Intratumoral nanofluidic system enhanced tumor biodistribution of PD-L1 antibody in triple-negative breast cancer.
Intratumoral nanofluidic system enhanced tumor biodistribution of PD-L1 antibody in triple-negative breast cancer.
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DOI：
10.1002/btm2.10594
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发表时间：
2023-11
影响因子：
7.4
通讯作者：
中科院分区：
文献类型：
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作者：
免疫检查点抑制剂（ICI），派姆单抗和阿特唑单抗，最近被批准用于治疗难治性三阴性乳腺癌（TNBC），其中程序性死亡配体1 （PD‐L1）阳性的早期疾病患者有改善的反应。在临床中，ICIs是系统给药，然而，由于严重的肿瘤外毒性，达到有效的治疗剂量是具有挑战性的。因此，肿瘤内（IT）注射作为一种替代给药方法越来越受到研究。然而，由于间质液压力增加导致药物迅速从肿瘤中清除，因此需要反复给药，有时是侵入性的。为了最大限度地减少脱靶药物的生物分布，我们开发了纳米流体药物洗脱种子（NDES）平台，通过分子扩散持续释放肿瘤内的治疗药物。本研究采用荧光标记PD‐L1单克隆抗体（αPD‐L1）比较了NDES、腹腔注射（IP）和瘤内注射（IT）之间的药物生物分布。我们使用了两种同基因TNBC小鼠模型，EMT6和4T1，它们在PD‐L1表达、免疫原性和转运表型上有所不同。我们使用不同的治疗方法研究了靶上（肿瘤）和靶外分布。随着放疗越来越多地与免疫治疗联合使用，我们试图研究其对αPD‐L1肿瘤积累和全身分布的影响。与IP或IT注射组相比，NDES治疗组在14天的研究期间肿瘤中αPD‐L1水平持续升高，靶外器官分布明显降低。然而，我们观察到αPD‐L1在不同肿瘤模型和放疗前的生物分布存在差异。因此，我们试图通过组织学分析，扩散评估和纳米颗粒对比增强CT广泛表征肿瘤特性。总的来说，我们证明通过NDES给药是一种有效的方法，可以在肿瘤模型和联合治疗中持续靶向给药。
Immune checkpoint inhibitors (ICI), pembrolizumab and atezolizumab, were recently approved for treatment‐refractory triple‐negative breast cancer (TNBC), where those with Programmed death‐ligand 1 (PD‐L1) positive early‐stage disease had improved responses. ICIs are administered systemically in the clinic, however, reaching effective therapeutic dosing is challenging due to severe off‐tumor toxicities. As such, intratumoral (IT) injection is increasingly investigated as an alternative delivery approach. However, repeated administration, which sometimes is invasive, is required due to rapid drug clearance from the tumor caused by increased interstitial fluid pressure. To minimize off‐target drug biodistribution, we developed the nanofluidic drug‐eluting seed (NDES) platform for sustained intratumoral release of therapeutic via molecular diffusion. Here we compared drug biodistribution between the NDES, intraperitoneal (IP) and intratumoral (IT) injection using fluorescently labeled PD‐L1 monoclonal antibody (αPD‐L1). We used two syngeneic TNBC murine models, EMT6 and 4T1, that differ in PD‐L1 expression, immunogenicity, and transport phenotype. We investigated on‐target (tumor) and off‐target distribution using different treatment approaches. As radiotherapy is increasingly used in combination with immunotherapy, we sought to investigate its effect on αPD‐L1 tumor accumulation and systemic distribution. The NDES‐treated cohort displayed sustained levels of αPD‐L1 in the tumor over the study period of 14 days with significantly lower off‐target organ distribution, compared to the IP or IT injection. However, we observed differences in the biodistribution of αPD‐L1 across tumor models and with radiation pretreatment. Thus, we sought to extensively characterize the tumor properties via histological analysis, diffusion evaluation and nanoparticles contrast‐enhanced CT. Overall, we demonstrate that ICI delivery via NDES is an effective method for sustained on‐target tumor delivery across tumor models and combination treatments.
影响因子：
4.8
作者：
Ghaghada, Ketan B.;Badea, Cristian T.;Karumbaiah, Lohitash;Fettig, Nicole;Bellamkonda, Ravi V.;Johnson, G. A.;Annapragada, Ananth
通讯作者：
Annapragada, Ananth
DOI：
10.3390/s100605927
发表时间：
2010
期刊：
Sensors (Basel, Switzerland)
影响因子：
--
作者：
Rayan G;Guet JE;Taulier N;Pincet F;Urbach W
通讯作者：
Urbach W
影响因子：
--
作者：
Starosolski Z;Courtney AN;Srivastava M;Guo L;Stupin I;Metelitsa LS;Annapragada A;Ghaghada KB
通讯作者：
Ghaghada KB