Mechanical Drugs: Harnessing Cancer Aggressiveness to Overcome Its Resistance

 描述(申请人提供)：耐药和侵袭性肿瘤，不能通过手术完全和安全地切除，并在化疗和放射治疗后复发，导致癌症患者的存活率和生活质量最低。这一最重要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的癌症治疗。这将通过按需的物理细胞内非平稳事件来实现，这些事件的有效性在具有癌症侵袭性的细胞中自我放大，其安全性由其隐蔽性和癌细胞特异性确保。这样的事件就是等离子体纳米气泡(PNB)--一种由短激光脉冲围绕胞内等离子体(金)胶体簇触发的细胞内爆炸，在被激活之前保持安全和被动。细胞内PNB产生机械的非静态阈值激活效应，检测和摧毁癌细胞，并通过使用低剂量的仅经临床批准的成分，通过简单的方案有效地将手术、化疗和放射治疗转化为细胞水平的模式。这种癌症物理方法的创新本质是将机械事件与生物机制相结合，将当前的宏观药物转变为针对癌细胞的按需细胞内治疗。与标准的基于材料的治疗相比，三种PNB效应--机械细胞内撞击、细胞内药物从内化脂质体中喷射和外部辐射的放大--的细胞内协同作用从根本上放大了治疗效果，并且这种治疗放大作用随着癌症侵袭性驱动的金簇大小而增加。这项提议将探索这样一个假设，即PNB的机械冲击将克服癌症耐药性，并将标准手术、化疗和放射治疗转化为细胞水平的按需模式，其疗效将被癌细胞侵袭性自我放大。这一方法将在侵袭性三阴性乳腺癌(TNBC)中作为模型进行研究。该项目将在体外分析癌细胞对非平稳细胞内机械冲击的生物反应，以及体内耐药和侵袭性肿瘤对非平稳机械冲击的生理反应，以从根本上放大标准治疗的疗效，而不增加其剂量和非特异性毒性。因此，基于PNB的自我调节细胞内治疗性机制(“机械药物”)将被开发用于治疗侵袭性和耐药肿瘤，并将在现有的护理标准下评估PNB机制的最佳临床应用。该项目将带来几个好处。在科学上，多功能的细胞内PNBs将在新的治疗机制中融合物理和生物方法。在肿瘤学方面，当标准临床模式失败时，PNBs将支持后者的细胞内扩增，将通过为那些目前仅被转介到姑息治疗的患者提供安全的新疗法来扩大患者的资格，并将提供新的 有效使用目前被认为效率低下的标准药物。

 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.