Department of Microbiology and Immunology , School of Medicine, University of Texas Rio Grande Valley , McAllen , Texas 78504 , United States.
Department of Pharmaceutical Sciences and Center for Cancer Research , University of Tennessee Health Science Center , Memphis , Tennessee 38163 , United States.
ACS Appl Mater Interfaces. 2019 Oct 23;11(42):38537-38554. doi: 10.1021/acsami.9b14738. Epub 2019 Oct 8.
Cellular senescence is one of the prevailing issues in cancer therapeutics that promotes cancer relapse, chemoresistance, and recurrence. Patients undergoing persistent chemotherapy often develop drug-induced senescence. Docetaxel, an FDA-approved treatment for prostate cancer, is known to induce cellular senescence which often limits the overall survival of patients. Strategic therapies that counter the cellular and drug-induced senescence are an unmet clinical need. Towards this an effort was made to develop a novel therapeutic strategy that targets and removes senescent cells from the tumors, we developed a nanoformulation of tannic acid-docetaxel self-assemblies (DSAs). The construction of DSAs was confirmed through particle size measurements, spectroscopy, thermal, and biocompatibility studies. This formulation exhibited enhanced therapeutic activity in various biological functional assays with respect to native docetaxel treatments. Microarray and immunoblot analysis results demonstrated that DSAs exposure selectively deregulated senescence associated TGFβR1/FOXO1/p21 signaling. Decrease in β-galactosidase staining further suggested reversion of drug-induced senescence after DSAs exposure. Additionally, DSAs induced profound cell death by activation of apoptotic signaling through bypassing senescence. Furthermore, and imaging analysis demonstrated the tumor targeting behavior of DSAs in mice bearing PC-3 xenograft tumors. The antisenescence and anticancer activity of DSAs was further shown by inhibiting TGFβR1 proteins and regressing tumor growth through apoptotic induction in the PC-3 xenograft mouse model. Overall, DSAs exhibited such advanced features due to a natural compound in the formulation as a matrix/binder for docetaxel. Overall, DSAs showed superior tumor targeting and improved cellular internalization, promoting docetaxel efficacy. These findings may have great implications in prostate cancer therapy.
细胞衰老（cellular senescence）是癌症治疗中一个普遍存在的问题，它促进了癌症的复发、化疗耐药和再发。接受持续化疗的患者常常会产生药物诱导的衰老。多西他赛（Docetaxel）是一种获得 FDA 批准用于治疗前列腺癌的药物，已知它会诱导细胞衰老，这往往会限制患者的总体生存率。因此，需要开发对抗细胞和药物诱导衰老的策略。为此，我们努力开发了一种新的治疗策略，即靶向并从肿瘤中去除衰老细胞，我们开发了单宁酸-多西他赛自组装体（DSAs）的纳米制剂。通过粒径测量、光谱学、热学和生物相容性研究证实了 DSAs 的构建。与天然多西他赛治疗相比，该制剂在各种生物学功能测定中表现出增强的治疗活性。微阵列和免疫印迹分析结果表明，DSAs 暴露选择性地下调了与衰老相关的 TGFβR1/FOXO1/p21 信号通路。β-半乳糖苷酶染色的减少进一步表明，DSAs 暴露后药物诱导的衰老发生了逆转。此外，DSAs 通过绕过衰老激活凋亡信号诱导了深刻的细胞死亡。此外，和 成像分析表明，DSAs 在携带 PC-3 异种移植肿瘤的小鼠中具有肿瘤靶向行为。DSAs 通过抑制 TGFβR1 蛋白和通过诱导凋亡来抑制肿瘤生长，进一步显示了其抗衰老和抗癌活性在 PC-3 异种移植小鼠模型中。总之，DSAs 由于制剂中存在天然化合物作为多西他赛的基质/粘合剂，因此表现出这些先进的特性。总之，DSAs 表现出优越的肿瘤靶向性和改善的细胞内化作用，从而提高了多西他赛的疗效。这些发现可能对前列腺癌治疗具有重要意义。
