近-短波红外成像引导纳米载体用于癌症光动力治疗

Despite advances in therapeutic interventions, clinical response rates in cancer therapy has not dramatically improved in the last few decades. Photodynamic therapy (PDT) is one of the methods being established for management of cancer, possessing advantages of localized, highly specific treatment without long-term systemic effects, lesser morbidity and faster recovery. PDT is based on administration of the non-toxic photosensitizer (PS) into the organism, followed by selective PS accumulation in tumor tissue. Upon irradiation of tumor with light at wavelength of PS absorption and in the presence of molecular oxygen, its reactive forms are generated, eradicating tumor cells. Besides of important advantages, the PDT has several drawbacks, such as superficial action due to limited tissue penetration of visible light, poor water solubility of most PSs and degradation of PS upon light irradiation. Optical “tissue transparency window” in the near-infrared (NIR) range allows for deeper light penetration, improving PDT efficiency. In addition to the conventional NIR window (NIR-I, ~700-950 nm), other windows have recently been identified at ~1000-1350nm and ~1550-1800 nm (NIR-II/III or short-wave infrared, SWIR), which benefit imaging due to the.reduced tissue scattering and autofluorescence. Porphyrin-based PS activated in NIR-I (~800 nm) have been recently reported; due to their limited water solubility, they have to be formulated and administered using surfactants, which are toxic at certain concentrations. Tumor-avid PS can be also decorated with imaging contrast agents for tracking PS delivery to cancer site, tumor imaging and imaging guided PDT. With introduction of NIR photoluminescence (PL) imaging agents, an intriguing “see and treat” approach could be offered via combination of photodiagnosis (PD) or PL guided resection with PDT treatment. However, synthetic conjugation of PL imaging agents (IA) with PS changes the pharmacokinetics/pharmacodynamics of PS, making them less tumor specific and efficient. There is also a significant difference between the imaging of dose for IA and therapeutic dose for PS, which hinders use of both modalities with a PS-IA conjugate. Application of nanotechnology is known to address many current pitfalls in cancer therapy by bringing together multiple diagnostic and therapeutic modalities for more efficient cancer treatment. Theranostics nanoparticles (NP), controllably loaded with PDT and PL IA, protect load from degradation and deliver the following benefits: (i) IA and PS can be incorporated to NPs at any desired ratio and dose, providing “see and treat” approach, (ii) NPs can be conjugated with cancer targeting biomolecules, (iii) a nanoparticle can be engineered to increase imaging contrast, and (iv) polymer-based nanoparticles can be formulated to be biocompatible., with minimal toxicity. Use of IA with high absorptivity in NIR range (e.g., organic dyes) suggests that dye-loaded NP can serve as powerful contrast agents not only for PL imaging, but also for photoacoustic imaging (PAI), where image contrast is determined by optical absorption and the NIR range is known to greatly enhance the imaging depth of PAI. .Furthermore, NP can be formulated to boost the PA and PL responses. The objective of this proposal is to develop polymeric nanoparticles loaded with PS and (PL/PA) IA and actively targeting cancer. NIR organic dyes and rare-earth ion doped nanocrystals, which absorb in NIR-I and emit in SWIR, will be employed as IA incorporated into the polyacrylamide-based NPs, specifically engineered to increase PL/PA signals from the incorporated IA. The nanoformulation would enable (i) highly efficient PA/PL bioimaging in NIR-SWIR range; (ii) targeted tumor.imaging, (iii) efficient, image monitored delivery of PS to tumor through active targeting, followed by image-guided PDT.

光动力疗法（PDT）是一种重要的癌症治疗方法，具有特异性高、副作用小和术后易恢复等优点。但由于PDT一般采用短波长可见光，在组织中穿透深度小，只能治疗表层肿瘤；大部分光敏剂水溶性差，遇光照容易降解；另外目前还缺乏有效的PDT量效监控方法，从而限制了PDT的研究和临床应用。本项目构建包载光敏剂、光致发光、光声成像对比剂的肿瘤靶向聚合物纳米颗粒，其在近红外区(700-950nm)具有吸收峰，在短波红外区(1000-1700nm)具有发射峰。通过特殊结构设计，增强光致发光和光声信号，使其在近红外到短波红外区能进行高效光声和光致发光生物成像，能对肿瘤组织进行靶向成像，有效地向肿瘤组织递送光敏剂，并进行实时监控和成像引导光动力治疗。本项目将发展一种基于纳米技术的新型PDT诊疗一体化平台，解决PDT在治疗深度、光敏剂易降解以及量效关系监控方面的问题，对于肿瘤的治疗具有重要的研究意义和和应用前景。

该项目的主要目标是研发集近红外-短波光致发光(NIR-SWIR PL)和光声成像(PA)为一体的多模成像纳米制剂，使其能够将光敏剂(PS)靶向递送到肿瘤部位，并实现有效的癌症光动力治疗(PDT)。在该项目的实施过程中，创新性的构建了核壳和核多壳稀土纳米颗粒，使我们能够实现包括计算机断层扫描(CT)、近红外二区光致发光和磁共振成像(MRI)结合的多模成像。所研发的稀土纳米颗粒具有很高的近红外二区光致发光效率和CT成像对比度。此外，我们选择了聚苯乙烯(PolySt)核/PNIPAM壳PNPs作为平台来实现NIR-SWIR PL/PA引导的PDT。开发了由共聚物NIPAM和丙烯酰胺(NIPAM-co-AA)组成的具有聚St核(~30nm)和不同厚度壳的聚合物纳米颗粒(PNPs)壳厚度显示为随温度变化（当温度达到40℃时，核/壳直径的相应变化为约220nm至约140nm），并且可以包载分子药物、光敏剂或医学成像剂等各种小分子。此外，包载有在NIR-SWIR光谱范围内发射荧光的有机染料的PNP可靶向肿瘤，从而实现对肿瘤区域的成像并同时进行有效的PDT。同时，我们还开发了包载有含碘CT造影剂和PS或NIR荧光染料的纳米脂质体、蛋白质（过氧化氢酶和血红蛋白）纳米晶体和多种类型的多模成像生物相容性纳米载体系统，并对其进行了肿瘤靶向和成像引导的PDT研究。纳米脂质体和蛋白质纳米晶体作为成像和治疗剂的纳米载体极具潜力，可用于高效的肿瘤靶向和成像引导的肿瘤特异性PDT，并可与其他类型的癌症治疗方法相结合增强治疗效果。我们相信，我们所研发的纳米脂质体、蛋白质纳米晶体和聚St-聚（NIPAM-co-AA）核壳PNP作为纳米平台具有巨大的应用前景，可将多种成像和治疗试剂结合起来，具有潜在的临床应用价值，为实现基于多模式成像的癌症早期诊断和高效、成像引导的肿瘤靶向药物递送奠定基础。