National Institute of Oncology, Department of Experimental Pharmacology, National Tumor Biology Laboratory, Budapest, Hungary.
School of Ph.D. Studies, Semmelweis University, Budapest, Hungary.
Drug Deliv. 2023 Dec;30(1):2174210. doi: 10.1080/10717544.2023.2174210.
Chemotherapy is still a leading therapeutic approach in various tumor types that is often accompanied by a poor prognosis because of metastases. PEGylated liposomes with CREKA targeting moiety are well-known therapeutic agents, especially in highly metastatic experimental models. CREKA specifically targets tumor-associated ECM, which is present at the primary, as well as metastatic tumor sites. To better understand the function of the targeting moieties, we decided to design various liposome formulations with different amounts of targeting moiety attached to their DSPE-PEG molecules. Moreover, a new tumor-homing pentapeptide (SREKA) was designed, and a novel conjugation strategy between SREKA and DSPE-PEGs. First, the proliferation inhibition of drug-loaded liposomes and the cellular uptake of their cargo were investigated. Afterward, liposome stability in murine blood and drug accumulation in different tissues were measured. Furthermore, tumor growth, and metastasis inhibition potencies of the different liposome formulations were examined. According to our comparative studies, SREKA-liposomes have a uniform phenotype after formulation and have similar characteristics and tumor-homing capabilities to CREKA-liposomes. However, the exchange of the N-terminal cysteine to serine during conjugation results in a higher production yield and better stability upon conjugation to DSPE-PEGs. We also showed that SREKA-liposomes have significant inhibition on primary tumor growth and metastasis incidence; furthermore, increase the survival rate of tumor-bearing mice. Besides, we provide evidence that the amount of targeting moiety attached to DSPE-PEGs is largely responsible for the stability of liposomes, therefore it plays an important role in toxicity and targeting.
化疗仍然是各种肿瘤类型的主要治疗方法，但由于转移，预后往往较差。带有 CREKA 靶向部分的聚乙二醇化脂质体是众所周知的治疗剂，特别是在高度转移性的实验模型中。CREKA 特异性靶向肿瘤相关的细胞外基质，这些基质存在于原发性和转移性肿瘤部位。为了更好地了解靶向部分的功能，我们决定设计具有不同数量靶向部分连接到其 DSPE-PEG 分子的各种脂质体配方。此外，还设计了一种新的肿瘤归巢五肽（SREKA），并设计了一种新的 SREKA 和 DSPE-PEG 之间的连接策略。首先，研究了载药脂质体的增殖抑制作用及其货物的细胞摄取作用。之后，测量了脂质体在小鼠血液中的稳定性和药物在不同组织中的积累。此外，还研究了不同脂质体配方的肿瘤生长和转移抑制作用。根据我们的比较研究，SREKA 脂质体在配方后具有均匀的表型，并且具有与 CREKA 脂质体相似的特性和肿瘤归巢能力。然而，在连接过程中 N 端半胱氨酸被丝氨酸取代导致更高的产率和更好的 DSPE-PEG 连接稳定性。我们还表明，SREKA 脂质体对原发性肿瘤生长和转移发生率具有显著的抑制作用，并且提高了荷瘤小鼠的存活率。此外，我们提供的证据表明，连接到 DSPE-PEG 的靶向部分的数量在很大程度上决定了脂质体的稳定性，因此在毒性和靶向方面起着重要作用。
