协同靶向透明质酸纳米联合化疗药物复合物的制备与应用及其疗效的PET评估

Breast cancer is one of the most common malignant diseases in women. The tumor type with HER2 over-expression is characterizedwith rapid growing, high invasiveness, poor prognosis, high recurrence rate and early metastasis. A HER2 specific monoclonal antibody Trastuzumab (Herceptin) has been approved for breast cancer therapy. However, the application of Herceptin is limited by drug resistance, heart and pulmonary toxicity. Combination of Herceptin with chemotherapy can reduce the incidence of drug resistance and improve progression free survival and overall survival significantly. Unfortunately, the conventional combination chemotherapy is prone to increased toxicity and side effects, and thus developing of new chemotherapy combination system is in urgent need. Our preliminary study demonstrated that hyaluronic acid nanoparticle (HANP) loaded paclitaxel (PTX) is very promising for its good solubility, high stability, low immunogenicity and prolonged plasma half-life. Moreover, with active CD44 targeting and passive enhanced permeable retention (EPR), the delivery and accumulation of chemotherapeutic drugs in tumor cells was improved significantly and therefore reduced the systemic side effects. To further our previous work, here we propose to load tumor targeting HANP with traditional chemotherapy drug PTX, and then couple Herceptin with HANP/PTX covalently to form a multi-targeting nanocomposite for breast cancer therapy. The yielding nanocomplex is expected to implement the targeting complementary, reduce resistance and side effects, and achieve the "1+1>2" therapeutic efficacy. Consequently, the survival rate and quality of life of patients will be improved. To further evaluate and confirm the therapeutic effects, multiplexing PET/CT using 68Ga-DH6F, 18F-FRGD2 and 18F-FDG will be applied for monitoring the changes of HER2 expression, tumor angiogenesis, and glucose metabolism in tumors after drug treatments.Overall, our proposed project will be very helpful in developing new types of HA based tumor-targetedsynergistic nanomedicine for breast cancer treatment, as well as demonstrating the advantages of molecularimaging in assessing the efficacy for personalized cancer treatment.

乳腺癌是女性最常见的恶性肿瘤之一，其中HER2过表达型具有侵袭性高、发展快及预后差的特点。曲妥珠单抗（Herceptin）是已被批准应用临床的HER2特异性人源化抗体，但临床上仍面临着耐药及心、肺毒性等问题。而常规联合用药常会进一步增加其毒副作用和不良反应。协同靶向被证实可增强抗肿瘤药物疗效，同时降低两者毒副作用。结合前期工作基础，本课题组提出以肿瘤靶向透明质酸为基础，将Herceptin与透明质酸-紫杉醇纳米颗粒共价偶联，形成协同靶向纳米联合化疗药物，实现靶向互补，达到“1+1＞2”的治疗效果，降低耐药和毒副作用。同时利用靶向HER2特异性多肽合成的 68Ga-DH6F，辅以常规18F-FRGD2及18F-FDG分子探针，应用PET/CT技术多角度阐明纳米药物作用机制并监测疗效。本项目的实施，将有助于新型透明质酸纳米药物开发，并充分展示分子影像在评估新药疗效方面的优势。

乳腺癌是女性最常见的恶性肿瘤之一，其中HER2过表达型具有侵袭性高、发展快及预后差的特点。曲妥珠单抗（Herceptin）是已被批准应用临床的HER2特异性人源化抗体，但临床上仍面临着耐药及心、肺毒性等问题。而常规联合用药常会进一步增加其毒副作用和不良反应。协同靶向被证实可增强抗肿瘤药物疗效，同时降低两者毒副作用。因此，本课题组以肿瘤靶向透明质酸为基础，Herceptin与透明质酸-紫杉醇纳米颗粒（HINP/PTX）共价偶联，制备了协同靶向纳米联合化疗药物Her-HINP/PTX，实现靶向互补，并通过引入近红外二区荧光染料实现了纳米颗粒聚集程度的可视化。我们在细胞水平和小鼠模型中验证了Her-HINP/PTX具有增强的靶向肿瘤的特异性和药物递送能力，同时由于肿瘤部位存在透明质酸酶，因此Her-HINP/PTX可以在肿瘤部位实现酶响应后的荧光恢复，可及时显示肿瘤部位药物聚集情况，有利于早期预测疗效、及时调整治疗方案，实现个体化、最优化治疗。最后，我们通过裸鼠体内抗肿瘤疗效的研究，证实了该协同靶向纳米药物Her-HINP/PTX治疗可以更好地抑制肿瘤生长、延长存活期。同时，利用靶向HER2特异性多肽合成了 99mTc-HYNIC-H10F，并证明了其可特异且准确地监测肿瘤HER2表达状况，为接受HER2靶向治疗的乳腺癌患者提供早期、精确的疗效监测手段，以利于及时、准确地调整治疗方案，为最终实现精细化、个体化临床治疗提供了有力支持。.综上，本研究设计构建了协同靶向透明质酸纳米化疗药物Her-HINP/PTX，进一步增加了化疗药物的肿瘤递送效果，减少毒副作用，改善抗肿瘤治疗效果，具有潜在的临床应用价值。本项目的实施为新型透明质酸纳米药物及新型靶向分子探针的开发及临床转化提供了有力的基础研究依据，并充分展示分子影像在评估药物疗效方面的优势。

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