A NOVEL EXTRACELLULAR AND INTRACELLULAR TREATMENT PARADIGM FOR ERADICATING CANCER

描述（由申请人提供）：治疗癌症已经取得了巨大的进展，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临床抗性再次推动了对抑制癌症的普遍生物化学标志的兴趣。最近的证据表明，恶性肿瘤酸化局部细胞外环境，以激活蛋白酶降解肿瘤基质，这有利于转移，并解释了为什么更具侵略性的肿瘤更酸性。目前的疗法仅集中于使用低pH来增强肿瘤中的药物释放，从而仍然依赖于细胞内抑制途径的传统范例，这种方法继续具有混合的结果。因此，该提案的目标是通过开发协同双功能纳米颗粒平台来更好地根除癌症，该平台可以调节酸性细胞外环境（pHe）并递送细胞内治疗剂。我们提出：（目的1）局部长期中和肿瘤pHe，抑制肿瘤生长。酸中和纳米颗粒将通过共价连接到在酸性条件下插入肿瘤质膜的多肽而锚定到局部细胞外微环境。将通过荧光pH探针评估鼠肿瘤模型中的pH变化和治疗反应。(Aim（2）细胞内药物作用与纵向中和肿瘤的pH值有协同作用。多柔比星将与纳米颗粒标记的肽锚的内化片段连接。这种双重作用疗法将在肿瘤细胞体外和体内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，可以用来监测和改变关键的肿瘤细胞外环境，并保留协同细胞内药物递送的能力。因此，这个平台将能够将目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）协同靶向癌症的方法。通过特异性中和肿瘤细胞外微环境，所提出的平台旨在防止肿瘤进展和转移，并最大限度地减少传统的基于细胞内的耐药途径。由于在癌症中，特别是在更恶性的肿瘤中，低细胞外pH的广泛的普遍方面，该平台还将具有 广泛的适用性，对最具侵袭性的癌症具有特别的效力。

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.