Nanotechnology Platform for the Delivery of Docetaxel and Tyrosine Kinase Inhibitors for HER2-Positive Breast Cancer Therapy.

Q2 Pharmacology, Toxicology and Pharmaceutics

Pharmaceutical nanotechnology Pub Date : 2025-02-24 DOI:10.2174/0122117385373466250219070753

Bharathi Mandala, Yvonne Berko, Gantamur Battogtok, Funmilola Fisusi, Haijun Gao, Emmanuel O Akala

{"title":"Nanotechnology Platform for the Delivery of Docetaxel and Tyrosine Kinase Inhibitors for HER2-Positive Breast Cancer Therapy.","authors":"Bharathi Mandala, Yvonne Berko, Gantamur Battogtok, Funmilola Fisusi, Haijun Gao, Emmanuel O Akala","doi":"10.2174/0122117385373466250219070753","DOIUrl":null,"url":null,"abstract":"Background: HER2-positive breast cancer is an aggressive subtype characterized by the overexpression of the HER2 receptor, a transmembrane glycoprotein critical for tumor progression. Current therapies often face challenges like drug resistance and systemic toxicity, necessitating the development of advanced drug delivery systems.Objective: This study aimed to fabricate and determine the cytotoxicity of pH-sensitive PLA nanoparticles dual-loaded with docetaxel and each of the small molecule tyrosine kinase inhibitors (STKIs) (tucatinib, neratinib, lapatinib) in HER2-positive breast cancer cells.Method: Nanoparticles were synthesized by a dispersion polymerization method using an acidlabile crosslinking agent, and PEG and lactide macromonomers. They were characterized for structure (TEM), surface morphology (SEM), particle size, polydispersity index, zeta potential, and drug loading capacity. Cytotoxicity was assessed in vitro on SKBR3 and MCF7 breast cancer cell lines, with IC50 values compared across formulations.Results: The nanoparticles were spherical with nanoscale sizes and negative zeta potential values. In vitro studies demonstrated enhanced antiproliferative effects of the drug-loaded nanoparticles, with synergistic activity observed between docetaxel and the STKIs. The drug concentrations were halved in combination formulations and resulted in better cytotoxicity compared to single-drug treatments, particularly against SKBR3 cells. The IC50 values were lower in SKBR3 cells than in MCF7 cells, highlighting the role of HER2 expression in the activity of TKIs.Conclusion: The pH-sensitive PLA nanoparticles effectively co-delivered docetaxel and STKIs and demonstrated enhanced efficacy and reduced drug dosages in HER2-positive breast cancer models. This study provides a foundation for further exploration of nanoparticle-based combination therapies with potential applications in treating other aggressive cancer types.","PeriodicalId":19774,"journal":{"name":"Pharmaceutical nanotechnology","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmaceutical nanotechnology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2174/0122117385373466250219070753","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Pharmacology, Toxicology and Pharmaceutics","Score":null,"Total":0}

引用次数: 0

Abstract

Background: HER2-positive breast cancer is an aggressive subtype characterized by the overexpression of the HER2 receptor, a transmembrane glycoprotein critical for tumor progression. Current therapies often face challenges like drug resistance and systemic toxicity, necessitating the development of advanced drug delivery systems.

Objective: This study aimed to fabricate and determine the cytotoxicity of pH-sensitive PLA nanoparticles dual-loaded with docetaxel and each of the small molecule tyrosine kinase inhibitors (STKIs) (tucatinib, neratinib, lapatinib) in HER2-positive breast cancer cells.

Method: Nanoparticles were synthesized by a dispersion polymerization method using an acidlabile crosslinking agent, and PEG and lactide macromonomers. They were characterized for structure (TEM), surface morphology (SEM), particle size, polydispersity index, zeta potential, and drug loading capacity. Cytotoxicity was assessed in vitro on SKBR3 and MCF7 breast cancer cell lines, with IC50 values compared across formulations.

Results: The nanoparticles were spherical with nanoscale sizes and negative zeta potential values. In vitro studies demonstrated enhanced antiproliferative effects of the drug-loaded nanoparticles, with synergistic activity observed between docetaxel and the STKIs. The drug concentrations were halved in combination formulations and resulted in better cytotoxicity compared to single-drug treatments, particularly against SKBR3 cells. The IC50 values were lower in SKBR3 cells than in MCF7 cells, highlighting the role of HER2 expression in the activity of TKIs.

Conclusion: The pH-sensitive PLA nanoparticles effectively co-delivered docetaxel and STKIs and demonstrated enhanced efficacy and reduced drug dosages in HER2-positive breast cancer models. This study provides a foundation for further exploration of nanoparticle-based combination therapies with potential applications in treating other aggressive cancer types.

查看原文本刊更多论文

纳米技术平台递送多西紫杉醇和酪氨酸激酶抑制剂用于her2阳性乳腺癌治疗。

背景：HER2阳性乳腺癌是一种侵袭性亚型，其特征是HER2受体过表达，HER2受体是一种跨膜糖蛋白，对肿瘤进展至关重要。目前的治疗方法经常面临耐药性和全身毒性等挑战，需要开发先进的给药系统。目的：制备双负载多西紫杉醇和各小分子酪氨酸激酶抑制剂（STKIs）（图卡替尼、纳拉替尼、拉帕替尼）的ph敏感聚乳酸纳米颗粒，并测定其对her2阳性乳腺癌细胞的细胞毒性。方法：以酸性交联剂、聚乙二醇和丙交酯为原料，采用分散聚合法制备纳米颗粒。对其结构（TEM）、表面形貌（SEM）、粒径、多分散性指数、zeta电位和载药量进行了表征。体外评估SKBR3和MCF7乳腺癌细胞系的细胞毒性，并比较不同配方的IC50值。结果：纳米颗粒呈纳米级球形，zeta电位为负。体外研究表明，载药纳米颗粒具有增强的抗增殖作用，并在多西紫杉醇和STKIs之间观察到协同作用。在联合制剂中，药物浓度减半，与单药治疗相比，产生更好的细胞毒性，特别是针对SKBR3细胞。IC50值在SKBR3细胞中低于MCF7细胞，突出了HER2表达在TKIs活性中的作用。结论：ph敏感的聚乳酸纳米颗粒在her2阳性乳腺癌模型中有效地共同递送多西紫杉醇和STKIs，并显示出增强的疗效和减少的药物剂量。该研究为进一步探索基于纳米颗粒的联合疗法在治疗其他侵袭性癌症类型中的潜在应用提供了基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Pharmaceutical nanotechnology Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science

CiteScore

4.20

自引率

0.00%

发文量

期刊介绍： Pharmaceutical Nanotechnology publishes original manuscripts, full-length/mini reviews, thematic issues, rapid technical notes and commentaries that provide insights into the synthesis, characterisation and pharmaceutical (or diagnostic) application of materials at the nanoscale. The nanoscale is defined as a size range of below 1 µm. Scientific findings related to micro and macro systems with functionality residing within features defined at the nanoscale are also within the scope of the journal. Manuscripts detailing the synthesis, exhaustive characterisation, biological evaluation, clinical testing and/ or toxicological assessment of nanomaterials are of particular interest to the journal’s readership. Articles should be self contained, centred around a well founded hypothesis and should aim to showcase the pharmaceutical/ diagnostic implications of the nanotechnology approach. Manuscripts should aim, wherever possible, to demonstrate the in vivo impact of any nanotechnological intervention. As reducing a material to the nanoscale is capable of fundamentally altering the material’s properties, the journal’s readership is particularly interested in new characterisation techniques and the advanced properties that originate from this size reduction. Both bottom up and top down approaches to the realisation of nanomaterials lie within the scope of the journal.