Developing Engineered Nano-Immunopotentiators for the Stimulation of Dendritic Cells and Inhibition and Prevention of Melanoma.

IF 3.5 3区医学 Q2 CHEMISTRY, MULTIDISCIPLINARY

Pharmaceutical Research Pub Date : 2024-06-01 Epub Date: 2024-06-05 DOI:10.1007/s11095-024-03722-1

Sitah Alharthi, Seyed Zeinab Alavi, Mehr Un Nisa, Maedeh Koohi, Aun Raza, Hasan Ebrahimi Shahmabadi, Seyed Ebrahim Alavi

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Abstract

Objective: This study aims to utilize PEGylated poly (lactic-co-glycolic acid) (PLGA) nanoparticles as a delivery system for simultaneous administration of the BRAF^V600E peptide, a tumor-specific antigen, and imiquimod (IMQ). The objective is to stimulate dendritic cell (DC) maturation, activate macrophages, and facilitate antigen presentation in C57BL6 mice.

Methods: PEG-PLGA-IMQ-BRAF^V600E nanoparticles were synthesized using a PLGA-PEG-PLGA tri-block copolymer, BRAF^V600E, and IMQ. Characterization included size measurement and drug release profiling. Efficacy was assessed in inhibiting BPD6 melanoma cell growth and activating immature bone marrow DCs, T cells, macrophages, and splenocyte cells through MTT and ELISA assays. In vivo, therapeutic and immunogenic effects potential was evaluated, comparing it to IMQ + BRAF^V600E and PLGA-IMQ-BRAF^V600E nanoparticles in inhibiting subcutaneous BPD6 tumor growth.

Results: The results highlight the successful synthesis of PEG-PLGA-IMQ-BRAF^V600E nanoparticles (203 ± 11.1 nm), releasing 73.4% and 63.2% of IMQ and BARF^V600E, respectively, within the initial 48 h. In vitro, these nanoparticles demonstrated a 1.3-fold increase in potency against BPD6 cells, achieving ~ 2.8-fold enhanced cytotoxicity compared to PLGA-IMQ-BRAF^V600E. Moreover, PEG-PLGA-IMQ-BRAF^V600E exhibited a 1.3-fold increase in potency for enhancing IMQ cytotoxic effects and a 1.1- to ~ 2.4-fold increase in activating DCs, T cells, macrophages, and splenocyte cells compared to IMQ-BRAF^V600E and PLGA-IMQ-BRAF^V600E. In vivo, PEG-PLGA-IMQ-BRAF^V600E displayed a 1.3- to 7.5-fold increase in potency for inhibiting subcutaneous BPD6 tumor growth compared to the other formulations.

Conclusions: The findings suggest that PEG-PLGA nanoparticles effectively promote DC maturation, T cell activation, and potentially macrophage activation. The study highlights the promising role of this nanocomposite in vaccine development.

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开发用于刺激树突状细胞、抑制和预防黑色素瘤的工程纳米免疫诱导剂。

研究目的本研究旨在利用聚乙二醇（PEG）化聚（乳酸-共聚乙酸）（PLGA）纳米颗粒作为一种给药系统，同时给药肿瘤特异性抗原 BRAFV600E 肽和咪喹莫特（IMQ）。目的是刺激树突状细胞（DC）成熟、激活巨噬细胞并促进 C57BL6 小鼠的抗原呈递：方法：使用 PLGA-PEG-PLGA 三嵌段共聚物、BRAFV600E 和 IMQ 合成了 PEG-PLGA-IMQ-BRAFV600E 纳米粒子。表征包括尺寸测量和药物释放分析。通过 MTT 和酶联免疫吸附试验评估了该药物在抑制 BPD6 黑色素瘤细胞生长以及激活未成熟骨髓 DC、T 细胞、巨噬细胞和脾细胞方面的功效。通过比较 IMQ + BRAFV600E 纳米颗粒和 PLGA-IMQ-BRAFV600E 纳米颗粒在抑制皮下 BPD6 肿瘤生长方面的作用，对其体内治疗和免疫效应潜力进行了评估：结果：成功合成了PEG-PLGA-IMQ-BRAFV600E纳米颗粒（203 ± 11.1 nm），在最初的48小时内分别释放了73.4%和63.2%的IMQ和BARFV600E。在体外，与PLGA-IMQ-BRAFV600E相比，这些纳米颗粒对BPD6细胞的效力提高了1.3倍，细胞毒性增强了约2.8倍。此外，与 IMQ-BRAFV600E 和 PLGA-IMQ-BRAFV600E 相比，PEG-PLGA-IMQ-BRAFV600E 增强 IMQ 细胞毒性效果的效力提高了 1.3 倍，激活 DC、T 细胞、巨噬细胞和脾细胞的效力提高了 1.1- ~ 2.4 倍。在体内，与其他制剂相比，PEG-PLGA-IMQ-BRAFV600E抑制皮下BPD6肿瘤生长的效力提高了1.3-7.5倍：结论：研究结果表明，PEG-PLGA纳米颗粒能有效促进DC成熟、T细胞活化以及潜在的巨噬细胞活化。该研究强调了这种纳米复合材料在疫苗开发中的重要作用。

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来源期刊

Pharmaceutical Research 医学-化学综合

CiteScore

6.60

自引率

5.40%

发文量

276

审稿时长

3.4 months

期刊介绍： Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to: -(pre)formulation engineering and processing- computational biopharmaceutics- drug delivery and targeting- molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)- pharmacokinetics, pharmacodynamics and pharmacogenetics. Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.