Successful integration of nanotechnology into the current paradigm of cancer therapy requires proper understanding of the interface between nanoparticles (NPs) and cancer cells, as well as other key components within the tumor microenvironment (TME), such as normal fibroblasts (FBs) and cancer-associated FBs (CAFs). So far, much focus has been on cancer cells, but FBs and CAFs also play a critical role: FBs suppress the tumor growth while CAFs promote it. It is not yet known how NPs interact with FBs and CAFs compared to cancer cells. Hence, our goal was to elucidate the extent of NP uptake, retention, and toxicity in cancer cells, FBs, and CAFs to further understand the fate of NPs in a real tumor-like environment. The outcome of this would guide designing of NP-based delivery systems to fully exploit the TME for a better therapeutic outcome. We used gold nanoparticles as our model NP system due to their numerous applications in cancer therapy, including radiotherapy and chemotherapy. A cervical cancer cell line, HeLa, and a triple-negative breast cancer cell line, MDA-MB-231 were chosen as cancer cell lines. For this study, a clinically feasible 0.2 nM concentration of GNPs was employed. According to our results, the cancer cells and CAFs had over 25- and 10-fold higher NP uptake per unit cell volume compared to FBs, respectively. Further, the cancer cells and CAFs had over 30% higher NP retention compared to FBs. There was no observed significant toxicity due to GNPs in all the cell lines studied. Higher uptake and retention of NPs in cancer cells and CAFs vs FBs is very important in promoting NP-based applications in cancer therapy. Our results show potential in modulating uptake and retention of GNPs among key components of TME, in an effort to develop NP-based strategies to suppress the tumor growth. An ideal NP-based platform would eradicate tumor cells, protect FBs, and deactivate CAFs. Therefore, this study lays a road map to exploit the TME for the advancement of “smart” nanomedicines that would constitute the next generation of cancer therapeutics.

中文翻译：

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阐明纳米颗粒在肿瘤微环境关键细胞成分中的命运，以促进癌症纳米技术的发展。

纳米技术成功融入当前的癌症治疗范式需要正确理解纳米颗粒（NP）和癌细胞之间的界面，以及肿瘤微环境（TME）内的其他关键成分，例如正常成纤维细胞（FB）和癌症细胞。关联的 FB (CAF)。到目前为止，人们的注意力主要集中在癌细胞上，但 FB 和 CAF 也发挥着关键作用：FB 抑制肿瘤生长，而 CAF 则促进肿瘤生长。与癌细胞相比，目前尚不清楚 NPs 如何与 FBs 和 CAFs 相互作用。因此，我们的目标是阐明癌细胞、FB 和 CAF 中 NP 的摄取、保留和毒性程度，以进一步了解 NP 在真实肿瘤样环境中的命运。这一结果将指导基于 NP 的递送系统的设计，以充分利用 TME 以获得更好的治疗结果。我们使用金纳米颗粒作为我们的模型纳米颗粒系统，因为它们在癌症治疗（包括放射治疗和化疗）中具有广泛的应用。选择宫颈癌细胞系 HeLa 和三阴性乳腺癌细胞系 MDA-MB-231 作为癌细胞系。本研究采用临床上可行的 0.2 nM 浓度的 GNP。根据我们的结果，与 FB 相比，癌细胞和 CAF 每单位细胞体积的 NP 摄取量分别高出 25 倍和 10 倍。此外，与 FB 相比，癌细胞和 CAF 的 NP 保留率高出 30% 以上。在所有研究的细胞系中，没有观察到 GNP 引起的显着毒性。与 FB 相比，癌细胞和 CAF 中纳米颗粒的更高摄取和保留对于促进基于纳米颗粒的癌症治疗应用非常重要。我们的结果显示了调节 TME 关键成分中 GNP 的吸收和保留的潜力，以努力开发基于 NP 的策略来抑制肿瘤生长。理想的基于 NP 的平台将根除肿瘤细胞、保护 FB 并停用 CAF。因此，这项研究奠定了利用 TME 来推进“智能”纳米药物的发展的路线图，这些纳米药物将构成下一代癌症治疗方法。