Science Advances
·
2021
·Vol. 7
·期 6
·
IF 14.143
Yanmei He,Lei Lei,Jun Cao,Xiaotong Yang,Shengsheng Cai,Fan Tong,Dennis Huang,Heng Mei,Kui Luo,Huile Gao,Bin He,Nicholas A. Peppas
Nanoparticle-based drug delivery faces challenges from the imprecise targeted delivery and the low bioavailability of drugs due to complex biological barriers. Here, we designed cascade-targeting, dual drug–loaded, core-shell nanoparticles (DLTPT) consisting of CD44-targeting hyaluronic acid shells decorated with doxorubicin (HA-DOX) and mitochondria-targeting triphenylphosphonium derivative nanoparticle cores loaded with lonidamine (LND) dimers (LTPT). DLTPT displayed prolonged blood circulation time and efficiently accumulated at the tumor site due to the tumor-homing effect and negatively charged hyaluronic acid. Subsequently, the HA-DOX shell was degraded by extracellular hyaluronidase, resulting in decreased particle size and negative-to-positive charge reversal, which would increase tumor penetration and internalization. The degradation of HA-DOX further accelerated the release of DOX and exposed the positively charged LTPT core for rapid endosomal escape and mitochondria-targeted delivery of LND. Notably, when DLTPT was used in combination with anti–PD-L1, the tumor growth was inhibited, which induced immune response against tumor metastasis.
研究领域:
药学
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纳米技术
·
癌症研究
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免疫治疗
✓ 已验证
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Yilin Yang,Ning Wang,Zhihua Wang,Mingda Han,Fei Yan,Zhan Shi,Shouhua Feng
Sonodynamic therapy (SDT) has emerged as a promising strategy for treating tumors owing to its non-invasiveness and high tissue-penetrating depth. Improving the efficiency of electron-hole separation of sonosensitizers and alleviation of the hypoxic tumor microenvironment remain major challenges. Metal-organic frameworks (MOFs) have greatly potential in SDT application, however, exploring new sonosensitizers with high reactive oxygen species (ROS) generation and improving the efficacy through a synergistic effect in combination with other therapeutic modalities remain major challenges. Furthermore, the immunosuppressive tumor microenvironment (TME) is characterized by hypoxia, which limit the efficacy of O 2 -dependent cancer treatments including SDT and immunotherapy. Herein, we fabricated a defect-rich titanium-based MOFs using propionic acid-mediated self-templated hierarchical etching. Reductive platinum nanoparticles were embedded onto the surface of MOFs to enhance the spatial separation of electron-hole pairs and improve the quantum yield of ultrasound-generated singlet oxygen ( 1 O 2 ). Finally, perfluorobromooctane was encapsulated in the MOFs to function as an oxygen carrier to develop an oxygen self-feeding nanosensitizer. In vitro and in vivo assays demonstrated that this nanoplatform could produce high levels of 1 O 2 under ultrasound irradiation, which led to enhanced SDT. Moreover, this nanoplatform also relieved the immunosuppressive TME by overcoming hypoxia and enhancing immunogenic cell death to promote the infiltration of tumor-specific cytotoxic T cells into the immunologically “cold” tumor. Therefore, combination of nanoplatform-mediated SDT with anti-PDL1 antibodies effectively inhibited the primary tumors, as well as the metastatic tumors. This study provides an insightful strategy for improving SDT and broadens the application of MOF-based sonosensitizers for sono-immunotherapy.
研究领域:
癌症治疗
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纳米技术
·
生物医学工程
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材料科学
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免疫疗法
✓ 已验证
产品关联
DOI
高影响因子
ACS Applied Materials & Interfaces
·
2018
·
IF 8.097
Ling Mei,Yayuan Liu,Jingdong Rao,Xian Tang,Man Li,Zhirong Zhang,Qin He
Because of the limited drug concentration in tumor tissues and inappropriate treatment strategies, tumor recurrence and metastasis are critical challenges for effectively treating malignancies. A key challenge for effective delivery of nanoparticles is to reduce uptake by reticuloendothelial system and to enhance the permeability and retention effect. Herein, we demonstrated Cu(I)-catalyzed click chemistry triggered the aggregation of azide/alkyne-modified micelles, enhancing micelles accumulation in tumor tissues. In addition, combined doxorubicin with the adjuvant monophosphoryl lipid A, an agonist of toll-like receptor4, generated immunogenic cell death, which further promoted maturity of dendritic cells, antigen presentation and induced strong effector T cells in vivo. Following combined with anti-PD-L1 therapy, substantial antitumor and metastasis inhibitory effects were achieved because of the reduced PD-L1 expression and regulatory T cells. In addition, effective long-term immunity from memory T cell responses protected mice from tumor recurrence.
研究领域:
肿瘤学
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药学
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免疫学
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纳米技术
·
化学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
IF 5.8
Haiying Xu,Zhongping Su,Hui Zhang,Ying Zhang,Yujun Bao,Huanli Zhang,Xiaodan Wu,Rui Yan,Zhiqiang Wang,Yingxue Jin
Photodynamic therapy (PDT) and chemodynamic therapy (CDT) can activate immunogenicity, so PDT and CDT combined immunotherapy is a promising treatment strategy. However, insufficient hydrogen peroxide activity, hypoxia, and overexpressed glutathione in the tumor microenvironment (TME) significantly impaired the ability to activate immunogenicity. Thus, in this paper, self-reinforcing conjugates Cu 2+ -Pyropheophorbide-a-Cysteine (CuPPaCC), combined synergetic NIR and pH triggered PDT/CDT with glutathione depletion ability was constructed. CuPPaCC was encapsulated in mesoporous silica, and spherical HSCuPPaCC nanoparticles were prepared by Hyaluronic acid (HA) on the silica surface by Schiff base modification. HSCuPPaCC has tumor-specific targeting via HA mediated. In acidic solution, the Schiff base of HSCuPPaCC is destroyed and CuPPaCC is released (>70%), with excellent pH response release function. The results of the MTT analysis showed that the PDT/CDT synergistic anti-tumor effect was significant. HSCuPPaCC was activated in TME, catalyzing the decomposition of hydrogen peroxide to generate hydroxyl radicals and oxygen, alleviating TME hypoxia, replenishing oxygen to PDT, and significantly down regulating hypoxia factor HIF-1α expression. HSCuPPaCC has an excellent dual ROS mechanism and a dual depleting GSH mechanism resulting in a surge in intracellular ROS levels to efficiently kill cancer cells, enhance the ability to induce immunogenicity, and make tumors more sensitive to checkpoint PD-L1 blockade therapy. With the CT26 mouse model, not only the primary tumor was eradicated, but also the distal tumor at the end of treatment was completely suppressed by HSCuPPaCC combined with anti-PD-L1 immune checkpoint blockade therapy.
研究领域:
纳米技术
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癌症治疗
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生物医学工程
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药学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BMC Medicine
·
2022
·Vol. 20
·期 1
·1-18
·
IF 11.15
Cheng Yibin,Wang Caixia,Wang Huihui,Zhang Zhiwei,Yang Xiaopeng,Dong Yanming,Ma Lixin,Luo Jingwen
Background The application of combination therapy for cancer treatment is limited due to poor tumor-specific drug delivery and the abscopal effect. Methods Here, PD-L1- and CD44-responsive multifunctional nanoparticles were developed using a polymer complex of polyethyleneimine and oleic acid (PEI-OA) and loaded with two chemotherapeutic drugs (paclitaxel and chloroquine), an antigen (ovalbumin), an immunopotentiator (CpG), and an immune checkpoint inhibitor (anti-PD-L1 antibody). Results PEI-OA greatly improved the drug loading capacity and encapsulation efficiency of the nanoplatform, while the anti-PD-L1 antibody significantly increased its cellular uptake compared to other treatment formulations. Pharmacodynamic experiments confirmed that the anti-PD-L1 antibody can strongly inhibit primary breast cancer and increase levels of CD4+ and CD8+ T cell at the tumor site. In addition, chloroquine reversed the “immune-cold” environment and improved the anti-tumor effect of both chemotherapeutics and immune checkpoint inhibitors, while it induced strong immune memory and prevented lung metastasis. Conclusions Our strategy serves as a promising approach to the rational design of nanodelivery systems for simultaneous active targeting, autophagy inhibition, and chemotherapy that can be combined with immune-checkpoint inhibitors for enhanced breast cancer treatment.
研究领域:
肿瘤学
·
药学
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纳米技术
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2022
·
IF 15.304
Jie Zang,Yushan Yang,Xiao Zheng,Yan Yang,Yuge Zhao,Zhe Miao,Tingting Zhang,Jingjing Gu,Yiqiong Liu,Weimin Yin,Xiaoyi Ma,Quanming Ding,Haiqing Dong,Yan Li,Yongyong Li
L-arginine metabolism is essential for the activation, survival, and effector function of the T lymphocytes and critical in eliminating tumors via T-cell-mediated immunotherapy, such as immune checkpoint blockade (ICB). Unfortunately, efficient delivery of hydrophilic L-arginine to the tumor microenvironment (TME) has met tremendous difficulties because of the limited loading efficacy and rapid diffusion. Inspired by the small-molecule prodrug nanoassemblies with ultrahigh drug-loading, we screen out aromatic aldehydes compounds to be used as dynamic tags to decorate L-arginine (reversible imine). Nano-Arginine (ArgNP, 104 nm) was created based on dynamic tag-mediated self-assembly. Molecular dynamics simulations indicate that the driving force of this self-assembly process is intermolecular hydrogen bonds , π–π stacking, and cation–π interactions. Notably, ArgNP metabolic synergy with anti-PD-L1 antibody (aPDL1) can promote tumor-infiltrating T cells (3.3-fold than aPDL1), resulting in a tumor inhibition ratio of 2.6-fold than aPDL1. Besides, such a strategy efficiently reduces the myeloid-derived suppressor cells, increases the M1-macrophages against the tumor, and induces the production of memory T cells. Furthermore, this synergistic therapy effectively restrains lung metastasis and prolongs mouse survival (60% survival ratio). The study highlights the dynamic tags strategy with facility and advance to deliver L-arginine that can metabolically promote ICB therapy.
研究领域:
癌症免疫治疗
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纳米技术
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免疫学
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药物递送系统
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肿瘤生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Advances
·
2024
·Vol. 10
·期 13
·
IF 11.7
Gongxi Qiao,Shenglin Li,Xumin Pan,Ping Xie,Ruixi Peng,Xiangrong Huang,Mengyun He,Jianhui Jiang,Xia Chu
Directly activating CD8+ T cells within the tumor through antigen-presenting cells (APCs) hold promise for tumor elimination. However, M2-like tumor-associated macrophages (TAMs), the most abundant APCs in tumors, hinder CD8+ T cell activation due to inefficient antigen cross-presentation. Here, we demonstrated a personalized nanotherapeutic platform using surgical tumor–derived galactose ligand–modified cancer cell membrane (CM)–coated cysteine protease inhibitor (E64)–loaded mesoporous silica nanoparticles for postsurgical cancer immunotherapy. The platform targeted M2-like TAMs and released E64 within lysosomes, which reshaped antigen cross-presentation and directly activated CD8+ T cells, thus suppressing B16-OVA melanoma growth. Furthermore, this platform, in combination with anti–PD-L1 antibodies, enhanced the therapeutic efficacy and substantially inhibited 4T1 tumor growth. CMs obtained from surgically resected tumors were used to construct a personalized nanotherapeutic platform, which, in synergy with immune checkpoint blockade (ICB), effectively inhibited postsurgical tumor recurrence in 4T1 tumor. Our work offered a robust, safe strategy for cancer immunotherapy and prevention of postsurgical tumor recurrence.
研究领域:
癌症免疫疗法
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纳米技术
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免疫学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2024
·
IF 14.7
Jiaojiao Yu,Yujin Xiang,Yuzhen Gao,Shan Chang,Ren Kong,Xiaoxi Lv,Jinmei Yu,Yunjie Jin,Chenxi Li,Yiran Ma,Zhenhe Wang,Jichao Zhou,Hongyu Yuan,Shuang Shang,Fang Hua,Xiaowei Zhang,Bing Cui,Pingping Li
Protein kinase C α (PKC α ) regulates diverse biological functions of cancer cells and is a promising therapeutic target. However, clinical trials of PKC-targeted therapies have not yielded satisfactory results. Recent studies have also indicated a tumor-suppressive role of PKCs via unclear molecular mechanisms. In this study, we found that PKC α inhibition enhances CD8 + T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice. We further identified PKC α as a critical regulator of programmed cell death-ligand 1 (PD-L1) and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression. We demonstrated that PKC α -mediated PD-L1 phosphorylation promotes PD-L1 degradation through β transducin repeat-containing protein. Notably, the efficacy of PKC α inhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity in vivo . Clinical tissue array analysis revealed that PKC α expression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer. This study demonstrated the antitumor capability of PKC α , identified potential therapeutic strategies to avoid tumor evasion via PKC-targeted therapies, and provided a proof of concept for targeting PKC α in combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer, especially TNBC.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2022
·
IF 16.874
Zhilin Li,Hao Cai,Zhiqian Li,Long Ren,Xuelei Ma,Hongyan Zhu,Qiyong Gong,Hu Zhang,Zhongwei Gu,Kui Luo
To improve the response rate of immune checkpoint inhibitors such as anti-PD-L1 antibody in immunosuppressive cancers like triple-negative breast cancer (TNBC), induction of immunogenic cell death (ICD) at tumor sites can increase the antigenicity and adjuvanticity to activate the immune microenvironment so that tumors become sensitive to the intervention of immune checkpoint inhibitors. Herein, a self-amplified biomimetic nanosystem, mEHGZ, was constructed by encapsulation of epirubicin (EPI), glucose oxidase (Gox) and hemin in ZIF-8 nanoparticles and coating of the nanoparticles with calreticulin (CRT) over-expressed tumor cell membrane. EPI acts as an ICD inducer, Gox and hemin medicate the cascade generation of reactive oxygen species (ROS) to strengthen the ICD effect, and CRT-rich membrane as “eat me” signal promote presentation of the released antigens by dendritic cells (DCs) to invoke the tumor-immunity cycle. The biomimetic delivery system displays an amplified ICD effect via Gox oxidation, hydroxyl radical generation and glutathione (GSH) depletion. The induced potent ICD effect promotes DCs maturation and cytotoxic T lymphocytes (CTLs) infiltration, reversing an immunosuppressive tumor microenvironment to an immunoresponsive one. Treatment with the nanosystem in combination with anti-PD-L1 antibody results in distinctive inhibition of tumor growth and lung metastasis, supporting that a potent ICD effect can significantly boost the therapeutic efficacy of the anti-PD-L1 antibody. This self-amplified biomimetic nanoplatform offers a promising means of raising the response rate of immune checkpoint inhibitors.
研究领域:
肿瘤学
·
免疫治疗
·
纳米技术
·
生物医学工程
·
癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2024
·
IF 10.7
Xiaoju Guo,Xiaoxiao Chen,Jiayi Ding,Feng Zhang,Shunyang Chen,Xin Hu,Shiji Fang,Lin Shen,Chenying Lu,Zhongwei Zhao,Jianfei Tu,Gaofeng Shu,Minjiang Chen,Jiansong Ji
Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO 3 by a CaCO 3 -assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.
研究领域:
肿瘤学
·
药理学
·
纳米技术
·
免疫疗法
✓ 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）