Gemcitabine and doxorubicin in immunostimulatory monophosphoryl lipid A liposomes for treating breast cancer,Bioengineering & Translational Medicine

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Gemcitabine and doxorubicin in immunostimulatory monophosphoryl lipid A liposomes for treating breast cancer
Bioengineering & Translational Medicine ( IF 6.1 ) Pub Date : 2020-09-08 , DOI: 10.1002/btm2.10188
Debra Wu _{1,

2} , Zongmin Zhao _{1,

2} , Jayoung Kim _{1,

2} , Amaya Razmi ₁ , Lily Li-Wen Wang _{1,

2,

3} , Neha Kapate _{1,

2,

3} , Yongsheng Gao _{1,

2} , Kevin Peng _{1,

2} , Anvay Ukidve _{1,

2} , Samir Mitragotri _{1,

2}

Affiliation

Cancer therapy is increasingly shifting toward targeting the tumor immune microenvironment and influencing populations of tumor infiltrating lymphocytes. Breast cancer presents a unique challenge as tumors of the triple‐negative breast cancer subtype employ a multitude of immunosilencing mechanisms that promote immune evasion and rapid growth. Treatment of breast cancer with chemotherapeutics has been shown to induce underlying immunostimulatory responses that can be further amplified with the addition of immune‐modulating agents. Here, we investigate the effects of combining doxorubicin (DOX) and gemcitabine (GEM), two commonly used chemotherapeutics, with monophosphoryl lipid A (MPLA), a clinically used TLR4 adjuvant derived from liposaccharides. MPLA was incorporated into the lipid bilayer of liposomes loaded with a 1:1 molar ratio of DOX and GEM to create an intravenously administered treatment. In vivo studies indicated excellent efficacy of both GEM‐DOX liposomes and GEM‐DOX‐MPLA liposomes against 4T1 tumors. In vitro and in vivo results showed increased dendritic cell expression of CD86 in the presence of liposomes containing chemotherapeutics and MPLA. Despite this, a tumor rechallenge study indicated little effect on tumor growth upon rechallenge, indicating the lack of a long‐term immune response. GEM/DOX/MPLA‐L displayed remarkable control of the primary tumor growth and can be further explored for the treatment of triple‐negative breast cancer with other forms of immunotherapy.

中文翻译：

用于治疗乳腺癌的免疫刺激单磷酰脂质 A 脂质体中的吉西他滨和阿霉素

癌症治疗越来越转向针对肿瘤免疫微环境并影响肿瘤浸润淋巴细胞群。乳腺癌提出了独特的挑战，因为三阴性乳腺癌亚型的肿瘤采用多种免疫沉默机制，促进免疫逃避和快速生长。化疗治疗乳腺癌已被证明可以诱导潜在的免疫刺激反应，通过添加免疫调节剂可以进一步放大这种反应。在此，我们研究了两种常用化疗药物阿霉素 (DOX) 和吉西他滨 (GEM) 与单磷酰脂质 A (MPLA)（一种临床使用的脂糖衍生 TLR4 佐剂）联合使用的效果。 MPLA 被掺入脂质体的脂质双层中，该脂质体负载有 1:1 摩尔比的 DOX 和 GEM，以形成静脉注射治疗。体内研究表明 GEM-DOX 脂质体和 GEM-DOX-MPLA 脂质体对 4T1 肿瘤具有优异的疗效。体外和体内结果表明，在含有化疗药物和 MPLA 的脂质体存在下，CD86 的树突状细胞表达增加。尽管如此，肿瘤再攻击研究表明，再攻击对肿瘤生长影响很小，表明缺乏长期免疫反应。 GEM/DOX/MPLA-L 对原发肿瘤生长表现出显着的控制作用，可以进一步探索用其他形式的免疫疗法治疗三阴性乳腺癌。

更新日期：2020-09-08

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