Synthesis and characterization of a tumor-seeking LyP-1 peptide integrated lipid-polymer composite nanoparticle
Synthesis and characterization of a tumor-seeking LyP-1 peptide integrated lipid-polymer composite nanoparticle
复制标题
DOI：
10.1039/d0ma00203h
复制
发表时间：
2020-06-01
影响因子：
5
通讯作者：
Aryal, Santosh
中科院分区：
文献类型：
--
作者：
Marasini, Ramesh;Nguyen, Tuyen Duong Thanh;Aryal, Santosh
由于聚合物和脂质易于化学修饰以针对各自的疾病环境，生物相容性聚合物和脂质纳米颗粒作为抗癌纳米药物正在受到广泛的研究。然而，肿瘤中的微环境和分子异质性对将抗癌药物或显像剂精确递送至靶点提出了巨大的挑战，进一步限制了它们的应用。因此，现有的纳米药物制剂依赖于利用渗漏的肿瘤脉管系统的被动药物靶向机制。然而，由于癌症之间的分子差异，一种策略并不适合所有人。因此，需要对肿瘤特异性受体进行更多研究，以最大限度地提高药物输送，同时最大限度地减少药物相关的副作用。此外，递送装置的高度免疫相容性和水稳定性对于最大化递送效率至关重要。在此，我们通过将受体特异性抗癌纳米药物设计为聚合物和脂质的复合物来满足癌症管理中的上述要求。我们正在提出一种肿瘤寻找环状 LyP-1 肽集成核壳聚合物-脂质复合纳米颗粒 (NP)，其靶向癌细胞中过度表达的 p32 受体。设计的纳米结构由作为骨架的丙交酯-乙醇酸共聚物、作为稳定剂的磷脂和聚乙二醇以及作为靶向基序的LyP-1组成。我们使用近红外染料标记的纳米颗粒作为体内成像示踪剂，通过获取全谱生物分布来研究细胞相互作用和靶向能力。纳米颗粒呈球形且单分散，平均尺寸为 68 +/- 6 nm，具有负 zeta 电位。这些颗粒在生理条件下高度稳定，具有较低的多分散指数 (PDI = 0.15)。此外，纳米颗粒在体外表现出优异的生物相容性，与非癌性成纤维细胞相比，小鼠骨肉瘤的吸收明显更高。同样，与 K7M2 肿瘤中的非靶向对应物相比，LyP-1 NP 在体内的肿瘤积累增强了近三倍。考虑到 p32 在许多癌症中的过度表达，所提出的纳米结构可以在多种肿瘤的治疗计划中带来希望。
Biocompatible polymeric and lipid nanoparticles are under extensive investigation as anticancer nanomedicines due to the ease of chemical modification in both polymer and lipid in order to target the respective disease environment. However, microenvironment and molecular heterogeneity in tumors pose a great challenge to delivering anticancer drugs or imaging agents precisely to the target, further limiting their applications. As a result, existing nanomedicine formulations rely on a passive-drug targeting mechanism taking advantage of leaky tumor vasculature. However, one strategy is not fit for all due to the molecular dissimilarities between cancers. Therefore, more research on tumor-specific receptors is needed to maximize drug delivery, while minimizing drug-related adverse effects. In addition, a high degree of the immunocompatibility and aqueous stability of the delivery device is essential to maximize delivery efficiency. Herein, we are addressing the aforementioned requirements in cancer management by engineering a receptor-specific anticancer nanomedicine as a composite of polymer and lipids. We are presenting a tumor seeking cyclic LyP-1 peptide integrated core-shell polymer-lipid composite nanoparticle (NP) that targets the overexpressed p32 receptor in cancer cells. The designed nanoconstruct is composed of poly(lactide-co-glycolic acid) as a skeleton and a cargo reservoir, a phospholipid with polyethylene glycol as a stabilizer, and LyP-1 as a targeting motif. We studied cellular interaction and targeting ability by accessing the full spectrum of biodistribution using NPs labeled with near-infrared dye as an imaging tracer in vivo. The NPs are spherical and monodispersed with an average size of 68 +/- 6 nm and negative zeta potential. These particles are highly stable in physiological conditions over the period with a lower polydispersity index (PDI = 0.15). Furthermore, the nanoparticles showed excellent biocompatibility in vitro, with significantly higher uptake by mouse osteosarcoma compared to non-cancerous fibroblasts. Likewise, LyP-1 NP showed nearly three-fold enhancement in tumor accumulation in vivo compared to its non-targeted counterparts in the K7M2 tumor. Considering the overexpression of p32 in many cancers, the proposed nanoconstruct could hold promises in the therapeutic planning of a wide range of tumors.