Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705, United States.
Wisconsin Center for NanoBioSystems (WisCNano), School of Pharmacy, The University of Wisconsin-Madison, 777 Highland Ave., Madison, Wisconsin 53705, United States.
Biomacromolecules. 2021 Sep 13;22(9):3746-3755. doi: 10.1021/acs.biomac.1c00541. Epub 2021 Jul 28.
Dendron micelles have shown promising results as a multifunctional delivery system, owing to their unique molecular architecture. Herein, we have prepared a novel poly(amidoamine) (PAMAM) dendron-lipid hybrid nanoparticle (DLNP) as a nanocarrier for drug/gene co-delivery and examined how the dendron generation of DLNPs impacts their cargo-carrying capabilities. DLNPs, formed by a thin-layer hydration method, were internally loaded with chemo-drugs and externally complexed with plasmids. Compared to generation 2 dendron DLNP (D2LNPs), D3LNPs demonstrated a higher drug encapsulation efficiency (31% vs 87%) and better gene complexation (minimal N/P ratio of 20:1 vs 5:1 for complexation) due to their smaller micellar aggregation number and higher charge density, respectively. Furthermore, D3LNPs were able to avoid endocytosis and subsequent lysosomal degradation and demonstrated a higher cellular uptake than D2LNPs. As a result, D3LNPs exhibited significantly enhanced antitumor and gene transfection efficacy in comparison to D2LNPs. These findings provide design cues for engineering multifunctional dendron-based nanotherapeutic systems for effective combination cancer treatment.
树枝状聚合物胶束作为一种多功能递送系统，由于其独特的分子结构，已经显示出了很好的效果。在这里，我们制备了一种新型的聚酰胺-胺（PAMAM）树枝状聚合物-脂质杂化纳米粒子（DLNP）作为药物/基因共递药的纳米载体，并研究了 DLNP 的树枝化程度如何影响其载药能力。通过薄层水合方法形成的 DLNP 内部负载化疗药物，外部与质粒复合。与第二代树枝状聚合物 DLNP（D2LNPs）相比，由于其较小的胶束聚集数和较高的电荷密度，第三代树枝状聚合物 DLNP（D3LNPs）表现出更高的药物包封效率（31%比 87%）和更好的基因复合能力（复合所需的最小 N/P 比为 20:1 比 5:1）。此外，D3LNPs 能够避免内吞作用和随后的溶酶体降解，并表现出比 D2LNPs 更高的细胞摄取率。因此，与 D2LNPs 相比，D3LNPs 表现出显著增强的抗肿瘤和基因转染效果。这些发现为设计多功能基于树枝状聚合物的纳米治疗系统以实现有效的联合癌症治疗提供了设计思路。
