CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Yuxuan Wei,Zuxiao Chen,Chuyu Huang,Hong Cheng,Xiaofeng Jiang,Shiying Li
Spatiotemporal downregulation of immune checkpoint provides a promising strategy to activate anti-tumor immunity. In this work, a breast cancer targeted photodynamic degrader (designated as EIpro) is constructed to activate immunotherapy through EGFR degradation mediated PD-L1 downregulation. To be specific, we develop a chimeric peptide, comprising the photosensitizer Protoporphyrin IX (PpIX) and EGFR targeting peptide (QRHKPRE), to encapsulate an EGFR inhibitor afatinib (AFA) forming nanomicelle, namely EIpro. EIpro has a favorable stability and uniform nanosize distribution, preferring to accumulate in EGFR overexpressed breast cancer cells to amplify the chemotherapeutic effect and photodynamic elimination behavior. More interestingly, photodynamic therapy (PDT) produced reactive oxygen species (ROS) is able to damage breast cancer cells and induce immunogenic cell death (ICD) to release tumor associated antigens (TAAs), thereby degrading the nearby EGFR to downregulate PD-L1 and activate anti-tumor immunity. Beneficially, the multi-synergistic effects of EIpro show a robust therapeutic efficacy against primary and metastatic breast cancer with negligible systemic toxicity. This work provides a spatiotemporal strategy for protein degradation, which might inspire the development of sophisticated nanomedicine for effective tumor treatment.
研究领域:
肿瘤学
·
免疫治疗
·
纳米医学
·
光动力疗法
·
癌症生物学
✓ 已验证
产品关联
DOI
高影响因子
Advanced Healthcare Materials
·
2021
·Vol. 10
·期 21
·2101199
·
IF 9.933
Haihui Wang,Yongfei Liu,Xiaohui Zhu,Chengyun Chen,Zhangcheng Fu,Min Wang,Danying Lin,Zhaowei Chen,Chunhua Lu,Huanghao Yang
Combinatorial CpG oligonucleotide (CPG) and chemotherapy drug represent a promising approach to reactivate immune system. However, these two agents possess different physicochemical properties, hindering the application of direct self-assembly of these two cargos into a single nanostructure. Here, a multistage cooperative nanodrug is developed by the direct self-assembly of cis-platinum (CDDP, Pt), l -arginine ( l -Arg, R), and CPG (defined as PtR/CPG) for antitumor chemoimmunotherapy. First, the CDDP can induce cell apoptosis. Meanwhile, CDDP also promotes the production of H 2 O 2 , catalyzing the conversion of l -Arg into nitric oxide (NO). The generated NO decreases the multidrug resistance of cells toward CDDP. Thus, the synergistic effects of CDDP and NO can trigger immunogenic cell death to produce tumor-associated antigens (TAAs). The TAAs and CPG will induce the maturation of dendritic cells (DCs) and enhance antigen presentation ability of DCs. In this way, the PtR/CPG can reverse the immunosuppressive microenvironment, sensitizing tumors to immune checkpoint inhibitors mediated by the programmed death-ligand 1 (PD-L1) antibody. Furthermore, the PtR/CPG combined with the PD-L1 antibody decreases the exhaustion and dysfunction of cytotoxic T lymphocytes to elicit durable systemic immune response. As a result, the prepared PtR/CPG nanodrug in combination with PD-L1 may be highly significant for cancer immunotherapy.
研究领域:
癌症免疫治疗
·
纳米技术
·
药学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2022
·
IF 15.304
Jun Dai,Xiaoqi Dong,Rui Liu,Biao Chen,Xiyuan Dong,Quan Wang,Jing-Jing Hu,Fan Xia,Xiaoding Lou
Immunotherapy maintains the cancer-immunity cycle via re-activating the immune system, so as to achieve the purpose of anti-tumor. However, the response rate of current tumor immunotherapy strategies is still low. Even the most reported immune checkpoint block (ICB), the objective response rate (ORR) is only about 10–30%. Here, aiming at obtaining a higher response rate, we designed a cascade amplification nanocomposite consisting of the immune adjuvant polyinosinic:polycytidylic acid [Poly (I:C)] and aggregation-induced emission luminogen (AIEgen)-modified modular peptide (named PMRA). The PMRA includes: D PPA-1 peptide (P), an immune checkpoint inhibitor; PLGLAG peptide (M), a matrix metalloproteinase 2 (MMP-2) responsive sequence to promote the release of D PPA-1; RRRRRRRR peptide (R), for loading the Poly (I:C); PyTPA (A), a photosensitizer with AIE property. In cancer-immunity cycle, photodynamic therapy (PDT) mediated by PyTPA promotes the release of tumor-associated antigens (TAAs), and primes T lymphocytes . The cytokines coming from the stimulation of PDT and Poly (I:C) promote the activation of T lymphocytes. The high level of chemokines in tumor microenvironment promotes immune cells migration and infiltration in tumor with the assistance of PDT. Finally, through ICB with D PPA-1 peptide, T lymphocytes enhance the recognition of tumor cells and killing tumor cells. Immunogenic cell death induces the release of more TAAs, which will enter the next cycle and complete the full-loop again. Taking advantages of whole cancer-immunity cycle, the cascade amplification nanocomposite achieved almost 100% ORR in vivo . This concept of whole cancer-immunity cycle enhanced immunotherapy provides a novel perspective for tumor treatment.
研究领域:
癌症生物学
·
免疫学
·
纳米技术
·
治疗学
✓ 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）