Tumor Activated Cell Penetrating Peptides to Selectively Deliver Immune Modulatory Drugs.
Tumor Activated Cell Penetrating Peptides to Selectively Deliver Immune Modulatory Drugs.
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DOI：
10.3390/pharmaceutics13030365
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发表时间：
2021-03-10
期刊：
影响因子：
5.4
通讯作者：
Advani SJ
中科院分区：
文献类型：
--
作者：
Hingorani DV;Camargo MF;Quraishi MA;Adams SR;Advani SJ
免疫疗法的最新进展彻底改变了癌症治疗。免疫疗法可以利用免疫系统的适应性和先天性武器。靶向免疫检查点抑制剂的治疗剂（即，CTLA-4; PD-1和PD-L1）通过释放适应性抗肿瘤免疫应答，对癌症患者亚群显示出疗效。或者，正在开发用于癌症治疗的先天免疫系统的小分子免疫调节剂，例如toll样受体（TLR）激动剂。TLR作为微生物产物的模式识别受体起作用，并且也参与致癌作用。Reisquimod是一种TLR 7/8激动剂，具有抗肿瘤功效。然而，由于非特异性TLR 7/8活化的毒性，全身递送游离瑞喹莫特已被证明是具有挑战性的。因此，我们开发了一种靶向肽-药物缀合物策略用于全身递送瑞喹莫特。我们设计了一种可活化的细胞穿透肽，将瑞喹莫特特异性地递送到肿瘤组织，同时避开正常组织。可活化的细胞穿透肽（ACPP）支架通过细胞外基质中的基质金属蛋白酶2/9进行酶促裂解，然后通过细胞内溶酶体组织蛋白酶B介导释放游离瑞喹莫特。重要的是，当与ACPP缀合时，瑞喹莫特的肿瘤组织浓度比周围非癌组织的浓度高1000倍以上。此外，全身性ACPP-瑞喹莫特递送在同基因小鼠肿瘤中产生与局部游离瑞喹莫特相当的治疗功效。这些结果突出了精确的肽-药物缀合物递送。
Recent advances in immunotherapy have revolutionized cancer therapy. Immunotherapies can engage the adaptive and innate arms of the immune system. Therapeutics targeting immune checkpoint inhibitors (i.e., CTLA-4; PD-1, and PD-L1) have shown efficacy for subsets of cancer patients by unleashing an adaptive antitumor immune response. Alternatively, small molecule immune modulators of the innate immune system such as toll-like receptor (TLR) agonists are being developed for cancer therapy. TLRs function as pattern recognition receptors to microbial products and are also involved in carcinogenesis. Reisquimod is a TLR 7/8 agonist that has antitumor efficacy. However, systemic delivery free resiquimod has proven to be challenging due to toxicity of nonspecific TLR 7/8 activation. Therefore, we developed a targeted peptide-drug conjugate strategy for systemic delivery of resiquimod. We designed an activatable cell penetrating peptide to deliver resiquimod specifically to the tumor tissue while avoiding normal tissues. The activatable cell penetrating peptide (ACPP) scaffold undergoes enzymatic cleavage by matrix metalloproteinases 2/9 in the extracellular matrix followed by intracellular lysosomal cathepsin B mediated release of the free resiquimod. Importantly, when conjugated to ACPP; the tumor tissue concentration of resiquimod was more than 1000-fold greater than that of surrounding non-cancerous tissue. Moreover, systemic ACPP-resiquimod delivery produced comparable therapeutic efficacy to localized free resiquimod in syngeneic murine tumors. These results highlight a precision peptide-drug conjugate delivery.
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通过比例可激活的细胞穿透性肽，在致癌物诱导口腔癌啮齿动物模型中对鳞状细胞癌的早期检测。
影响因子：
4.8
作者：
Hingorani DV;Lemieux AJ;Acevedo JR;Glasgow HL;Kedarisetty S;Whitney MA;Molinolo AA;Tsien RY;Nguyen QT
通讯作者：
Nguyen QT
影响因子：
4.9
作者：
Collier MA;Junkins RD;Gallovic MD;Johnson BM;Johnson MM;Macintyre AN;Sempowski GD;Bachelder EM;Ting JP;Ainslie KM
通讯作者：
Ainslie KM
影响因子：
64.5
作者：
Brooks, PC;Stromblad, S;Cheresh, DA
通讯作者：
Cheresh, DA
影响因子：
14
作者：
Hingorani, Dina, V;Crisp, Jessica L.;Advani, Sunil J.
通讯作者：
Advani, Sunil J.
Toll 样受体 7 激动剂以延长给药方案皮下注射，用于治疗经过严格预处理的复发性乳腺癌、卵巢癌和宫颈癌。
DOI：
10.1007/s00262-010-0914-1
发表时间：
2010-12
期刊：
Cancer immunology, immunotherapy : CII
影响因子：
--
作者：
Geller MA;Cooley S;Argenta PA;Downs LS;Carson LF;Judson PL;Ghebre R;Weigel B;Panoskaltsis-Mortari A;Curtsinger J;Miller JS
通讯作者：
Miller JS