Nanotherapies, valued for their high efficacy and low toxicity, frequently serve as antitumor treatments, but do not readily penetrate deep into tumor tissues and cells. Here we developed an improved tumor-penetrating peptide (TPP)-based drug delivery system. Briefly, the established TPP iNGR was modified to generate a linear NGR peptide capable of transporting nanotherapeutic drugs into tumors through a CendR pathway-dependent, neuropilin-1 receptor-mediated process. Although TPPs have been reported to reach intended tumor targets, they often fail to penetrate cell membranes to deliver tumoricidal drugs to intracellular targets. We addressed this issue by harnessing cell penetrating peptide technology to develop a liposome-based multibarrier-penetrating delivery system (mbPDS) with improved synergistic drug penetration into deep tumor tissues and cells. The system incorporated doxorubicin-loaded liposomes coated with nona-arginine (R₉) CPP and cyclic iNGR (CRNGRGPDC) molecules, yielding Lip-mbPDS. Lip-mbPDS tumor-targeting, tumor cell/tissue-penetrating and antitumor capabilities were assessed using CD13-positive human fibrosarcoma-derived cell (HT1080)-based in vitro and in vivo tumor models. Lip-mbPDS evaluation included three-dimensional layer-by-layer confocal laser scanning microscopy, cell internalization/toxicity assays, three-dimensional tumor spheroid-based penetration assays and antitumor efficacy assays conducted in an animal model. Lip-mbPDS provided enhanced synergistic drug penetration of multiple biointerfaces for potentially deep tumor therapeutic outcomes.

中文翻译：

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基于协同渗透策略的多屏障穿透给药系统用于深部肿瘤治疗

纳米疗法因其高效低毒而受到重视，经常用作抗肿瘤治疗，但不容易渗透到肿瘤组织和细胞深处。在这里，我们开发了一种改进的基于肿瘤穿透肽（TPP）的药物输送系统。简而言之，对已建立的 TPP iNGR 进行修饰，生成线性 NGR 肽，能够通过 CendR 途径依赖性、neuropilin-1 受体介导的过程将纳米治疗药物转运到肿瘤中。尽管据报道 TPP 可以达到预期的肿瘤靶点，但它们通常无法穿透细胞膜将杀肿瘤药物递送至细胞内靶点。我们通过利用细胞穿透肽技术来开发基于脂质体的多屏障穿透递送系统（mbPDS）来解决这个问题，该系统可以改善药物对深层肿瘤组织和细胞的协同渗透。该系统结合了负载阿霉素的脂质体，该脂质体涂有九精氨酸（R ₉）CPP和环状iNGR（CRNGRGPDC）分子，产生Lip-mbPDS。使用基于 CD13 阳性人纤维肉瘤衍生细胞 (HT1080) 的体外和体内肿瘤模型评估 Lip-mbPDS 肿瘤靶向、肿瘤细胞/组织穿透和抗肿瘤能力。Lip-mbPDS 评估包括三维逐层共焦激光扫描显微镜、细胞内化/毒性测定、基于三维肿瘤球体的渗透测定和在动物模型中进行的抗肿瘤功效测定。Lip-mbPDS 增强了多个生物界面的协同药物渗透，从而实现潜在的深层肿瘤治疗结果。