Development and characterization of temozolomide-PAMAM-siRNA dendriplexes for the effective management of glioblastoma multiforme

IF 2.6 4区材料科学 Q3 CHEMISTRY, MULTIDISCIPLINARY Journal of Nanoparticle Research Pub Date : 2024-06-13 DOI:10.1007/s11051-024-06037-9

Tanisha Gupta, Rakesh Kumar Sahoo, Awesh Kumar Yadav, Umesh Gupta

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Abstract

This study was aimed to develop and evaluate the TMZ-PAMAM-siRNA [temozolomide-polyamidoamine dendimer-siRNA] dendriplexes for the effective treatment of glioblastoma multiforme (GBM). In the present study, TMZ-PAMAM-siRNA dendriplexes were designed with optimized N/P ratio for the effective management of GBM. Complexation was performed using mixing followed by incubation in nuclease free water. The particle size and zeta potential of the developed dendriplexes were found to be 121.54 ± 8.21 nm and 12.56 ± 0.91 mV, respectively. Drug loading and entrapment efficiency of TMZ-PAMAM-siRNA were observed to be 38.41 ± 3.47% and 56.24 ± 3.94%, respectively. TMZ-PAMAM-siRNA exhibited minimal toxicity towards RBCs with controlled drug release behaviour in the acidic medium. TMZ-PAMAM-siRNA complex was reversible in nature and was able to release siRNA from dendriplexes. IC₅₀ values were reduced in case of TMZ-PAMAM (p < 0.0001) and TMZ-PAMAM-siRNA (p < 0.0001). TMZ-PAMAM resulted in the IC₅₀ values to be 419.47 ± 17.24 and 252.21 ± 15.64 μM after 24 and 48 h of treatment, respectively. The developed dendriplexes showed significantly higher cytotoxic effect with IC₅₀ values of 295.30 ± 21.56 μM after 24 h of treatment against LN229 cells. However, maximum cytotoxic effect was observed after 48 h of treatment and calculated IC₅₀ value was 197.52 ± 18.12 μM. The results of cellular internalization supported the results obtained through MTT assay. The siRNA complexed PAMAM dendrimers have shown excellent potential in delivering drugs to the targeted cells. Such dendriplex-based approach can result into promising output if explored further.

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开发和鉴定替莫唑胺-PAMAM-siRNA二元复合物，以有效治疗多形性胶质母细胞瘤

本研究旨在开发和评估用于有效治疗多形性胶质母细胞瘤（GBM）的 TMZ-PAMAM-siRNA [替莫唑胺-多胺二聚体-siRNA] 二聚体。本研究设计了具有优化 N/P 比的 TMZ-PAMAM-siRNA 二聚体，用于有效治疗多形性胶质母细胞瘤。络合采用混合法，然后在无核酸酶水中培养。研究发现，所开发的树枝状核酸复合物的粒度和 zeta 电位分别为 121.54 ± 8.21 nm 和 12.56 ± 0.91 mV。据观察，TMZ-PAMAM-siRNA 的载药量和包埋效率分别为 38.41 ± 3.47% 和 56.24 ± 3.94%。在酸性介质中，TMZ-PAMAM-siRNA 对红细胞的毒性极小，且药物释放受控。TMZ-PAMAM-siRNA 复合物具有可逆性，能够从树枝状复合物中释放 siRNA。TMZ-PAMAM (p < 0.0001) 和 TMZ-PAMAM-siRNA (p < 0.0001) 的 IC50 值均有所降低。处理 24 和 48 小时后，TMZ-PAMAM 的 IC50 值分别为 419.47 ± 17.24 和 252.21 ± 15.64 μM。开发出的树枝状化合物对 LN229 细胞的细胞毒性效果明显更高，处理 24 小时后的 IC50 值为 295.30 ± 21.56 μM。然而，处理 48 小时后观察到的细胞毒性效应最大，计算出的 IC50 值为 197.52 ± 18.12 μM。细胞内化的结果证实了 MTT 试验的结果。siRNA 复合物 PAMAM 树枝状聚合物在向靶细胞递送药物方面表现出卓越的潜力。如果进一步探索这种基于树枝状聚合物的方法，将会有很好的结果。

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来源期刊

Journal of Nanoparticle Research 工程技术-材料科学：综合

CiteScore

4.40

自引率

4.00%

发文量

198

审稿时长

3.9 months

期刊介绍： The objective of the Journal of Nanoparticle Research is to disseminate knowledge of the physical, chemical and biological phenomena and processes in structures that have at least one lengthscale ranging from molecular to approximately 100 nm (or submicron in some situations), and exhibit improved and novel properties that are a direct result of their small size. Nanoparticle research is a key component of nanoscience, nanoengineering and nanotechnology. The focus of the Journal is on the specific concepts, properties, phenomena, and processes related to particles, tubes, layers, macromolecules, clusters and other finite structures of the nanoscale size range. Synthesis, assembly, transport, reactivity, and stability of such structures are considered. Development of in-situ and ex-situ instrumentation for characterization of nanoparticles and their interfaces should be based on new principles for probing properties and phenomena not well understood at the nanometer scale. Modeling and simulation may include atom-based quantum mechanics; molecular dynamics; single-particle, multi-body and continuum based models; fractals; other methods suitable for modeling particle synthesis, assembling and interaction processes. Realization and application of systems, structures and devices with novel functions obtained via precursor nanoparticles is emphasized. Approaches may include gas-, liquid-, solid-, and vacuum-based processes, size reduction, chemical- and bio-self assembly. Contributions include utilization of nanoparticle systems for enhancing a phenomenon or process and particle assembling into hierarchical structures, as well as formulation and the administration of drugs. Synergistic approaches originating from different disciplines and technologies, and interaction between the research providers and users in this field, are encouraged.