection against tumor rechallenge. Our study thus represents an innovative approach with broad applicability for overcoming cancer chemoresistance. This article is protected by copyright. All rights reserved
研究领域:
肿瘤学
·
纳米技术
·
免疫疗法
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2024
·
IF 10.7
Chenglin Liang,Ge Zhang,Linlin Guo,Xinyi Ding,Heng Yang,Hongling Zhang,Zhenzhong Zhang,Lin Hou
Induction of tumor cell senescence has become a promising strategy for anti-tumor immunotherapy, but fibrotic matrix severely blocks senescence inducers penetration and immune cells infiltration. Herein, we designed a cancer-associated fibroblasts (CAFs) triggered structure-transformable nano-assembly (HSD-P@V), which can directionally deliver valsartan (Val, CAFs regulator) and doxorubicin (DOX, senescence inducer) to the specific targets. In detail, DOX is conjugated with hyaluronic acid (HA) via diselenide bonds (Se-Se) to form HSD micelles, while CAFs-sensitive peptide is grafted onto the HSD to form a hydrophilic polymer, which is coated on Val nanocrystals (VNs) surface for improving the stability and achieving responsive release. Once arriving at tumor microenvironment and touching CAFs, HSD-P@V disintegrates into VNs and HSD micelles due to sensitive peptide detachment. VNs can degrade the extracellular matrix, leading to the enhanced penetration of HSD. HSD targets tumor cells, releases DOX to induce senescence, and recruits effector immune cells. Furthermore, senescent cells are cleared by the recruited immune cells to finish the integrated anti-tumor therapy. In vitro and in vivo results show that the nano-assembly remarkably inhibits tumor growth as well as lung metastasis, and extends tumor-bearing mice survival. This work provides a promising paradigm of programmed delivering multi-site nanomedicine for cancer immunotherapy.
研究领域:
纳米技术
·
药学
·
免疫治疗
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2023
·Vol. 11
·期 14
·4890-4906
·
IF 6.6
Jianhao Liu,Xiaoman Xu,Yanying Li,Jingxia Xu,Ruogang Zhao,Siwei Liu,Jingliang Wu,Li Zhang,Bo Zhang
Comprehensively regulating the TME is now regarded as a promising approach for cancer treatment. Herein, a novel “three-in-one” effect is presented for simultaneously killing tumor cells, inhibiting the EMT of CAFs, and improving immune responses. In this study, bortezomib (BTZ) is selected for the treatment of breast cancer; it has multiple pharmacological mechanisms for killing tumor cells through the NF-κB signaling pathway, inhibiting the activity of CAFs by activating caspase-3, and enhancing the function of CD8+ T cells by regulating the expression of immune-stimulating factors. To improve the druggability of BTZ in solid tumors, BTZ-loaded lipid/glycocholic acid mixed micelles (BTZ-LGs) were prepared to verify the “three-in-one” effect in killing tumor cells, inhibiting CAFs, and improving immune responses. In the present work, BTZ-LGs were verified to show enhanced in vitro cytotoxicity in both 4T1 cells and 4T1/NIH3T3 co-cultured cells, as well as a superior in vivo treatment effect in different tumor-bearing mouse models. Additionally, BTZ-LGs could regulate the expression of α-SMA, caspase-3, E-cadherin, and N-cadherin, indicating their good inhibiting ability on both tumor cells and CAFs. More importantly, immunological analysis revealed that BTZ-LGs promoted the expression of the immunostimulatory factor IL-2 in tumor tissues, activated anti-tumor T cells, and overcame tumor-induced CD8+ T cell dysfunction. All these findings suggest that BTZ-LGs can achieve a “three-in-one” effect in terms of killing tumor cells, suppressing CAFs, and improving immune responses. This simple and multi-effective therapeutic strategy offers a promising approach for cancer therapy.
研究领域:
癌症治疗
·
药学
·
免疫学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small Methods
·
2023
·Vol. 7
·期 5
·2201327
·
IF 12.4
Xinyang Li,Yang Luo,Zhengjie Huang,Yi Wang,Jian Wu,Shaobing Zhou
In the treatment of solid tumors, the complex barriers composed of cancer-associated fibroblasts (CAFs) prevent drug delivery and T cells infiltration into tumor tissues. Although nanocarriers hold great prospects in drug delivery, fibrosis causes the biological barrier and immunosuppressive tumor microenvironment (ITM) that impairs the anti-tumor efficacy of nanocarriers. Here, a small dendritic macromolecule loaded with doxorubicin (PAMAM-ss-DOX) (DP) is synthesized and encapsulated into pH-responsive nanoliposome, together with adjuvant toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) and losartan (LOS). The pH-responsive liposome facilitates the simultaneous and effective delivery of DP, R848, and LOS, which can decompose and release these drugs under the acidic tumor microenvironment. The small sized DP (≈25 nm) with the ability to penetrate into tumor tissue and immunogenic cell death (ICD) can reverse the ITM and elicit immune response, which is equivalent to the effect of an in situ vaccine. Moreover, LOS reduces the activity of CAFs effectively, which can contribute to the infiltration of T cells. Therefore, this nano-platform provides a new therapeutic strategy for enhanced chemo-immunotherapy.
研究领域:
肿瘤学
·
药学
·
免疫学
·
纳米技术
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）