通过双相应性脂质白蛋白纳米颗粒靶向肿瘤相关的成纤维细胞，以此达到增强药物灌注治疗胰腺肿瘤的效果

文献标题   ：Targeting cancer-associated fifibroblasts by dual-responsive lipid-albumin nanoparticles to enhance drug perfusion for pancreatic tumor therapy

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is rich in cancer-associated fibroblasts (CAFs), which participate inthe formation of tumor stroma. However, the dense tumor stroma of PDAC presents major barriers to drugdelivery, resulting in an obstacle for PDAC therapy. Considering the special tumor microenvironment of PDAC,we constructed a novel nanoparticle which is responsive to the membrane biomarker FAP-α on CAFs and nearinfrared (NIR) laser irradiation. Small sized albumin nanoparticle of paclitaxel (HSA-PTX) with strong tumorpenetration ability was encapsulated into the CAP-(a FAP-α responsive cleavable amphiphilic peptide) modifiedthermosensitive liposomes (CAP-TSL). Moreover, IR-780, a photothermal agent, was incorporated into CAP-TSLto afford CAP-ITSL. The designed HSA-PTX@CAP-ITSL increased the drug retention of HSA-PTX in solid tumorand HSA-PTX was released via FAP-α (specifically expresses on CAFs) triggered. Under sequential stimulation ofNIR laser irradiation, IR-780 produced hyperthermia to kill tumor cells and expand the tumor interstitial space atthe same time, which further promoted the release of small sized HSA-PTX in deep tumor regions. Consequently,the excellent antitumor efficacy of HSA-PTX@CAP-ITSL was demonstrated in Pan 02 subcutaneous and orthotopic tumor mouse models. Therefore, HSA-PTX@CAP-ITSL well combined chemotherapy with photothermaltherapy, providing a promising drug delivery strategy for PDAC treatment.

摘要

胰腺导管腺癌(PDAC)富含与癌症相关的成纤维细胞(CAFs)，这些细胞参与了肿瘤间质的形成。然而，PDAC致密的肿瘤间质是药物传递的主要障碍，从而阻碍了PDAC的治疗。考虑到PDAC特殊的肿瘤微环境，我们构建了一种新型的纳米颗粒，该颗粒对膜生物标志物FAP-α在CAFs和近红外(NIR)激光照射下反应。将具有较强肿瘤穿透能力的紫杉醇白蛋白纳米粒(HSA-PTX)封装到CAP-(FAP-α反应的可剪切两亲肽)修饰的热敏感脂质体(CAP- tsl)中。此外，在cap - tsl中加入IR-780光热剂，形成CAP-ITSL。设计的HSA-PTX@CAP-ITSL增加了HSA-PTX在实体肿瘤中的药物滞留，并通过触发FAP-α(CAFs特异性表达)释放HSA-PTX。在近红外激光照射的连续刺激下，IR-780产生热疗杀死肿瘤细胞的同时扩大肿瘤间质间隙，进一步促进肿瘤深部小尺寸HSA-PTX的释放。结果表明:HSA-PTX@CAP-ITSL在Pan 02皮下和原位肿瘤小鼠模型中均表现出良好的抗肿瘤作用。因此，HSA-PTX@CAP-ITSL很好地结合了化疗和光热疗法，为PDAC治疗提供了一个有前景的药物传递策略。