A NOVEL EXTRACELLULAR AND INTRACELLULAR TREATMENT PARADIGM FOR ERADICATING CANCER

描述(申请人提供)：治疗癌症已经取得了巨大的进步，但癌症的死亡率仍然高得令人无法接受。对分子靶向治疗的高度临床耐药性再次推动了人们对抑制癌症普遍生化特征的兴趣。最近的证据表明，恶性肿瘤使局部细胞外环境酸化，激活蛋白酶降解肿瘤基质，从而促进转移，并解释了为什么更具侵袭性的肿瘤更具酸性。目前的治疗方法只专注于利用低pH值来促进肿瘤中的药物释放，从而仍然依赖于细胞内抑制通路的传统范例，这种方法仍然有不同的结果。因此，这项建议的目标是通过开发一种协同的双功能纳米颗粒平台来更好地根除癌症，该平台既可以调节酸性细胞外环境(Phe)，又可以提供细胞内治疗药物。我们建议：(目的1)局部长期中和肿瘤Phe将抑制肿瘤生长。在酸性条件下，酸中和纳米粒子将通过共价连接到插入肿瘤质膜的多肽上，从而锚定到局部细胞外微环境。小鼠肿瘤模型的pH变化和治疗反应将通过荧光pH探针进行评估。(目的2)细胞内药物作用与肿瘤苯丙氨酸的纵向中和作用具有协同作用。阿霉素将与纳米颗粒标记的多肽锚定的内化片段相连。这种双重作用疗法将在体外和体内的肿瘤细胞治疗反应方面与传统的细胞内治疗进行比较。这项研究将开发一种新的平台，可以监测和修改关键的肿瘤细胞外环境，并保持细胞内协同给药的能力，因此，该平台将能够将当前癌症治疗的范式从单一的细胞内方法转变为双重(细胞外+细胞内)协同的肿瘤靶向方法。通过特别中和肿瘤细胞外微环境，建议的平台旨在防止肿瘤的进展和转移，并最大限度地减少传统的基于细胞内的耐药途径。由于细胞外低pH值在癌症中普遍存在，特别是在更恶性的肿瘤中，这一平台也将 适用范围广，对最具侵袭性的癌症特别有效。

DESCRIPTION (provided by applicant): Enormous progress has been made to treat cancer, and yet the mortality rate of cancer remains unacceptably high. High clinical resistance to molecularly targeted therapeutics has pushed interest again towards inhibiting universal biochemical hallmarks of cancer. Recent evidence suggests that malignant tumors acidify the local extracellular environment to activate proteases for degrading the tumor matrix, which facilitates metastasis, and explains why more aggressive tumors are more acidic. Current therapies have only focused on using the low pH for enhancing drug release in tumors, thereby still relying on the traditional paradigm of intracellular inhibition of pathways, a method that continues to have mixed results. Thus, the goal of this proposal is to better eradicate cancer by developing a synergistic bifunctional nanoparticle platform that can both modulate the acidic extracellular environment (pHe) and deliver intracellular therapeutics. We propose: (Aim 1) Local long term neutralization of tumor pHe will inhibit tumor growth. Acid-neutralizing nanoparticles will be anchored to the local extracellular microenvironment by being covalently attached to a polypeptide that inserts into tumor plasma membranes under acidic conditions. pH change and treatment response in murine tumor models will be assessed by fluorescent pH probes. (Aim 2) Intracellular drug action combined with longitudinal neutralization of pHe of tumors will be synergistic. Doxorubicin will be linked to the internalizing segment of the nanoparticle-labeled peptide anchor. This dual acting therapy will be compared to traditional intracellular treatment in terms of tumor cells in vitro and in vivo treatment response. This research will develop a novel platform that can be made to monitor and modify the critical tumor extracellular environment as well as retain the ability for synergistic intracellular drug delivery Thus, this platform will be able to shift the paradigm of current cancer therapy from a solely intracellular approach to a dual (extracellular + intracellular) synergistic method of targeting cancer. By specifically neutralizing the tumor extracellular microenvironment, the proposed platform aims to prevent tumor progression and metastasis as well as minimize the traditional intracellular based pathways of resistance. Because of the broad universal aspect of low extracellular pH in cancer, particularly in the more malignant tumors, this platform will have also wide applicability, with particular potency on the most aggressive of cancers.