Mechanical Drugs: Harnessing Cancer Aggressiveness to Overcome Its Resistance

机械药物：利用癌症的攻击性来克服其耐药性

• 批准号: 10012760
• 负责人: Surya Nauli
• 金额: $ 50.96万
• 依托单位: MASIMO CORPORATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012760
• 关键词: Address; Antibodies; Biological; Breast Cancer Cell; Cancer Patient; Caring; Cells; Clinical; Coupled; Cytoplasm; Diagnostic; Dose; Drug resistance; Eligibility Determination; Endosomes; Ensure; Event; Explosion; External Beam Radiation Therapy; Failure; Generations; Goals; Gold; Gold Colloid; Head and Neck Squamous Cell Carcinoma; In Vitro; Lasers; Liposomes; Liquid substance; Malignant Neoplasms; Mechanics; Medicine; Modality; Modeling; Nature; Normal Cell; Oncology; Operative Surgical Procedures; Organ; Palliative Care; Patients; Pharmaceutical Preparations; Physiologic pulse; Physiological; Process; Property; Protocols documentation; Quality of life; Radiation; Radiation therapy; Radiosensitization; Research; Resected; Residual state; Resistance; Safety; Science; Source; Specificity; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Studies; Tissues; Toxic effect; Treatment Efficacy; Unresectable; aggressive therapy; anticancer research; anticancer treatment; base; cancer cell; cancer therapy; chemoradiation; chemotherapy; clinical application; comparative efficacy; evaporation; improved; in vivo; innovation; malignant breast neoplasm; mouse model; nanobubble; novel; novel therapeutics; plasmonics; public health relevance; receptor mediated endocytosis; response; standard care; stem; synergism; triple-negative invasive breast carcinoma; tumor; vapor

 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.

 描述（由适用提供）：无法完全安全地通过手术切除治疗和侵略性肿瘤，并且经常出现所需的化学和放射性治疗，这会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自我调节的细胞水平癌症治疗。这将通过需求的物理细胞内非固定事件来实现，其有效性在癌症侵袭性的细胞中是自我扩增，并且通过其隐形和癌细胞特异性的性质确保其安全性。此类事件是等离子体纳米泡（PNB） - 围绕细胞内等离子体（金）菌落的细胞内激光脉冲触发的细胞内爆炸，该爆炸液在细胞内（金）菌落群周围保持安全和被动直至被激活。细胞内PNB创建了机械非平稳阈值激活的效应，该作用通过仅使用低剂量的临床批准的组件，通过简单方案来检测和破坏癌细胞，并有效地将手术，化学和放射性治疗转化为细胞水平模态。这种物理方法在癌症中的创新性质在于将机械事件与生物学机制合并，以将当前的宏米医师转化为癌细胞特异性的按需细胞内治疗。三种PNB效应的细胞内协同作用 - 机械性细胞内冲击，内部脂质体的细胞内药物射血以及外部辐射的扩增 - 从根本上放大剂与标准基于材料的治疗相比，治疗效率与基于标准的材料的治疗相比，这种治疗性放大因素而随着金聚类的大小而增加，这是由癌症侵蚀性驱动的。该提案将探讨以下假设：PNB的机械影响将克服癌症的耐药性，并将标准手术以及化学和放射性变化转化为细胞水平的按需模态，其效率将通过癌细胞细胞的侵袭性自我扩张。这种方法将以侵略性三阴性乳腺癌（TNBC）为模型进行研究。该项目将分析癌细胞对体外抗细胞内机械影响的生物学反应以及耐药性和侵袭性肿瘤对体内非平稳机械影响的物理反应，从而从根本上扩大了标准处理的效率而不会增加其剂量和非特异性毒性。结果，将开发基于PNB的自我调节的基于PNB的机制（“机械药物”）来治疗侵袭性和抗性肿瘤，并将估算现有护理标准内PNB机制的最佳临床应用。该项目将带来一些好处。在科学中，多函数细胞内PNB将在新型热机制中融合物理和生物学方法。在肿瘤学中，PNB将在后者失败时支持标准临床方式的细胞内扩增，将通过向目前仅被称为姑息治疗的患者提供安全，新的治疗方法来扩大患者的可用性 有效使用目前认为效率低下的标准识别药物。