Mechanical Drugs: Harnessing Cancer Aggressiveness to Overcome Its Resistance

 描述（由申请人提供）：治疗抗性和侵袭性肿瘤，不能完全和安全地手术切除，尽管化疗和放疗，复发，导致癌症患者的生存率和生活质量最低。这种过度的肿瘤学问题将通过新的物理方法来解决，以创造自我调节的细胞水平癌症治疗。这将通过按需物理细胞内非稳态事件来实现，其功效在具有癌症侵袭性的细胞中自我放大，并且其安全性通过其隐形性和癌细胞特异性来确保。这种事件是等离子体纳米气泡（PNB）-一种细胞内爆炸，由细胞内等离子体（金）胶体簇周围的短激光脉冲触发，这些胶体在激活之前保持安全和被动。细胞内PNB产生机械非稳态阈值激活效应，检测和破坏癌细胞，并通过使用低剂量的仅临床批准的组分的简单方案将手术，化疗和放疗有效地转化为细胞水平的模式。这种物理方法在癌症中的创新性质是将机械事件与生物机制相结合，以将当前的宏观医学转化为癌细胞特异性的按需细胞内治疗。与基于标准材料的治疗相比，三种PNB效应的细胞内协同作用-机械细胞内冲击、细胞内药物从内化脂质体排出和外部辐射的放大-从根本上放大了治疗功效，并且这种治疗放大随着由癌症侵袭性驱动的金簇大小而增加。该提案将探索PNB的机械影响将克服癌症抗性并将标准手术和化疗和放疗转化为细胞水平的按需模式的假设，其功效将通过癌细胞侵袭性自我放大。这种方法将在侵袭性三阴性乳腺癌（TNBC）中作为模型进行研究。该项目将分析癌细胞对体外非稳态细胞内机械冲击的生物学反应以及抗性和侵袭性肿瘤对体内非稳态机械冲击的生理反应，以在不增加其剂量和非特异性毒性的情况下从根本上增强标准治疗的功效。因此，将开发基于PNB的自我调节细胞内治疗机制（“机械药物”）以治疗侵袭性和抗性肿瘤，并将在现有护理标准内估计PNB机制的最佳临床应用。该项目将带来几个好处。在科学上，多功能细胞内PNB将在新的治疗机制中融合物理和生物方法。在肿瘤学中，PNB将在标准临床模式失败时支持标准临床模式的细胞内扩增，将通过为目前仅接受姑息治疗的患者提供安全的新治疗来扩大患者资格，并将提供新的治疗方案。 有效使用目前被认为效率低下的标准未被认可的药物。

 DESCRIPTION (provided by applicant): Treatment-resistant and aggressive tumors that cannot be fully and safely resected with surgery, and recur despite chemo- and radio-therapies, cause the lowest survival rate and quality of life among cancer patients. This over-arching oncology problem will be addressed with novel physical approaches to create self-regulated cell level cancer treatment. This will be realized through on-demand physical intracellular non-stationary events whose efficacy is self-amplified in cells with cancer aggressiveness, and whose safety is ensured by their stealth and cancer cell-specific nature. Such event is plasmonic nanobubble (PNB) - an intracellular explosion triggered with a short laser pulse around an intracellular cluster of plasmonic (gold) colloids that remain safe and passive until activated. Intracellular PNB creates the mechanical non-stationary threshold-activated effects that detect and destroy cancer cells and efficiently convert surgery, chemo- and radio-therapies into the cell level modality through a simple protocol by using low doses of only clinically-approved components. The innovative nature of this physical approach in cancer is in merging the mechanical event with the biological mechanisms to transform current macro-medicine into a cancer cell-specific on-demand intracellular treatment. The intracellular synergy of three PNB effects - mechanical intracellular impact, intracellular drug ejection from internalized liposomes and amplification of the external radiation - radically amplifies the therapeutic efficacy as compared to standard material-based treatments, and this therapeutic amplification increases with the gold cluster size which is driven by the cancer aggressiveness. This proposal will explore the hypothesis that that the mechanical impact of PNB will overcome cancer resistance and will convert standard surgery and chemo- and radio- therapies into a cell level on-demand modality whose efficacy will be self-amplified by cancer cell aggressiveness. This approach will be studied in aggressive triple-negative breast cancer (TNBC) as a model. The project will analyze the biological response of cancer cells to non-stationary intracellular mechanical impact in vitro and physiological response of resistant and aggressive tumor to non-stationary mechanical impact in vivo to radically amplify the efficacy of standard treatments without increasing their doses and non- specific toxicity. As a result, the self-regulated intracellular therapeutic PNB-based mechanisms ("mechanical drugs") will be developed to treat aggressive and resistant tumors, and will estimate optimal clinical applications of PNB mechanisms within existing standards of care. The project will bring several benefits. In science, the multifunctiona intracellular PNBs will merge the physical and biological approaches in novel therapeutic mechanisms. In oncology, PNBs will support the intracellular amplification of standard clinical modalities when the latter fail, will broaden the patient eligibility by offering a safe, new treatment to those patients who currently are referred only to palliative care and will offer a new efficient use of standard under-recognized drugs currently considered inefficient.