iBB-Institute for Bioengineering and Biosciences, Biological Sciences Research Group, Instituto Superior Técnico, University of Lisbon, Av. Rovisco Pais, 1, 1049-001 Lisbon, Portugal; Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, University of Lisbon, Av. Rovisco Pais, 1, 1049-001 Lisbon, Portugal; i3S- Instituto de Inovação e Investigação em Saúde, University of Porto, R. Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB-Instituto de Engenharia Biomédica, University of Porto, R. Alfredo Allen, 208, 4200-135 Porto, Portugal.
i3S- Instituto de Inovação e Investigação em Saúde, University of Porto, R. Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB-Instituto de Engenharia Biomédica, University of Porto, R. Alfredo Allen, 208, 4200-135 Porto, Portugal.
J Control Release. 2021 Sep 10;337:329-342. doi: 10.1016/j.jconrel.2021.07.035. Epub 2021 Jul 24.
Lung cancer is still the main cause of cancer-related deaths worldwide. Its treatment generally includes surgical resection, immunotherapy, radiotherapy, and chemo-targeted therapies such as the application of tyrosine kinase inhibitors. Gefitinib (GEF) is one of them, but its poor solubility in gastric fluids weakens its bioavailability and therapeutic activity. In addition, like all other chemotherapy treatments, GEF administration can cause damage to healthy tissues. Therefore, the development of novel GEF delivery systems to increase its bioavailability and distribution in tumor site is highly demanded. Herein, an innovative strategy for GEF delivery, by functionalizing PLGA nanoparticles with p28 (p28-NPs), a cell-penetrating peptide derived from the bacterial protein azurin, was developed. Our data indicated that p28 potentiates the selective interaction of these nanosystems with A549 lung cancer cells (active targeting). Further p28-NPs delivering GEF (p28-NPs-GEF) were able to selectively reduce the metabolic activity of A549 cells, while no impact was observed in non-tumor cells (16HBE14o-). In vivo studies using A549 subcutaneous xenograft showed that p28-NPs-GEF reduced A549 primary tumor burden and lung metastases formation. Overall, the design of a p28-functionalized delivery nanosystem to effectively penetrate the membranes of cancer cells while deliver GEF could provide a new strategy to improve lung cancer therapy.
肺癌仍然是全球癌症相关死亡的主要原因。其治疗通常包括手术切除、免疫疗法、放疗和化疗靶向治疗，如酪氨酸激酶抑制剂的应用。吉非替尼（GEF）就是其中之一，但它在胃液中的溶解度差，削弱了其生物利用度和治疗活性。此外，与所有其他化疗治疗一样，GEF 给药会对健康组织造成损害。因此，开发新型 GEF 递送系统以提高其在肿瘤部位的生物利用度和分布是非常需要的。在此，通过用来源于细菌蛋白天青蛋白的穿膜肽 p28 对 PLGA 纳米粒进行功能化，开发了一种用于 GEF 传递的创新策略（p28-NPs）。我们的数据表明，p28 增强了这些纳米系统与肺癌 A549 细胞的选择性相互作用（主动靶向）。进一步的 p28-NPs 递送 GEF（p28-NPs-GEF）能够选择性地降低 A549 细胞的代谢活性，而对非肿瘤细胞（16HBE14o-）没有影响。使用 A549 皮下异种移植的体内研究表明，p28-NPs-GEF 减少了 A549 原发性肿瘤负担和肺转移的形成。总之，设计一种 p28 功能化的递送纳米系统，能够有效地穿透癌细胞的膜，同时递送 GEF，可能为改善肺癌治疗提供一种新策略。
