预约演示
更新于：2025-12-12
Doxorubicin Hydrochloride liposomal(Imunon)
盐酸多柔比星脂质体(Imunon)
更新于：2025-12-12
概要
基本信息
原研机构 |
在研机构- |
最高研发阶段终止临床3期 |
首次获批日期- |
最高研发阶段(中国)终止 |
特殊审评- |
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17
项与 盐酸多柔比星脂质体(Imunon) 相关的临床试验NCT04791228
A Pilot Study of Lyso-thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox®) and Magnetic Resonance-Guided High Intensity Focused Ultrasound (MR-HIFU) for Treatment of Relapsed or Refractory Solid Tumors
This is a pilot study of LTLD with MR-HIFU hyperthermia followed by ablation in subjects with refractory/relapsed solid tumors.
开始日期2022-11-10 |
NCT04852367
PanDox: Feasibility of Enhanced Chemotherapy Delivery to Non-resectable Primary Pancreatic Tumours Using Thermosensitive Liposomal Doxorubicin (ThermoDox®) and Focused Ultrasound
This study will combine focused ultrasound to generate heat, and a heat-sensitive chemotherapy drug (ThermoDox®), delivered into the blood of participants with non-resectable pancreatic cancer. We will compare this to standard delivery of chemotherapy - the drug Doxorubicin given into the blood without the addition of ultrasound. We aim to determine whether the novel approach to delivering chemotherapy with heating the tumour by focused ultrasound can enhance the amount of drug delivered to pancreatic tumours. This will be measured by analysing a biopsy sample of treated tumour.
开始日期2021-06-16 |
申办/合作机构  University of Oxford [+1] |
NCT03749850
Image-guided Targeted Doxorubicin Delivery With Hyperthermia to Optimize Loco-regional Control in Breast Cancer. Phase I Feasibility Study of Hifu-Induced Hyperthermia, LTLD and Cyclophosphamide for Metastatic Breast Cancer
In this phase I feasibility study, the investigators evaluate the combination of lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox) with local hyperthermia and cyclophosphamide (C), for the local treatment of the primary breast tumour in patients with metastatic breast cancer.
When heated to 40-43 degrees Celsius (ºC), LTLD releases a very high concentration of doxorubicin locally within seconds. Hyperthermia of the primary tumour will be induced by Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU) on a dedicated Sonalleve MR-HIFU breast system.
The investigators hypothesize that by substituting doxorubicin (A) in the AC-chemotherapy regimen for the combination of LTLD and MR-HIFU induced hyperthermia, optimal local tumour control can be achieved without compromising systemic toxicity or efficacy.
This will be the first study to evaluate LTLD with MR-HIFU hyperthermia in breast cancer patients.
When heated to 40-43 degrees Celsius (ºC), LTLD releases a very high concentration of doxorubicin locally within seconds. Hyperthermia of the primary tumour will be induced by Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU) on a dedicated Sonalleve MR-HIFU breast system.
The investigators hypothesize that by substituting doxorubicin (A) in the AC-chemotherapy regimen for the combination of LTLD and MR-HIFU induced hyperthermia, optimal local tumour control can be achieved without compromising systemic toxicity or efficacy.
This will be the first study to evaluate LTLD with MR-HIFU hyperthermia in breast cancer patients.
开始日期2021-03-01 |
申办/合作机构 |
100 项与 盐酸多柔比星脂质体(Imunon) 相关的临床结果
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100 项与 盐酸多柔比星脂质体(Imunon) 相关的转化医学
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100 项与 盐酸多柔比星脂质体(Imunon) 相关的专利（医药）
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25
项与 盐酸多柔比星脂质体(Imunon) 相关的文献（医药）2025-03-01·EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
Ultrasound-assisted efficient targeting of doxorubicin to the tumor microenvironment by lyso-thermosensitive liposomes of varying phase transition temperatures
Article
作者: Vahdat-Lasemi, Fatemeh ; Farhoudi, Leila ; Gheybi, Fatemeh ; Arabi, Leila ; Mirzavi, Farshad ; Hosseinikhah, Seyedeh Maryam ; Alavizadeh, Seyedeh Hoda ; Jaafari, Mahmoud Reza ; Sazgarnia, Ameneh
Premature drug release is the primary hindrance to the effective function of the lyso-thermosensitive liposomes (LTSLs) of doxorubicin (Dox), known as ThermoDox® for the treatment of cancer. Herein, we have optimized LTSLs by using a combination of phospholipids (PLs) with high transition temperatures (Tm) to improve the therapeutic outcome in an assisted ultrasound approach. For this, several Dox LTSLs were prepared using the remote loading method at varying molar ratios (0 to 90 %) of DPPC (Tm 41 °C) and HSPC (Tm 54.5 °C), as well as a constant molar ratio of MSPC (10 %), DSPE-mPEG2000 (4 %). The treatment efficacy was explored by using ultrasound as external hyperthermia (HT) (40-42℃) in mice bearing C26 murine colon carcinoma. All the formulations had an average diameter of around 110 nm, PDI ≤ 0.15, zeta potential of around -12 mV, and Dox encapsulation of >90 %. The cytotoxicity results indicated a higher IC50 value of Dox-LTSLs compared to the ThermoDox® (F0: DPPC:MSPC:DSPE-mPEG2000, 90:10:4), attributed to the faster Dox release in F0 formulation devoid of HSPC. Among various formulations, F25 (DPPC: MSPC: DSPE-mPEG2000: HSPC, 65:10:4:25) showed the highest cellular uptake at 42℃ and significantly improved the antitumor and survival efficacy in mice bearing C26 colon carcinoma in combination with ultrasonic HT compared to F0. Collectively, results demonstrated that optimizing the rigidity of the liposomal bilayers through the combinatorial selection of PLs of different transition temperatures could improve the plasma stability of the liposome, and hence ameliorate the outcome of therapy in assistance with an effective HT approach.
2023-10-01·Data in brief
Data demonstrating the in vivo anti-tumor efficacy of thermosensitive liposome formulations of a drug combination in pre-clinical models of breast cancer
Article
作者: Wang, Xuehan ; Allen, Christine ; Bannigan, Pauric ; Regenold, Maximilian ; Dunne, Michael
Thermosensitive liposomes in combination with localized mild hyperthermia can improve the delivery of drug to solid tumor sites. For this reason, thermosensitive liposome formulations of a range of chemotherapy drugs have been designed. Our group previously developed and characterized a thermosensitive liposome formulation of the heat shock protein 90 inhibitor alvespimycin as a companion therapeutic to a thermosensitive liposome formulation equivalent in composition to ThermoDox (i.e., ThermoDXR), with the goal of increasing the therapeutic index of doxorubicin as the combination was revealed to be highly synergistic in a panel of human breast cancer cell lines including MDA-MB-231 (Dunne et al., 2019). The data presented here further describes the effect of the doxorubicin (DXR) and alvespimycin (ALV) combination in vitro and in vivo. Specifically, the combination effect in mouse breast cancer 4T1 cells and the in vivo efficacy of this heat-activated chemotherapy combination in both immunocompromised (MDA-MB-231 tumor bearing female SCID mice) and immunocompetent (4T1 tumor bearing female BALB/c mice) models of breast cancer.
2022-02-01·Nanomedicine : nanotechnology, biology, and medicine2区 · 医学
Turning down the heat: The case for mild hyperthermia and thermosensitive liposomes
2区 · 医学
Article
作者: Allen, Christine ; Bannigan, Pauric ; Regenold, Maximilian ; Temple, Michael J ; Waspe, Adam ; Evans, James C
"A single disappointing study does not mean an end to the future of ThermoDox®", writes Michael Tardugno (CEO of Celsion Corporation), after announcing the termination of Celsion's second Phase III clinical trial. The OPTIMA trial, as it was known, evaluated their thermosensitive liposome (TSL) formulation of doxorubicin (ThermoDox®) in combination with radiofrequency ablation for the treatment of hepatocellular carcinoma (HCC). The purpose of this perspective is to review the case of ThermoDox and to address questions related to its clinical translation. Specifically, what has prevented the clinical translation of this once highly regarded breakthrough technology? Is this the end of TSLs? What can we learn from the challenges faced in the clinical development of this multi-modal therapy? As formulation scientists working in the field, we continue to believe that heat-triggered drug delivery platforms have tremendous potential as chemotherapy. Herein, we highlight potential limitations in the design of many of the Thermodox clinical trials, and we propose that despite these setbacks, TSLs have the potential to become an effective component of cancer therapy.
26
项与 盐酸多柔比星脂质体(Imunon) 相关的新闻（医药）2025-03-14
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孙会敏
二级研究员，中国食品药品检定研究院化学药品检定所所长、首席专家。兼任国家市场监督管理局标准物质技术评审专家；中国药品监督管理研究会药品辅料与包材监督管理研究专委会主任委员；国家药典委员会第十一、十二届药用辅料与药包材专委会委员；农业部第七、八届兽药评价委员会委员；农业农村部兽药评审中心专家；中国合格评定国家认可委员会实验室技术委员会药品专业委员会委员；美国药典委员会药用辅料专委会委员；中国食品药品检定研究院第八、九届学术委员会委员；中国食品药品检定研究院第八、九届国家药品标准物质委员会委员；国家药品监督管理局保健食品技术规范专门委员会委员；国家药品监督管理局药品审评中心专家；国家药品监督管理局药包材审评专家；全国工商联医药业商会专家指导委员会委员；中国颗粒学会生物颗粒专业委员会委员；全国包装标准技术委员会第三届玻璃容器分技术委员会副主任委员；中国医药质量管理协会理事会常务理事；Asian J Pharm Sci 编委；《药物分析杂志》《分析测试学报》《中国医药工业杂志》等编委。长期从事药品检定、进口药品的标准复核、药用辅料和药包材检验、药用辅料和药包材质量控制和安全性评价、药包材注册审评指导原则制定、标准物质质量研究等工作。承担国家药典委员会课题和国家重大科技专项课题几十项，发表学术论文 130 余篇，编写专著 9 部，获国家发明专利 10 项。
赵霞
主任药师，药物分析专业博士，硕士生导师，现任中国食品药品检定研究院药用辅料和包装材料检定所副所长（主持工作）兼包装材料室主任。兼任第十二届国家药典委员会药包材专委会委员，国家药品监督管理局药用辅料质量研究与评价重点实验室主任，中国药品监督管理研究会药品辅料与包材监督管理研究专委会副主任委员，药物制剂及辅料研究与评价重点实验室学术委员会委员，CNAS 药品专业委员会委员，国家药品监督管理局药品审评中心外聘专家，北京市科学技术奖评审专家。专注于药用辅料检验、药包材的质量研究。主要从事药包材的检验、标准制定、质量研究工作。多年开展玻璃类、塑料类、橡胶类及金属类药包材与药物的相容性研究以及药品包装系统的密封完整性的评价工作。承担国家级课题多项。组织完成 130 个国家药包材标准的首次制修订工作、国家药监局玻璃专项调研与验证工作。完成国家药典委员会标准提高课题 20 余项，为《中华人民共和国药典》2025 年药包材新标准体系构建与起草的核心专家。获中国药学发展奖食品药品质量检测技术杰出青年学者奖、中国石油和化学工业联合会科技进步二等奖。已累计发表学术论文 100 余篇，参与编写专著 7 部，获国家专利 7 项。
刺激响应性药物载体及其材料的研究进展 PPS
张雪妍 #，王珏 #，王晓锋，贺刘莹，王会娟，杨锐，赵霞 *，孙会敏 **
（国家药品监督管理局药用辅料质量研究与评价重点实验室，中国食品药品检定研究院，北京 100050）
[ 摘要 ] 刺激响应性药物载体因具有载药稳定性好、生物相容性好等特点而成为研究热点，通过各种内在或外在条件给予适当刺激，刺激响应性药物载体能达到药物靶点精准控制释放的目的。简介天然和人工合成的刺激响应性药物载体材料，内源性和外源性刺激响应性载体的作用机制及设计策略，刺激响应性药物载体及其材料的评价指标与技术，旨在为刺激响应性药物的研发、临床转化、评价监管提供参考。
随着医学的进步，传统给药系统在治疗疾病时的局限性日益突出。为了实现更好的靶向性及可控性，研究人员设计了刺激响应性药物递送系统（stimuli-responsive drug delivery systems）。刺激响应性药物递送系统是一种能够对体内外环境刺激如pH、温度、光、磁场等化学或物理信号以及酶等生化物质发生特定响应的药物递送系统。该类系统的研究始于 20 世纪后期，随着化学、材料学、生物学、医学等相关学科的发展研究不断深入，刺激信号种类日益增多，响应性材料的种类和功能不断增加，灵敏度也不断提高。目前刺激响应性药物递送系统可用于肿瘤治疗、炎症治疗、抗菌治疗 [1]、糖尿病管理 [2]、手术辅助等。
针对不同部位微环境的不同，已开发多种刺激响应性递送系统，与传统的递送系统相比，刺激响应性药物递送系统具有以下优势：1）靶向给药，响应特定的体内外刺激，实现药物在病灶部位的定向聚集和释放。2）定点定时定量释放，根据治疗需要，精确控制药物的释放速率和模式，提高药物的生物利用度和疗效。3）减少药物在非靶部位的释放，降低药物的全身毒性和副作用。4）改变药物的释放模式和靶向部位，减少耐药性的发生。2000 年美国食品药品监督管理局（Food and Drug Administration，FDA）批准了首款刺激响应性药物 Visudyne，用于光动力治疗的眼科疾病。2024 年 4 月，Lumisight也获得 FDA 批准，作为一种酶响应性光学成像剂，在乳房肿瘤切除术中作为辅助手段。
目前常见的刺激响应性药物载体主要包括：聚肽纳米材料、纳米纤维、纳米管、脂质体、聚合物胶束、嵌段共聚物 [3]、树枝状大分子 [4]、纳米水凝胶 [5]、金属有机框架 [6] 等。目前对刺激响应性载体材料的研究集中在人工合成材料和天然材料 [7]。人工合成材料包括聚丙烯酸树脂类、非离子表面活剂、聚酯类的高分子材料；天然材料包括壳聚糖、透明质酸、纤维素、明胶等。本文综述了天然和人工合成的刺激响应性药物载体材料响应性原理及应用实例，内源性和外源性刺激响应性载体作用机制、设计策略及部分进入临床和上市阶段的刺激响应性药物，刺激响应性药物载体及材料常用的评价指标与技术，旨在为未来刺激响应性药物的研发、临床转化、评价监管提供参考。
1
刺激响应性载体材料
刺激响应性药物递送载体的刺激响应性来源于材料的响应性。刺激响应性材料可分为人工合成材料和天然材料。除了满足传统辅料改善溶解度、提高生物利用度等作用，刺激响应性材料还能够主动与生物功能相互作用，感知身体内部或外部的生理状态，从而调节其构型及性能，达到靶向用药、降低副作用、个性化医疗等作用。
1.1 人工合成材料
人工合成的刺激响应性材料通常是通过化学合成方法制备的高分子材料。该种材料可通过化学合成精确调控其分子结构与性质，如相对分子质量、结构、官能团等，其性能可广泛调节，以满足多样化的应用需求。人工合成的刺激响应性材料常展现出卓越的化学稳定性和机械性能，长时间不降解，保持长期稳定性。部分用于合成刺激响应性载体的人工合成材料如表 1 所示。
1.1.1 聚丙烯酸衍生物 聚丙烯酸衍生物如聚丙烯 酸 [poly(acrylic acid)，PAA]、聚甲基丙烯酸
[poly(methacrylic acid)，PMAA]、聚丙烯酰胺[poly(acrylamide)，PAAM]、聚 N-异丙基丙烯酰胺[poly(N-isopropylacrylamide)，PNIPAAM] 等具有良好的生物相容性、稳定性、pH 和温度的敏感性。PAA 是由丙烯酸聚合而成，丙烯酸是由一个乙烯基直接连接到羧酸末端组成。丙烯酸中的羧基可通过氢键的形成和解离对 pH 变化做出响应，并通过静电相互作用携带正电荷的粒子。PAA 可进行羧基反应与其他功能团共轭，获得多功能的聚丙烯酸衍生物。弱酸性环境可质子化 PAA 或其衍生物的羧基和胺基，导致亲水部分收缩，溶酶体膜不稳定破裂，药物被释放到细胞质基质中，这被称为质子海绵效应 [25]。
杨龙花 [26] 通过原子转移自由基聚合技术，合 成 了 聚（ 甲 基 丙 烯 酸-N，N-二甲氨基乙酯）（PDMAEMA）， 再 与 苯 丙 氨 酰-赖 氨 酸（Phe-Lys）二肽结合，合成了两代线形-树枝状嵌段共聚物 PDMAEMA-b-dendr(Phe-Lys)n（n = 1, 2），PDMAEMA 中的叔胺基团 pKa 值约为 7。当 pH 值低于 pKa，PDMAEMA 的胺基被质子化，聚合物表现为亲水性，聚合物链之间的静电斥力增加，胶束结构变得疏松，从而加速药物的释放；而在 pH 值高于 pKa 时，胺基去质子化，聚合物表现为疏水性。这种性质使得 PDMAEMA 能够在不同的 pH 值下实现对药物的控制释放。
PNIPAAM 具有较低的低临界溶液温度（lower critical solution temperature，LCST），其在低温下高度水合并在水溶液中溶解良好，加热会导致其疏水性增加。聚 N-丙烯酰基甘氨酰胺具有上临界溶液温度（upper critical solution temperature，UCST），其在一定温度以下不溶，而在该温度以上则可溶。目前研究最多的热敏性 PAA 是具有 LCST 的聚合物即 PNIPAAM 的纳米颗粒。PNIPAAM 由疏水性的异丙基侧链 [-CH(CH3)2-] 和亲水性的酰胺基团（-CONH-）组成。当温度低于 LCST 时，PNIPAAM 中具有亲水性的酰胺基团与水分子之间形成氢键，从而展现出良好的水溶性；随着温度逐渐升高，PNIPAAM 由亲水性变为疏水性，其侧链会先发生坍塌，随后进一步聚集成球形结构。PNIPAAM 的 LCST 约 为 32 ℃， 低于人体正常体温 37℃，通过将其与亲水性聚合组分如 N，N-二甲基丙烯酰胺和丙烯酰胺 [27] 杂化，可将 PNIPAAM的 LCST 调节至更高的温度，以达到在体内运用的目的。
1.1.2 泊洛沙姆 泊洛沙姆又称普朗尼克，是一种聚（环氧乙烷）-聚（环氧丙烷）-聚（环氧乙烷）（PEO-PPO-PEO）三嵌段共聚物，由中心疏水聚（环氧丙烷）核心组成 , 两侧有亲水性聚（环氧乙烷）链。升温后，泊洛沙姆胶束内的疏水性聚环氧丙烷基团脱水发生溶胀，达到一定温度时，胶束之间开始互相接触并形成网络结构，最终形成凝胶，这一变化过程中最直接的表现是体系的黏度显著上升。泊洛沙姆家族中作为温敏凝胶材料最常用的是泊洛沙姆407（F127）和泊洛沙姆 188（F68），F127 相对分子质量为 9 840 ~ 14 600，其具有独特的反向热凝胶作用，低温时为液体，高温时为固体，在 17.5% ~ 30% 浓度范围内具有成胶性 , 且随浓度增大胶凝温度逐渐下降。F68 作为一种温度调节剂，2% ~ 10% 的 F68 加入到 F127 中可升高胶凝温度，F68 浓度越大，胶凝温度越高 [28]。Dang 等 [15] 设计了一种基于海藻酸钠和 F127 的温度响应性递送载体，用于甲氨蝶呤的按需释放。通过动态光散射测试，低温时F127 段膨胀，纳米粒子结构松弛；37℃下，F127段收缩，尺寸缩小了 36.71%，结构紧凑。体外释放研究发现，37℃下，甲氨蝶呤的释放速率会因 F127段的收缩而增加。泊罗沙姆的温敏性使其在温度刺激响应性载体中应用广泛。
1.1.3 聚酯类材料 可生物降解的聚乳酸（polylactic acid，PLA）、聚己内酯（polycaprolactone，PCL）、乳酸-羟基乙酸共聚物 [poly(lactic-co-glycolic acid)，PLGA] 等聚酯类材料，被广泛应用于刺激响应性载体的制备，可在聚酯类材料表面键合敏感基团，从而产生相应的响应性[21]。其中聚乙二醇（polyethylene glycol，PEG）可与聚丙交酯乙交酯形成 B-A-B 三嵌段共聚物 PLGA-PEG-PLG，溶于水后会形成一种具有核壳结构的球状胶束，除了键合其他敏感基团产生相应响应性，该共聚物自身有良好的温敏性。温度低于相转变温度时 , 疏水的 PLGA 内核和亲水性的 PEG 外壳自组装形成胶束呈现溶液状态；当温度上升至相转变温度时，PLGA 链之间的相互作用力增强并伴有 PEG 外壳脱水，胶束聚集增加，使聚合物溶液形成凝胶。聚合物发生溶胶-凝胶转变的温度可通过 PEG、PLGA 的比例来调控，当 PLGA-PEG-PLGA 共聚物中 PEG 与 PLGA 比值为 0.56 或更低以及该共聚物在溶质中浓度超过 15% 时，在37℃的环境下，该共聚物可实现温度响应型的溶胶-凝胶转变 [18]。
Ran 等 [19] 以 PLGA-PEG-PLGA 作为原始材料，负载黑磷纳米片自组装成水凝胶。通过动态光散射和流变学测试评估该水凝胶的温度响应性。该实验结果显示，在 25℃时，该水凝胶呈现溶液状态；当温度升至 37℃转变为凝胶状态，该水凝胶的储能模量、损耗模量及黏度均增加，这种转变归因于PLGA 嵌段的温度敏感性。基于上述特征，该水凝胶可设计应用于递送药物，在体内循环时其保持溶液状态，到达病变部位时，转变为凝胶状态，从而实现药物的可控释放。
1.2 天然材料
天然的刺激响应性材料主要来源于生物体内的天然高分子，如蛋白质、多糖和核酸等。与合成材料相比，天然材料及其衍生物因其具有生物降解性、生物相容性、天然丰度高等优势 [29] 而受到越来越多的关注，同时其有望解决传统给药过程中难以实现的水溶性靶向，实现更精确的靶向性、特异性分散和低毒性 [30-31]，为有效治疗各种疾病提供了新的选择。部分用于合成刺激响应性载体的天然材料如表2 所示。
1.2.1 多糖 壳聚糖（chitosan，CS）是天然甲壳素（从甲壳类动物中提取）脱乙酰化后的产物，是由 β-(1-4)糖苷键连接的葡萄糖胺和葡萄糖的 N-乙基酰胺基团组成的碱性多糖。在酸性条件下，壳聚糖的氨基被质子化，可通过静电相互作用、氢键和偶极相互作用与溶液中其他带负电的阴离子或聚阴离子发生溶胶-凝胶转化过程，具有优异的 pH 响应性 [45]。此外，壳聚糖可被溶菌酶和壳聚糖酶降解并转化为寡糖和单糖，促进药物在特定的目标区域释放，从而更好地发挥药效 [46]。Zhao 等 [47] 利用静电自组装将氧化石墨烯纳米颗粒与壳聚糖结合，并基于静电相互作用涂覆二甲基顺丁烯酸酐改性的壳聚糖，设计了一种电荷逆转的药物递送系统。该药物递送系统通过引入 pH 响应性、可切割的 2，3-二甲基马来酸酐，带负电荷的纳米复合材料处于肿瘤细胞外基质中可逆转为正电荷，从而提高了多柔比星被肿瘤细胞摄取内化的效率，可用于潜在的抗癌治疗。
海藻酸盐是从褐藻中提取的一种天然阴离子多糖，具有优异的生物降解性和生物相容性，其主链分子由 α-L- 乌糖酸和 β-D- 甘露糖醛酸通过 β-1，4-葡萄糖苷键连接而成。海藻酸盐含有大量的-COO-基团，在水溶液中可表现出聚阴离子行为，且具有黏附性，可作为治疗黏膜组织的药物载体 [48]。在酸性条件下 -COO- 可转化为 -COOH，电离度和亲水性降低，分子链收缩；当 pH 值升高时 -COOH基团持续解离，亲水性增加，分子链伸展，显示出明显的 pH 响应性。由于海藻酸盐中 -COO- 的分子间相互作用，可通过与阳离子的离子交联形成水凝胶，用于药物输送。Sarika 等 [49] 合成了一种阳离子明胶和海藻酸钠的 pH 响应性聚电解质复合纳米颗粒。酸性环境中，阳离子明胶的正电荷增加，增强了与海藻酸钠的静电相互作用，该复合物稳定性增加；中性或碱性环境中，羧基的质子化减少，阳离子明胶的正电荷减少，与海藻酸钠的静电相互作用减弱，该复合物的稳定性降低。该复合物用于姜黄素递送时，在 pH 7.4 时约 65% 的姜黄素释放，在pH 5.0 时 87% 的姜黄素释放，显示出较好的 pH 响应性。
透明质酸（hyaluronic acid，HA）是一种由 D-葡萄糖醛酸和 D-N-乙酰氨基葡萄糖交替单元组成的天然黏多糖，并通过 β-1，3 和 β-1，4 糖苷键连接。HA 广泛存在于脊椎动物的表皮和结缔组织中，是细胞外基质的主要成分，具有良好的生物相容性、生物降解性和非免疫原性。HA 可通过与细胞表面受体 CD44 的特异性结合来调节细胞运动、黏附、分化和聚集等生理功能，此外，与 CD44 的结合使HA 具有靶向肿瘤细胞的能力 [50]。在疾病部位（如肿瘤组织）高表达的透明质酸酶（HAase）可以降解HA以控制药物释放。Hu等 [51]以HAase为引发剂，将近红外激光敏感的一氧化氮供体引入 HA 纳米颗粒中，以多柔比星为化疗药，吲哚菁绿为光热剂制备纳米颗粒（IDDHN-Dox-ICG）。在近红外光照射下，该纳米颗粒借助 HAase 介导的酶降解一氧化氮供体壳和激光增强的一氧化氮释放触发的强热疗效应，实现了体内外协同的深穿透作用。
纤维素是地球上最丰富、最广泛且成本最低的天然多糖聚合物，由通过 β-1，4-葡萄糖苷键连接的葡萄糖单元组成，其生物相容性好、高模量、低密度、改性潜力大。羧甲基纤维素是一种水溶性的阴离子纤维素衍生物，其分子链中含有大量的羧基，可通过多价金属阳离子的交联形成凝胶 [52]。由于羧基的存在，该凝胶适合作为 pH 触发的药物载体。羟丙基纤维素是一种热响应性衍生物，在水溶液中表现出41℃的LCST，当处于接近LCST的水溶液中，随着相应的反应变化，其表现出明显的水合 - 脱水转变 [39]。
1.2.2 蛋白质 明胶是从动物胶原中提取的一种
常 用 的 生 物 聚 合 物， 具 有 由 18 种氨基酸交联而 成 直 链。明 胶 可 被 基 质 金 属 蛋 白 酶（matrix metalloproteinase，MMP）降解为低分子多肽，从而引起药物释放，可用于制备酶响应性药物载体 [43]。此外，氨基的质子化和去质子化引起的电荷变化以及羟基和羧基共同作用引起的亲水性变化，使明胶在肿瘤酸性环境中药物释放增强。Ruan 等 [42] 设计了一种 pH 和酶响应型纳米复合材料（G-AuNPs-DOX-PEG），由明胶纳米粒子涂层、结合多柔比星的金纳米粒子和长链聚乙二醇组成，肿瘤中高度表达的 MMP-2 可降解该明胶纳米粒子，其尺寸从186.5 nm减至59.3 nm，进而增强了多柔比星的释放。丝素蛋白（silk fibroin，SF）主要来源于蚕茧和蜘蛛丝，具有不溶性 β- 折叠晶体结构，含有通过二硫键共价结合的重链和轻链。SF 富含易于修饰的官能团，对官能团的修饰可调节自组装过程和实现药物有效负载与释放。作为一种天然蛋白质，SF 具有良好的生物相容性和生物降解性，引起的免疫反应和毒性反应极小 [53]。通过调整制备条件和加工方法对 SF 的结构和性质进行控制，以满足特定的药物输送要求。
2
刺激响应性载体
刺激响应性载体是指由刺激响应性材料构成的能够根据环境变化（如温度、pH、光照、磁场等）而发生特定物理或化学变化的载体。根据刺激类型，刺激响应性载体可分为内源刺激响应性载体和外源刺激响应性载体。
2.1 内源刺激响应性载体
内源刺激响应性载体会对体内的刺激如 pH、氧化还原、蛋白酶等产生响应，从而调节药物的释放。病变部位环境的改变会引起递送系统的化学或物理变化，从而实现有效载荷的释放。pH 响应性载体利用人体内不同区域间的显著pH 差异，实现药物的局部精准递送。人体正常生理环境 pH 为 7.4。感染、炎症和肿瘤的病理部位的pH 与正常组织不同，病变区域的微环境显示出低pH。口腔内 pH 为 6.6 ~ 7.1，胃内 pH 为 1.0 ~ 3.0，呈强酸性；小肠 pH 为 4.8~8.2，结肠 pH 为 7.0~7.5，接近中性；肿瘤细胞外环境的 pH 为 6.5 ~ 7.0，略低于正常组织；早期内体的 pH 为 6.0 ~ 6.5，次级内体的 pH 更低（4.5 ~ 5.0），随着内体的成熟，其酸性逐渐增强。当 pH 发生变化时，刺激响应性载体可通过膨胀、收缩、裂解、降解、质子化和去质子化官能团响应并释放药物。开发该类载体主要采用 2种策略，第 1 种是使用能够进行 pH 依赖性质子化的聚阳离子或聚阴离子。常用的阴离子 pH 响应单元有丙烯酸、甲基丙烯酸，阳离子 pH 响应单元有甲基丙烯酸二甲氨基乙酯、甲基丙烯酸二乙氨基乙酯、丙烯酰胺 [54]，已应用于各种类型的纳米材料，如脂质纳米颗粒、脂质体、两亲性聚合物纳米颗粒、纳米疫苗以及纳米凝胶。第2种策略是将pH响应性、可切割的酸敏感键结合到治疗载体材料中 [34]，主要应用于酸敏感聚合物、金属有机框架、杂化纳米颗粒和交联聚合物。
Du 等 [55] 开发了一种基于不对称的聚（乙二醇）- 聚（2，4，6-三甲氧基苯亚甲基 -1，1，1-三（羟甲基）乙烷甲基丙烯酸酯）-聚（丙烯酸）（PEG-PTTMA- PAA）三嵌段共聚物。该聚合物在 pH 7.4 时很稳定，但在酸性环境（pH 4.0~5.0）下，聚合物中的缩醛基团易发生快速水解，导致聚合物体膨胀并最终解体；同时丙烯酸部分在酸性环境下离子化状态发生变化，使得 PAA 从亲水性转变为疏水性，并从随机卷曲结构转变为 α- 螺旋结构，从而导致聚合物体的破坏，实现药物的释放。体外释放研究发现，盐酸多柔比星从该聚合物体中的释放过程高度依赖pH的变化，在 pH 7.4 时释放率较低，而在 pH 5.0 时释放率显著增加。
酶在许多生理和生物过程中均扮演至关重要的角色，在部分病变组织中酶的表达也会出现异常。肿瘤细胞中有多种酶的过表达，如基质金属蛋白酶、透明质酸酶、组织蛋白酶 B、吲哚胺 2，3-双加氧酶 1、成纤维细胞活化蛋白-α 和 γ-谷氨酰转肽酶 [56]。酶响应性载体通过酶的作用，可转变为解体结构，导致尺寸缩小，从而促进其渗透至病变和受损组织，有助于实现药物的精准释放，可应用于癌症诊断、预后评估及免疫治疗。设计酶响应性载体，最常见的策略是利用与免疫治疗药物相连的肽序列，在肿瘤部位由特定酶特异性切割，从而实现免疫治疗剂的精准释放。
骆飞翔 [57] 制备了一种 MMP-9 响应性纳米颗粒，其疏水性核用于递送他克莫司，亲水性外壳含有甲氧基聚乙二醇和 MMP-9 的底物多肽片段，当其暴露于移植肝脏内过表达的 MMP-9 酶时，MMP-9 酶会特异性切割 MMP-9 底物多肽片段，导致甲氧基聚乙二醇从纳米颗粒上脱落。该纳米颗粒从纳米级胶束转变为微米级聚集体，这种结构变化促进了他克莫司的释放，从而在移植肝脏内实现了药物的局部高浓度，减少了其他器官的药物分布，降低了系统性副作用。
谷胱甘肽（glutathione，GSH）是一种广泛存在于生物细胞内的重要物质，其在细胞内区室（细胞质、线粒体和细胞核）含量比细胞外液高 2~3 个数量级。肿瘤细胞通过异常的线粒体呼吸链和烟酰胺腺嘌呤二核苷酸磷酸氧化酶途径，产生比健康细胞高出 100倍的活性氧（reactive oxygen species，ROS），有助于肿瘤的发生和发展。ROS 在体内一般通过 GSH 进行调节，减少过量的 ROS 并维持组织的氧化还原状态。因此，肿瘤组织中的 GSH 浓度比健康组织高4 ~ 7 倍，有利于 GSH 在肿瘤细胞中特异性触发药物释放。设计氧化还原性载体常采用键合可还原键的策略，特别是二硒键（-Se-Se-）[58]、二硫键（-S-S-）[59-60]、硫代酰基键（-C=S-）[61]、半胱氨酸 - 丝氨酸 - 丝氨酸（CSS）键和硫酮键 [61]，用于连接和递送各种免疫治疗负载物，包括抗原、抗体、抑制剂、激动剂和 mRNA 疫苗。
Trastuzumab-DM1（T-DM1）[62] 是氧化还原响应性药物，已于 2013 年在美国、欧洲获得批准，用于治疗人表皮生长因子受体 2（human epidermal growth factor receptor 2，HER2）阳性转移性乳腺癌。2020 年 1 月 T-DM1 在中国获批，用于 HER2 阳性早期乳腺癌的辅助治疗。T-DM1 由抗 HER2 单克隆抗体曲妥珠单抗与微管抑制剂 DM1 通过稳定的硫醚键连接而成。在肿瘤细胞内，T-DM1 的抗体部分被溶酶体蛋白酶降解，释放出 DM1。T-DM1 在血液循环中保持稳定，其不可裂解的硫醚连接体结构有助于保持 DM1 的惰性状态，避免过早地释放 DM1，保证 DM1 在靶细胞内精准释放，从而减少了系统性毒性。
2.2 外源刺激响应性载体
外源刺激响应性载体是一类可在体外特定刺激下进行调控的载体。通过对外部刺激的持续时间和强度进行精确调控，可实现从时空维度对该类载体药物释放曲线的精确控制。目前针对该类载体的研究涉及热、光、超声、磁和电等多种刺激形式。
温度响应性载体是控制药物释放最方便、最有效的递送载体之一。炎症和肿瘤等病灶处的温度常高于正常组织 [63]，纳米颗粒可利用肿瘤组织与正常组织之间的温差，从而被激活以强化其在肿瘤中的药物释放能力。据此原理可开发温敏凝胶，低于其LCST 时，温敏凝胶呈现为溶胶状态 [64]；当温度升高至 LCST 或接近体温时，高分子链之间的相互作用增强，导致凝胶形成。此外，当肿瘤细胞所处的环境温度达到 42.5℃以上时，肿瘤细胞的生存率快速下降；正常细胞和组织可耐受较高的温度，因此高温可选择性地杀死肿瘤细胞而不会对正常组织造成过大损害。因此，采用温敏性递送载体，并施以外部温度刺激，高温可部分杀死肿瘤细胞，同时载体包裹药物可在肿瘤部位精准释放，以达到更好的疗效。对于温度的调控有多种加热策略，如超声波、近红外光和磁场。设计温度响应载体常用的温敏材料包括泊洛沙姆类、聚 N-异丙基丙烯酰胺 [65-66]、壳聚糖。温度响应性载体可用于鼻腔、眼部、阴部给药。
ThermoDox [67] 是一种新型抗癌药物，其温敏特性主要源于脂质体的组成成分产生。正常体温下，ThermoDox 的脂质体外壳稳定，药物不会释放；当通过射频消融技术、红外加热等方式将肝脏温度升高至 42℃并维持一段时间后，脂质体外壳的物理结构发生改变，形成多个微小开口，促使抗癌药物多柔比星快速释放，实现将高剂量药物直接输送至肝癌组织的目的并降低对正常组织的毒性影响。尽管ThermoDox在肝癌治疗方面已进行了Ⅲ期临床试验，但该药物并未成功上市。2021 年 2 月，Celsion 公司鉴于 ThermoDox 针对肝癌的Ⅲ期临床研究未取得预期效果，决定终止其临床研究进程。磁响应性载体在外部磁场作用下被引导并集中于身体特定区域，从而实现药物的靶点释放 [68]。磁性材料（包括超顺磁性纳米颗粒、磁铁矿、铁铂合金和钴铁合金）已被广泛研究，作为磁驱动靶向、磁激活远程药物输送和磁共振成像 [69] 的平台。靶向免疫治疗输送中最常见的磁响应材料是超顺磁性氧化铁纳米粒子，通常与聚合物、脂质或蛋白质递送系统相结合赋予其磁性。
NanoTherm [70] 是一种基于铁氧体纳米材料的磁响应性药物，于 2011 年在欧盟获得批准，临床上用于脑胶质瘤的局部颅内磁热治疗。NanoTherm 由悬浮于铁磁流体中的磁性纳米粒子组成，可直接注射至肿瘤组织内部。该磁性纳米粒子在交变磁场作用下被激活，持续产生热量，从而实现对肿瘤细胞的热损伤；也可与其他治疗方式相结合，以增强对脑胶质瘤的治疗效果。
光响应性载体由含有光敏感基团的材料制备而成。在特定波长光照下，光敏感基团吸收光子能量引发光化学反应，改变药物递送系统组成或构象，从而达到控制药物释放的目的。目前 , 根据光响应机制的不同 , 光敏感基团有 4 种：1）光致断裂型，如邻硝基苄基氧和香豆素基团，此类基团能够吸收光子的能量，促使特定共价键的断裂。2）光致异构型，如偶氮苯和螺吡喃，光照刺激使此类基团内部的双键进行顺反异构化反应或环闭合的反应。3）光致重排型，如 2-重氮-1，2-萘醌基团，其吸收特定光子能量能够进行 Wolff 重排反应。4）光致交联光型，如香豆素、肉桂酰和蒽，光照刺激下 , 香豆素或肉桂酰进行 [2 + 2] 环加成反应 , 蒽进行 [4 + 4] 的环加成反应形成二聚体。常用的近红外光可通过加热光热剂触发热敏感载体外的药物释放。近红外响应性的载体材料主要有纳米金 [71]、吲哚菁绿等。紫外 - 可见光响应性一般通过引入光活性基团来实现，如偶氮苯 [72]、肉桂酰、螺旋苯并吡喃或三苯基甲烷。此外，光敏生物材料主要包括抗体-siRNA 偶联物 [73] 和聚酰胺树状大分子 [74]（对紫外线光作出反应）以及聚合物纳米粒子和上转换纳米粒子 [75]（对近红外光作出反应），这些材料具备物理化学性质可调节的特点，表现出高度模块化的光敏化学性质。
Visudyne [76] 是用于治疗湿性年龄相关性黄斑变性的光响应性药物，通过静脉注射进入血液循环，并与脂蛋白结合，进而聚集于黄斑中央处的新生血管。在（689±3）nm 的非致热红光源照射下，Visudyne的卟啉基团在有氧环境下发生光化学反应，产生活性氧自由基，损伤局部新生血管内皮细胞，帮助血管闭合。Visudyne 疗效明确，对正常视网膜组织损伤小，且可重复治疗，目前已获得美国 FDA的批准，也已在日本上市。
Nanobiotix 公司开发的 NBTXR3 [77] 由氧化铪纳米粒子构成，是一种光响应性药物。在头颈部鳞状细胞癌治疗中 NBTXR3 具有显著疗效，客观缓解率高达 81.8%。目前该药在中国和美国均已进入Ⅲ期临床试验阶段。NBTXR3 是一种无机结晶的氧化铪纳米粒子水悬液，其原子序数高（Z = 72）、电子密度大，在无X射线时该纳米粒子呈惰性“关闭”状态，在其被 X 射线激活时则呈“开启”状态，并显著增强放射治疗的疗效。
AuroShell [78] 纳米粒子是用于前列腺癌的金-硅纳米壳疗法，目前已应用于临床试验。该纳米粒子通过静脉注射递送，并在肿瘤部位积累。利用近红外激光照射肿瘤，该纳米粒子吸收光能并转化为热能，从而破坏肿瘤组织及其供应血管。AuroShell 的光响应性来源于其金属壳在近红外区域具有强烈的消光系数，能够有效吸收光能并转化为热能。此外，还有超声波响应性载体和电响应性载体。超声波响应性载体能够接收并响应超声波信号，实现特定的功能，因而在医学成像和无损检测等领域得到广泛应用。电响应性载体能够感应电场变化，借助导电聚合物对于电脉冲的响应特性，实现药物在靶部位的按需释放 [79]。
2.3 刺激响应性载体小结
内源刺激响应性载体的优势体现在其能够借助体内固有的刺激因素调控药物的释放过程，从而实现对病变区域的精准靶向治疗。该方法减少了外部干预，降低了对机体的创伤性，更适用于个性化医疗策略的实施。然而，内源刺激响应性载体在体外精准控制其于体内的释药行为较为困难，且由于体内刺激因素并非全是疾病所特有，可能导致药物在非病灶部位的意外释放。此外，不同肿瘤类型、生理阶段及个体差异均会限制内源刺激响应性载体的临床应用。目前针对 pH 响应性和酶响应性药物递送载体研究较多，但难以精确控制病灶处的药物释放，可重复性差，进入到临床阶段的相关药物较少。
外源刺激响应性载体的显著优势是具有远程可控性。目前，上市的大多数刺激响应性药物均为外源性响应型。药物载体可通过外部信号如温度、光、磁、超声等触发药物释放，为疾病的精准治疗提供可能。外源刺激响应性载体的缺点在于实施外源性刺激的时空位置难以精确定位，需要引入指示定位功能的部件，使得载体设计更为复杂；同时，外源性刺激源的组织穿透深度也限制了其应用。
ThermoDox 曾作为一款极具潜力的温度响应性药物用于肿瘤治疗，在Ⅱ期临床试验中期其治疗效果表现良好。然而，Ⅲ期临床试验 ThermoDox 未能取得预期成功，主要原因在于射频消融技术对肿瘤的杀伤范围有限。在 ThermoDox 的Ⅲ期临床试验中，选取的肿瘤大小为 3 ~ 7 cm，需要采用多点叠加射频消融技术。然而，ThermoDox 在相变温度时释放速度最快，超过相变温度释放速度变慢；同时在轻微高温下长时间加热或在更高温度下短时间加热均会引发血管分流，进而导致转运至此区域的 ThermoDox 减少，阻碍药物输送。基于此，Regenold 等 [80] 提出关于 ThermoDox 在体内分布和释放的研究理论，用以解释其临床试验失败的原因。该研究将肿瘤分成了 3 个区域，最中间的区域是消融区，直接通过射频消融术杀死肿瘤细胞；最外层是轻度加热区域，在此温度环境下，ThermoDox 能够大量输送至该区域，药物释放快且完全，进而有效杀死外围的肿瘤细胞；中间区域的温度介于外层和消融区域之间，这一温度不足以杀死肿瘤细胞，且存在血管分流，致使此区域的 ThermoDox 输送减少，过高的温度也使药物释放量降低。该中间区域的存在导致了ThermoDox 的临床疗效不理想。因此，在外源刺激响应性载体设计时，需要综合考虑更全面的因素，例如肿瘤的大小、形状以及肿瘤内部的温度分布。同时，ThermoDox 的配方和释放机制也需改进，以便在更广的温度范围内能保持高效的药物释放，从而提高治疗效果。
3
刺激响应性载体及其材料的评价技术及指标
3.1 刺激响应性载体材料的评价
刺激响应性载体材料的评价，主要是针对其理化性质与表征的评价。只有确保所使用的材料的质量达到标准，才能制造出符合规定要求的药物递送载体。具体评价指标主要包括高分子链结构、聚集态结构、相对分子质量、溶解性与溶胀性、黏度、吸湿性、降解与老化机制等。
高分子链结构研究材料的基本组成并预测其可能的反应性，核磁共振 [81]、红外光谱 [82] 等技术可用于分析高分子链的结构和化学组成。聚集态结构是研究材料内部的微观排列方式及分子间的相互作用，对于了解材料的物理化学性质和优化材料性能具有重要意义。X 射线衍射和差示扫描量热法（differential scanning calorimetry，DSC）[83] 可用来研究高分子材料的晶体结构。
相对分子质量及其分布的测定对于评估材料的加工性能和最终产品的稳定性至关重要，即使相同种类不同相对分子质量的聚合物也展现出不同的物理化学特性，所以对于材料的相对分子质量及其分布须做出明确规定。凝胶渗透色谱是测定材料相对分子质量及其分布的主要技术 [84]。
溶解性与溶胀性的研究是指通过将材料置于不同溶剂中，观察其溶解或溶胀行为来评估溶解性和溶胀性，有助于确定材料在不同溶剂中的行为。黏度的测量可以反映材料在加工过程中的流动特性，流变学测试可用来测量材料的黏度和流动特性，包括剪切应力与剪切速度的关系 [85]。吸湿性分析对于预测材料在储存和使用过程中的稳定性具有重要意义，通过热重分析可测定材料中水分的含量，从而评估吸湿性 [86]。
降解与老化机制的研究有助于了解材料在体内或环境中的长期稳定性 [87]，热重分析和 DSC 法可用来研究材料的热稳定性和降解机制。
3.2 刺激响应性载体的评价
作为纳米递送系统的一种，刺激响应性载体的评估方法和指标与大多数纳米载体基本一致，主要围绕物理化学特性、药物包封率和载药量及药物体外释放 3 个维度的评价指标及评价方法（见表 3）。
分子大小及其分布的控制对于刺激响应性载体至关重要。NanoTherm [70] 纳米颗粒由氧化铁核和氨基硅烷涂层构成。这些纳米颗粒悬浮于水中，形成胶态分散体。纳米颗粒的结构与稳定性受其尺寸与形态的影响。不同的合成技术可能导致尺寸相近而磁性各异的纳米颗粒。最小化尺寸分布范围对于精确控制关键特性至关重要，这直接决定了治疗效果的一致性。
针对特定刺激响应性载体，须对其特殊性能指标进行评估。大多数温度响应性载体是基于 LCST设计的，故评价其 LCST 对于温度响应性载体尤为重要。光谱法是最常用的一种 LCST 的测定方法，通过测量溶液在不同温度下的吸光度或透光率变化来确定 LCST，具体将为溶液透光率降至一半时的温度定义为 LCST。此外，透射电子显微镜可通过观察在不同温度下聚合物溶液的形态变化确定LCST；DSC 法通过在 LCST 附近检测 DSC 曲线上的吸热峰或放热峰确定 LCST；温度扫描测试法则通过测定载体黏度变化确定 LCST。Zong 等 [94]分别采用光谱法和 DSC 法测定 LCST。采用光谱法时，将水凝胶样品置于不同温度（24 ~ 42℃）下浸泡 5 min，以模拟体温变化对其透明度的影响。该研究结果显示，随着温度的升高，水凝胶的透光率下降，表明水凝胶从亲水状态转变为疏水状态，发生了相变；在 15 ~ 60℃的温度范围内进行 DSC 分析，最终确定了纤维素纳米纤维-聚 N-异丙基丙烯酰胺（CNF-PNIPAM）水凝胶的 LCST 为 39.78℃，高于纯 PNIPAM 水凝胶的 LCST（约 32℃）。
基 于 光 热 效 应 设 计 的 光 响 应 性 载 体， 如AuroShell 纳米粒，其功能和性能的验证需通过光热效应检测来实现。光热效应是指载体在吸收光能后，通过非辐射跃迁将光能转化为热能的过程。通过测量载体在特定波长下，温度随着光照强度及光照时间的变化，采用热成像相机监测样品表面温度，以记录样品温度的动态变化，评估其热转换效率 [97]。药物体外释放度指药物在特定条件下从制剂中释放的速度和程度，是纳米药物质量控制的关键指标之一。通常情况下，刺激响应性药物载体在装载药物后，会通过体外释放实验以评估其对特定刺激的响应性。体外释放的主要测定方法包括取样分离法、透析法、流通池法等 [98]。若刺激响应性药物载体在药物释放前后的粒径、形态或其他性质有明显变化，也可通过对药物释放前后的载体进行粒径、形态或其他性质进行分析，辅助证明载体对特定刺激的响应性释放。
4
结语与展望
虽然刺激响应性药物载体和材料在医药研究中具有重要的应用前景，国内对这一领域的研究投入和关注也较高，但目前的研究多处于理论研究阶段，导致其在药物开发和应用方面存在一定的滞后性。此外，一些刺激响应性药物载体在动物模型实验中表现出较好的靶向效果，能够精准地将药物递送至病变部位，但在进入临床试验阶段时，却常常出现脱靶效应，从而影响治疗效果。从基础研究到临床应用的转化过程中，载体的设计和功能还需进一步优化。同时，大分子物质的代谢物在研究中往往未得到足够重视，可能导致对药物安全性评估的不全面，进而影响药物的临床应用。因此，加强对大分子物质代谢物的研究，确保药物的安全性和有效性，是当前该类药物研究中亟待解决的问题。
国内外关于刺激响应性药物载体及其材料的评价指标研究相对较少，尚未形成完善的评价体系，这在一定程度上限制了相关药物的市场准入速度。目前关于刺激响应性药物载体的结构性能表征及体外释放性能的研究逐渐趋于成熟，但在细胞摄取和毒性评估、体内分布和稳定性测试等方面的评价指标研究相对较少。为确保上述药物载体在临床应用中的有效性和安全性，进一步深入研究其在细胞水平和整体生物体中的行为和稳定性至关重要。
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美编排版：史鑫宇
感谢您阅读《药学进展》微信平台原创好文，也欢迎各位读者转载、引用。本文选自《药学进展》2025年第 2 期。
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一致性评价高管变更
2023-08-10
Advances Non-Viral DNA-Mediated Immunotherapy and Next-Generation Vaccine Programs with Multiple Near-Term Milestones Supported by a Strong Balance Sheet
Conference Call Begins Today at 11:00 a.m. EDT
LAWRENCEVILLE, N.J., Aug. 10, 2023 (GLOBE NEWSWIRE) -- IMUNON, Inc. (NASDAQ: IMNN), a clinical-stage drug-development company focused on developing non-viral DNA-mediated immuno-oncology therapies and next-generation vaccines, today announced financial results for the three and six months ended June 30, 2023. The Company also provided an update on its clinical development programs with IMNN-001 (formerly GEN-1), a DNA-based interleukin-12 (IL-12) immunotherapy in Phase 2 clinical development for the treatment of advanced-stage ovarian cancer, and on its PlaCCine modality, a proprietary mono- or multi-cistronic non-viral and synthetic DNA technology for the expression of pathogen antigens, being evaluated in preclinical studies for the development of next-generation vaccines.
Highlights of the second quarter of 2023 and recent weeks include:
On track to submit an Investigational New Drug (IND) application in the first quarter of 2024 for a proposed Phase 1/2 program with a seasonal COVID-19 booster vaccine, following positive pre-IND feedback from the U.S. Food and Drug Administration (FDA)
Reported data suggesting PlaCCine vaccines elicit robust and more durable T-cell responses than commercial mRNA vaccines, signaling that these vaccines may provide greater protection against reinfection, hospitalization or death
Unveiled new current Good Manufacturing Practices (cGMP) clinical materials production facility to support R&D efficiencies and lower costs for infectious disease and cancer vaccines, and non-viral DNA-based immune-oncology therapies
Reported cash and cash equivalents of $24.1 million as of June 30, 2023, which along with planned sales of State of New Jersey net operating losses (NOLs) is expected to fund operations through 2024
“We have now successfully de-risked our PlaCCine modality preclinically across many pathogens of interest by demonstrating in animal models the immunogenicity and safety of our vaccines. We have generated compelling data in SARS-CoV-2 and with IMNN-101, a next-generation COVID-19 seasonal booster, and expect to be in the clinic in first quarter of 2024. In addition, we have generated excellent immunological responses for vaccines against other pathogens of concern including monkeypox, flu and arenaviruses. Our DNA vaccines are well positioned to become the next generation of vaccines and I am excited about their potential with the demonstration preclinically of durability of IgG antibody response, without a booster dose, and higher T-cell activation than mRNA vaccines. Another significant advantage over commercial mRNA vaccines is the demonstration of more than 12 months stability at standard refrigerated temperature of 4°C,” said Dr. Corinne Le Goff, IMUNON’s President and Chief Executive Officer.
“Based on positive FDA feedback in July from a pre-IND meeting for our seasonal COVID-19 booster vaccine, we are on track to submit an IND application in the first quarter of 2024. The FDA confirmed in a written response that our plug-and-play strategy for our platform approach was acceptable. This confirms the flexibility and versatility of our platform, which allows for the rapid production and development of any vaccine simply by changing the antigen coding cassette. In addition, we expect to announce our next pathogen target for our PlaCCine modality in the coming weeks.”
Dr. Le Goff continued, “In June we unveiled our new pilot manufacturing capability for DNA plasmids and nanoparticle delivery systems. Our scientists are now able to select any protein from the human or pathogen proteomes to be engineered. Our existing labs also have the ability to conduct testing and to run experiments in a variety of animal disease models. These internal capabilities will allow us to control both the costs and the process. The objective of our vaccine program is to establish the platform’s safety and efficacy in various Phase 1 studies, and then seek to license this powerful technology and/or establish non-dilutive partnerships to develop vaccines for pathogens of interest,” she added.
“We expect to reach several value-creating milestones over the next six to 18 months. Among them is reporting additional interim data on IMNN-001 from our OVATION 2 Study and the combination study with bevacizumab in advanced ovarian cancer, reporting topline data from the OVATION 2 Study, filing the IND for our SARS-CoV-2 vaccine and announcing proof-of-concept vaccine data for our next pathogen target. We intend to discuss all of this and more during a virtual R&D Day event we are planning for this fall,” Dr. Le Goff concluded.
RECENT DEVELOPMENTS
PlaCCine: Developing the Prophylactic Vaccines of the Future
Publication of Preclinical Data with PlaCCine DNA-based Vaccines Modality Available Online on bioRxiv. In August 2023 the Company announced that a manuscript titled “Strong immunogenicity & protection in mice with PlaCCine: A COVID-19 DNA vaccine formulated with a functional polymer” is available on the preprint server bioRxiv [here]. The study used IMUNON’s proprietary formulation against the spike proteins from two SARS-CoV-2 variants, both alone and in combination. These results add to the growing body of preclinical data confirming the efficacy and superior desirable features of IMUNON’s PlaCCine vaccine modality. Data from the study show:
IMUNON’s proprietary formulation of functionalized polymer protected DNA from degradation, while the combination with an adjuvant led to an increase in protein expression
DNA formulated with PlaCCine resulted in a DNA vaccine product that was stable for up to one year at 4°C
DNA formulated in PlaCCine resulted in the induction of spike-specific neutralizing antibodies and cytotoxic T cells
In the in vivo challenge model, the vaccine-induced immune response was capable of suppressing viral replication
Multiple inserts can be cloned into the PlaCCine backbone (a plug-and-play strategy), therefore allowing for an immune response with broader protection
Presentation at the 2023 Viruses and Cells – Gordon Research Conference Describes Compelling Preclinical Data ShowingContinued Durability of Response Over14 Months with Humoral Immune Response Increasing Over Time. In May 2023 Khursheed Anwer, Ph.D., IMUNON’s Executive Vice President and Chief Science Officer, presented new PlaCCine preclinical data at the 2023 Viruses and Cells – Gordon Research Conference in Barcelona. Dr. Khursheed’s presentation, titled “A Novel DNA Vaccine Approach to Prophylactic and Therapeutic Vaccines,” described IMUNON’S PlaCCine technology platform for the development of next-generation vaccines, and is available here.
Results from preclinical studies in a PlaCCine COVID-19 vaccine demonstrated characteristics that address the limitations of current commercial vaccines by offering enhanced breadth of protection to emerging variants, persistence and robust cellular immunity, as well as stability at workable temperatures. Importantly, humoral immune responses specific to the SARS-CoV-2 spike antigen were persistent over a 14-month post-vaccination period in mice, while the T-cell responses from PlaCCine COVID-19 vaccines after 14 months were higher than a commercial mRNA vaccine. In another mouse study, the humoral response to a single dose of a commercial mRNA vaccine plateaued within 14 days after vaccination while the response continued to increase over time with a PlaCCine vaccine, demonstrating improved durability. In addition, PlaCCine was stable for at least nine months at refrigerated temperatures and for at least one month at room temperature.
Presentation at the Vaccine Technology Summit 2023Describes Compelling Preclinical Data Supporting Continued Development of PlaCCine as a Differentiated, Next-Generation Vaccine. In March 2023 Dr. Anwer presented data on the Company’s PlaCCine platform at the Vaccine Technology Summit 2023 in Boston. Dr. Anwer’s presentation is titled “A Novel DNA Vaccine Platform with Potential to Create Next Generation Vaccines” and is available here.
Dr. Anwer reviewed the Company’s work in advancing its PlaCCine modality and the promising preclinical data generated to date. Among topics presented was the ability of this multi-valent technology to achieve broad-spectrum immunity from a single DNA plasmid with a synthetic delivery system that is independent of virus, device or liquid nanoparticle formulations. The data presented showed:
Robust immunogenicity and protection in SARS-CoV-2 models
Durable cellular or humoral responses detectable for more than 12 months
Comparable protection activity to a commercial mRNA vaccine in a booster-dose comparison
Superior immune quality versus the mRNA vaccine in a single-dose comparison
In addition, the PlaCCine modality had important advantages for a commercial vaccine, including a shelf-life at 4⁰C for greater than nine months, and the ability for simple, rapid and scalable manufacturing.
IMNN-001 Immunotherapy
Presentation at the American Association for Cancer Research (AACR)Describes Findings from Mouse Model of Peritoneally Disseminated Ovarian Cancer that Suggest Biweekly Dosing Regimen for Further Evaluation in Human Clinical Studies. In April 2023 Jean Boyer, Ph.D., IMUNON’s Vice President of Preclinical Research, presented a poster titled “Efficacy of IMNN-001, an Interleukin-12 Immune Gene Therapy, at Different Dose Frequencies” at the AACR in Orlando, which is available here.
Researchers concluded that IMNN-001 demonstrated stimulation of the immune response in the ID8 ovarian tumor model. Of the three dosing regimens tested, the once every 2-week regimen demonstrated comparability to the weekly regimen while showing superiority over the once every 3-week regimen, particularly with respect to mortality and tumor burden. These findings suggest exploring once every 2-week dosing of IMNN-001 in human studies, which is already incorporated into the protocol of a new study evaluating IMNN-001 in combination with bevacizumab in the treatment of advanced ovarian cancer. This study is sponsored by the Break Through Cancer Foundation.
Corporate Developments
IMUNON Unveils New Manufacturing Facilityat Huntsville’s HudsonAlpha Biotech Campus. In June 2023, the Company unveiled its new cGMP clinical materials production facility on the Huntsville, Alabama campus of the HudsonAlpha Institute for Biotechnology. The facility is intended to support R&D efficiencies and lower development costs for infectious disease and cancer vaccines, and non-viral DNA-based immune-oncology therapies. This new capability complements the Company’s existing cGMP quality control facility for testing clinical products at the Huntsville site.
IMUNON has designed and built its own manufacturing capabilities to produce GMP-grade plasmid DNA (pDNA) and DNA-facilitating agents to support Phase 1 clinical studies with its PlaCCine infectious disease modality and its IndiPlas and FixPlas cancer vaccine modalities. The new facility’s specifications follow the 2008 FDA guidance cGMP for Phase 1 investigational drugs. The pDNA and DNA facilitating agents are key components of the final vaccine formulation, with GMP fill and finish carried out at a CDMO partner site.
IMUNON’s CEO Presents Business Overview at BIO 2023 International Convention and Mass General Brigham World Medical Innovation Forum 2023. Dr. Le Goff provided an overview of IMUNON’s business progress to an audience of investors and biopharmaceutical professionals at the BIO 2023 International Convention and at the Mass General Brigham World Medical Innovation Forum 2023, both in Boston. She highlighted the strength of IMUNON’s leadership team, and the status of the Company’s TheraPlas nucleic acid therapeutics platform and its PlaCCine nucleic acid vaccine platform while providing context on the promise of DNA as a therapeutic and a vaccine. For the PlaCCine and TheraPlas technologies, Dr. Le Goff described mechanisms of action and provided a closer look at the promising clinical results generated to-date. She provided background on the use of DNA in these medicines, characterizing its performance in terms of durability, development speed and ease of manufacturing, shipping and storage. Dr. Le Goff also highlighted the potential of IMNN-001 for the treatment of ovarian cancer during a panel discussion. Dr. Le Goff’s presentation is available here.
SECOND QUARTER FINANCIAL RESULTS
IMUNON reported a net loss for the second quarter of 2023 of $5.6 million, or $0.61 per share, compared with a net loss of $6.0 million, or $0.87 per share, for the second quarter of 2022. Operating expenses were $5.5 million for the second quarter of 2023, a decrease of $0.6 million, or 10%, from $6.1 million for the second quarter of 2022.
Net cash used for operating activities was $6.8 million for the second quarter of 2023 compared with $5.4 million for the comparable prior-year period. The increase was primarily due to the cash settlement in April 2023 along with related legal fees for arbitration with a former contract manufacturer for ThermoDox. Cash used by financing activities of $6.2 million during the second quarter of 2023 resulted from the early repayment of the Company’s loan facility with Silicon Valley Bank, offset by equity sales under the Company’s At-the-Market Equity Facility. The Company had $24.1 million in cash, investments and accrued interest receivable as of June 30, 2023. Combined with $1.8 million in planned future sales of IMUNON’s State of New Jersey NOLs, the Company believes it has sufficient capital resources to fund its operations through 2024.
Research and development (R&D) expenses were $3.1 million for the second quarter of 2023 compared with $3.2 million for the comparable period in 2022. R&D costs to support the OVATION 2 Study as well as the Phase 3 OPTIMA Study decreased to $0.3 million for the second quarter of 2023 compared with $0.8 million for the same period of 2022. Other clinical and regulatory costs were $0.4 million for the second quarter of 2023 compared with $0.7 million for the second quarter of 2022. R&D costs associated with the preclinical development of the PlaCCine DNA vaccine modality increased to $1.3 million for the second quarter of 2023 compared with $0.6 million for the same period of 2022. R&D costs associated with the preclinical development of IMNN-001 decreased to $0.4 million for the second quarter of 2023 compared with $0.8 million for the same period of 2022. Chemistry, manufacturing and controls (CMC) costs increased to $0.7 million for the second quarter of 2023 compared with $0.3 million for the second quarter of 2022 due to higher costs related to the development of in-house pilot manufacturing capabilities for DNA plasmids and nanoparticle delivery systems.
General and administrative expenses were $2.3 million for the second quarter of 2023 compared with $2.9 million for the comparable prior-year period. The decrease was primarily due to lower non-cash stock-compensation expense and lower professional fees, including legal fees to defend various lawsuits filed after the announcement in July 2020 of the Phase 3 OPTIMA Study results, offset by higher compensation expenses related to the CEO succession plan announced in July 2022 and higher staffing costs.
Other non-operating expenses were $85 thousand for the second quarter of 2023 compared with $65 thousand for the prior-year period. The Company incurred early debt extinguishment expense on its loan facility with Silicon Valley Bank totalling $0.3 million, offset by higher investment income from the Company’s short-term investments due to higher returns on these investments.
FIRST HALFFINANCIAL RESULTS
For the six months ended June 30, 2023, the Company reported a net loss of $11.2 million, or $1.28 per share, compared with a net loss of $16.5 million, or $2.59 per share, for the same period of 2022. Operating expenses were $11.2 million for the first six months of 2023, a decrease of $0.9 million, or 8%, from $12.1 million for the same period of 2022.
Net cash used for operating activities was $10.8 million for the first six months of 2023 compared with $13.4 million for the same period in 2022. The decrease was primarily due to the one-time payment of $4.5 million in interest expense resulting from the sale and subsequent redemption of $30 million of Series A & B convertible redeemable preferred stock in the first quarter of 2022. The Company’s projected cash utilization for the balance of 2023 is approximately $4.5 million per quarter. Cash used by financing activities of $3.7 million during the first six months of 2023 resulted from the early repayment of the Company’s loan facility with Silicon Valley Bank ($6.4 million), offset by sales of equity under the Company’s At-the-Market Equity Facility ($2.7 million). The Company also received net proceeds of $1.6 million from the sale of its unused New Jersey NOLs in the first quarter of 2023.
R&D expenses were $5.8 million for the first six months of 2023 compared with $6.3 million for the comparable period in 2022. R&D costs to support the OVATION 2 Study as well as the Phase 3 OPTIMA Study decreased to $0.6 million for the first six months of 2023 compared with $1.3 million for the comparable 2022 period. Other clinical and regulatory costs were $0.7 million for the first six months of 2023 compared with $1.5 million for the same period of 2022. R&D costs associated with the preclinical development of the PlaCCine DNA vaccine modality increased to $2.3 million for the first six months of 2023 compared with $1.2 million for the same period of 2022. R&D costs associated with the preclinical development of IMNN-001 decreased to $0.8 million for the first half of 2023 compared with $1.7 million for the same period of 2022. CMC costs increased to $1.4 million for the first six months of 2023 compared with $0.6 million for the comparable 2022 period due to higher costs related to the development of in-house pilot manufacturing capabilities for DNA plasmids and nanoparticle delivery systems.
General and administrative expenses were $5.4 million for the first six months of 2023 compared with $5.7 million for the same period of 2022. The $0.3 million decrease was primarily attributable to lower non-cash stock-compensation expense, offset by higher compensation expenses related to the CEO succession plan announced in July 2022 and higher staffing costs.
Other non-operating income was $9 thousand for the first six months of 2023 compared with $4.7 million for the comparable prior-year period. The decrease was primarily attributable to the one-time payment of $4.5 million in interest expense resulting from the sale and subsequent redemption of $30 million of Series A & B convertible redeemable preferred stock in the first quarter of 2022.
VIRTUAL R&D DAY EVENT
IMUNON management along with several guest key opinion leaders plan to host a virtual R&D Day event this fall to discuss the Company’s progress in developing its PlaCCine platform, IMNN-001, and other achievements. Presenters will also review strategic plans and opportunities for IMUNON. Additional information including date, time of day and instructions to participate will be announced in a separate news release.
CONFERENCE CALL AND WEBCAST
The Company is hosting a conference call to provide a business update, discuss second quarter 2023 financial results and answer questions at 11:00 a.m. EDT today. To participate in the call, please dial 866-777-2509 (Toll-Free/North America) or 412-317-5413 (International/Toll) and ask for the IMUNON Second Quarter 2023 Earnings Call. A live webcast of the call will be available here.
The call will be archived for replay until August 24, 2023. The replay can be accessed at 877-344-7529 (U.S. Toll-Free), 855-669-9658 (Canada Toll-Free) or 412-317-0088 (International Toll), using the replay access code 1202020. A webcast of the call will be available here for 90 days.
About IMUNON
IMUNON is a fully integrated, clinical stage biotechnology company focused on advancing a portfolio of innovative treatments that harness the body’s natural mechanisms to generate safe, effective, and durable responses across a broad array of human diseases, constituting a differentiating approach from conventional therapies. IMUNON is developing its non-viral DNA technology across 4 modalities. The first modality, Theraplas®, is developed for the coding of proteins and cytokines in the treatment of solid tumors where an immunological approach is deemed promising. The second modality, PlaCCine® is developed for the coding of viral antigens that can elicit a strong immunological response. This technology may represent a promising platform for the development of vaccines in infectious diseases. The third modality, Fixplas®, concerns the application of our DNA technology to produce universal cancer vaccines also called tumor associated antigen cancer vaccines. Finally, the fourth modality, which is still in the discovery phase, Indiplas®, will focus on the development of personalized cancer vaccines, or neoepitope cancer vaccines.
The Company’s lead clinical program, IMNN-001, is a DNA-based immunotherapy for the localized treatment of advanced ovarian cancer currently in Phase 2 development. IMNN-001 works by instructing the body to produce safe and durable levels of powerful cancer fighting molecules, such as interleukin-12 and interferon gamma, at the tumor site. Additionally, the Company is conducting IND enabling preclinical studies for the development of a COVID-19 booster vaccine: IMNN-101. The Company has also initiated preclinical studies to develop a Trp2 tumor associated antigen cancer vaccine in melanoma: IMNN-201. We will continue to leverage these modalities and to advance the technological frontier of plasmid DNA to better serve patients with difficult-to-treat conditions. For more information on IMUNON, visit .
Forward-Looking Statements
IMUNON wishes to inform readers that forward-looking statements in this news release are made pursuant to the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. Readers are cautioned that such forward-looking statements involve risks and uncertainties including, without limitation, unforeseen changes in the course of research and development activities and in clinical trials; the uncertainties of and difficulties in analyzing interim clinical data; the significant expense, time and risk of failure of conducting clinical trials; the need for IMUNON to evaluate its future development plans; possible acquisitions or licenses of other technologies, assets or businesses; possible actions by customers, suppliers, competitors or regulatory authorities; and other risks detailed from time to time in IMUNON’s periodic reports and prospectuses filed with the Securities and Exchange Commission. IMUNON assumes no obligation to update or supplement forward-looking statements that become untrue because of subsequent events, new information or otherwise.
Contacts:
IMUNON
LHA Investor Relations
Jeffrey W. Church
Kim Sutton Golodetz
Executive Vice President, CFO
212-838-3777
609-482-2455
Kgolodetz@lhai.com
jchurch@imunon.com
(Tables to Follow)
IMUNON, Inc.
Condensed Statements of Operations
(in thousands except per share amounts)
Three Months Ended
June 30,
Six Months Ended
June 30,
2023
2022
2023
2022
Licensing revenue
$
-
$
125
$
-
$
250
Operating expenses:
Research and development
3,134
3,226
5,754
6,322
General and administrative
2,340
2,877
5,405
5,748
Total operating expenses
5,474
6,103
11,159
12,070
Loss from operations
(5,474
)
(5,978
)
($
11,159
)
(11,820
)
Other income (expense):
Investment income
281
40
535
52
Interest expense
(37
)
(105
)
(197
)
(4,751
)
Loss on debt extinguishment
(329
)
-
(329
)
-
Other income
-
-
-
2
Total other (expense) income, net
(85
)
(65
)
9
(4,697
)
Net loss
$
(5,559
)
$
(6,043
)
$
(11,150
)
$
(16,517
)
Net loss per common share
Basic and diluted
$
(0.61
)
$
(0.87
)
$
(1.28
)
$
(2.59
)
Weighted average shares outstanding
Basic and diluted
9,137
6,982
8,711
6,373
IMUNON, Inc.
Selected Balance Sheet Information
(in thousands)
June 30,
2023
December 31,
2022
ASSETS
Current assets
Cash and cash equivalents
$
6,611
$
11,493
Investment securities and interest receivable
17,480
21,384
Money market investments, restricted cash
-
1,500
Advances, deposits and other current assets
2,640
2,778
Total current assets
26,731
37,155
Property and equipment
651
548
Other assets
Restricted cash invested in money market account
-
4,500
Deferred tax asset
-
1,567
Operating lease right-of-use assets, deposits, and other assets
1,339
206
Total other assets
1,339
6,273
Total assets
$
28,721
$
43,976
LIABILITIES AND STOCKHOLDERS’ EQUITY
Current liabilities
Accounts payable and accrued liabilities
$
5,846
$
8,381
Note payable – current portion
-
1,425
Operating lease liabilities – current portion
278
231
Total current liabilities
6,124
10,037
Notes payable – noncurrent portion
-
4,611
Operating lease liabilities – noncurrent portion
1,082
-
Total liabilities
7,206
14,648
Stockholders’ equity
Common stock
92
74
Additional paid-in capital
401,164
397,980
Accumulated other comprehensive gain (loss)
162
27
Accumulated deficit
(379,818
)
(368,668
)
21,600
29,413
Less: Treasury stock
(85
)
(85
)
Total stockholders’ equity
21,515
29,328
Total liabilities and stockholders’ equity
$
28,721
$
43,976
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疫苗临床2期财报免疫疗法临床结果
2023-06-24
引言：过去三十年纳米技术的进步给癌症治疗带来了新的希望。FDA批准的第一个纳米药物（多喜）于1995年上市。从那时起，人们合成了许多纳米载体，并对其抗肿瘤效果进行了广泛的评估，以将其确立为主要的治疗工具。尽管纳米医学是现代医学时代最有希望的突破之一，但从实验室放大到临床过程中，仍面临着一些挑战。在这篇综述中，我们描述和比较了各种类型的纳米粒子及其在促进癌症治疗中的作用。此外，我们重点介绍了目前可用于癌症治疗的各种纳米药物和正在进行临床试验的纳米制剂。摘要癌症是全球最常见的疾病之一，也是美国的第二大死因。尽管几十年来人们不断努力了解肿瘤的机制和各种治疗方法，但在癌症治疗方面未观察到显著改善。化疗药物缺乏肿瘤特异性、剂量相关毒性、生物利用度低以及缺乏稳定性是肿瘤治疗的主要障碍。纳米药物因其具有肿瘤特异性递送潜力，同时最大限度减少副作用而吸引了许多研究人员的注意。这些纳米粒子的应用不仅限于治疗用途；其中一些已经显示出极有希望的诊断潜力。在这篇综述中，我们描述和比较了各种类型的纳米粒子及其在促进癌症治疗中的作用。我们进一步强调了目前被批准用于癌症治疗的各种纳米制剂以及处于不同临床试验阶段的纳米制剂。最后，对纳米药物在肿瘤治疗中的应用前景进行了展望。1.介绍癌症是导致死亡的第二大原因，占死亡人数的六分之一。2020年，全世界约有1930万新发癌症病例（不包括非黑色素瘤皮肤癌1810万）和1000多万癌症死亡病例（不包括非黑色素瘤皮肤癌990万）;70%在低收入和中等收入国家[1]。癌症的预后不良主要是由于缺乏早期诊断工具和缺乏有效的治疗。目前的癌症诊断和治疗模式包括对有限数量的癌症类型进行标准化筛查，然后进行手术、放疗和化疗等治疗[2]。除了这些传统的治疗方法外，免疫治疗、激素治疗、基因治疗和干细胞治疗近年来也得到了广泛的研究。在所有这些可用的策略中，化疗仍然是最有效和最经济的选择，特别是对于晚期癌症。尽管近年来生物学和临床方面有了长足的进步，提高了癌症患者的治疗效果，但大多数化疗药物都有严重副作用，可能影响治疗的持续性，并对患者的生活质量产生负面影响[3]。化疗药物主要通过抑制有丝分裂的不同阶段起作用，使其快速靶向分裂的癌细胞。由于传统的化疗药物缺乏足够的癌细胞特异性，必须提供高剂量才能达到治疗水平，导致各种剂量依赖的副作用，因为其他快速分裂的健康细胞也受到影响。化疗药物的一些显著副作用包括神经病变、恶心、全身不适、骨髓抑制、脱发、肾毒性和心脏毒性。此外，大多数化疗药物水溶性较差，导致处方难度较大和药代动力学特征不好，生物利用度差[4]。另一个重要的问题是癌细胞经常对化疗产生耐药性。纳米技术已被证明在一定程度上绕过了传统化疗的许多限制，并成为改善整体癌症治疗结果的宝贵工具。通常，药物分子被溶解、吸附、包埋、包裹或附着在纳米材料上。由于它们的纳米尺寸（通常小于500nm）和大的表面积体积比，纳米载体可以改善包载药物的基本性质和生物活性[5]。此外，纳米颗粒可以提高水溶性较差的药物的生物利用度，同时提高包载药物的肿瘤选择性蓄积。最重要的是，纳米制剂促进了化疗药物优先在肿瘤中蓄积，提高了治疗效果，同时减少了全身毒性。Matsumura和 Maeda于1986年首次观察到[6]，纳米载体用于癌症治疗主要依赖于渗透性增强和滞留（EPR）效应。EPR效应依赖于实体瘤的血管渗透性较高和淋巴流出较少，以实现被动靶向和纳米颗粒在肿瘤部位的长期滞留（图1A）。因此，纳米药物显著改善了肿瘤治疗效果，同时将化疗药物的剂量依赖毒性降至最低。多年来，EPR效应已经成为基于纳米载体的癌症治疗的支柱，并使几种纳米药物获得批准[7]。许多其他基于纳米载体的治疗方法，如ABI-009（白蛋白结合的雷帕霉素纳米粒）[8]，CPX-351（阿糖胞苷和柔红霉素脂质体）[9]，以及多西紫杉醇纳米粒脂质混悬剂[10]，已在临床试验中显示出良好的抗癌效果。尽管人们对基于被动靶向的纳米药物在癌症治疗中表现出了极大的热情，但以EPR为基础的制剂的主要缺点是其非特异性分布、肿瘤蓄积不足、肿瘤内和肿瘤间以及个体间的异质性。此外，多种间质因素，如致密的细胞外基质、高间质流体压力、生长诱导的固体应力和低氧，可以进一步增加EPR的肿瘤靶向的异质性。由于肿瘤血流量和血管通透性的差异很大，EPR效应可能并不适用于所有实体瘤。临床上，肿瘤大小相关的肿瘤血流障碍是很常见的；小的早期肿瘤具有更一致的EPR效应，而大的肿瘤表现出更大的EPR效应变异性。最近的一项研究还显示，97%的纳米颗粒是通过跨内皮途径从血管细胞主动转运到肿瘤组织[11]。在这种情况下，研究人员专注于开发具有增强靶向的新一代纳米载体，例如基于配体的主动肿瘤靶向（图1B）和肿瘤微环境（TME）响应性药物递送（图1C）。基于配体的靶向策略依赖于纳米载体上配体的直接相互作用，这些配体选择性地与癌细胞上过度表达的受体或抗原相互作用，从而增强纳米载体的摄取。例如，西妥昔单抗结合纳米粒可主动靶向过度表达的结肠癌细胞表皮生长因子受体（EGFR）[12]。然而，健康细胞中缺乏这种受体会减少正常细胞与配体修饰的纳米载体之间的相互作用，从而阻止正常细胞摄取。另一方面，与健康组织不同，TME响应性递送系统可根据需要进行药物释放，以响应TME改变的生理特征。例如，实体瘤创造了一个酸性pH、低氧、氧化还原改变和活性氧（ROS）水平升高的微环境[13，14]。此外，通过改变纳米载体的组成、形状、大小和表面特征，可以很好地调节纳米载体的理化性质及其与生物系统的相互作用。例如，聚乙二醇纳米粒的表面修饰改善了药物的循环半衰期，从而提高了其在肿瘤部位的生物利用度[15]。2.纳米载体的类型到目前为止，在肿瘤学中已开发了各种纳米平台，包括基于脂质、无机材料、基于聚合物，甚至外泌体等生物纳米载体。无机纳米载体可以进一步细分为不同的类别，如金属纳米载体、介孔二氧化硅纳米载体、碳纳米管和氧化石墨烯纳米颗粒。图2列出了临床和临床前应用较广泛的纳米药物类别。下面的小节将用适当的示例简要讨论每一类。2.1脂基纳米载体在各种纳米载体中，基于脂质的制剂已经在癌症治疗方面进行了广泛的研究[16-18]。作为药物载体，它们具有许多优点，包括良好的生物相容性、生物降解性、卓越的生物利用度、灵活地结合大量的亲水和疏水药物、延长和控制药物释放，以及一系列可设计的理化性质来控制其生物学特性[8，16，19]。根据脂类纳米载体的组成和理化特性，将其分为三大类：脂质体、固体脂质纳米粒（SLNS）和纳米结构脂类载体（NLCS）。2.1.1 脂质体脂质体是由一个（单层）或多个（多层）同心双层包裹着一个水核的脂泡。由于其独特的结构，脂质体可以包裹亲水性和亲脂性分子，可应用于多种类型的药物。脂质体被认为是安全的纳米载体，因为它们由生物相容和生物可降解的脂质（如磷脂和胆固醇）制成[20，21]。此外，它们可以很容易地与各种基团功能化，以延长循环半衰期，实现靶向特异性，促进细胞摄取，甚至提供刺激反应性药物释放[22-26]。脂质体的这些有益特性为其在临床上的成功应用铺平了道路。几种脂质体制剂目前正在临床上常规使用，许多其他制剂正处于临床试验的不同阶段或等待批准[16，27，28]。除了几种用于癌症治疗的脂质体制剂的成功转化临床外，脂质体作为多模式纳米载体仍在积极研究中。传统的脂质体通过调节药代动力学和生物分布特征来改善药物递送至肿瘤组织，从而将化疗药物的副作用降至最低。然而，脂质体制剂容易迅速从循环中移除，限制了它们的治疗效果。脂质体的快速清除归因于血浆成分的调控和网状内皮系统（RES）摄取，主要在肝脏和脾[19，29]。脂质体清除的初始信号是调理素与脂质体表面的结合；事实上，RES并不识别脂质体本身，而是识别连接到脂质体表面的调理素。以聚乙二醇酯等亲水性聚合物为空间稳定剂合成隐形脂质体，以提高脂质体的稳定性和血液循环时间。脂质体上的聚乙二醇修饰保护脂质体表面免受聚集、调控和吞噬，从而延长体循环[30]。在一项临床研究中，Doxil®（聚乙二醇化阿霉素脂质体）呈现两相清除，在初始半衰期（1-3h）内，1/3的药量从血浆中清除，其余的Doxil®消除缓慢，终端半衰期为42-46h。然而，游离阿霉素的初始半衰期约为5min，终端半衰期为25-30h。此外，脂质体包裹后阿霉素的清除量和分布体积急剧减少，导致其AUC大约是游离药物的300倍[31]。如今，主动靶向治疗已成为癌症治疗的主要手段，在保留健康组织的同时促进肿瘤部位优先药物蓄积，从而提高了疗效，并将有害毒性降至最低。因此，脂质体通常被各种肿瘤特异性配体或抗体功能化，包括叶酸[32]、透明质酸[33]、抗体[34]和寡核苷酸适配子[35]，以实现活性肿瘤靶向作用。还可以用特定的材料构建脂质体和其他纳米载体，促进化疗药物在TME作用下释放。在最近的一项研究中[36]，Nunes等人设计用于肿瘤特异性递送伊立替康的叶酸偶联pH响应型脂质体。该制剂表现出pH依赖的药物缓释模型，具有更好的肿瘤细胞摄取能力。值得注意的是，双功能化脂质体对结直肠癌的抗肿瘤疗效显著高pH敏感系统单药或游离伊立替康。除了它们的药物输送潜力，脂质体制剂也被研究用于诊断目的。吲哚青绿，一种近红外（NIR）染料，和阿霉素共包裹的热响应脂质体，由天然相变材料制成，以开发一种图像引导的多模式药物传递平台[37]。除此之外，叶酸和Gd的修饰为脂质体提供了主动的肿瘤靶向和成像能力。该脂质体制剂包括近红外触发的药物释放和三模式（荧光、磁共振成像、MRI和光声）引导的联合化疗、光动力疗法（PDT）和光热疗法（PTT）。制备的脂质体在HeLa移植瘤小鼠模型中显示出有效的肿瘤蓄积和抑制作用，且没有明显的毒性。2.1.2 固体脂质纳米粒（SLN）SLNs由表面活性剂层包裹的固体脂核组成，以增强其在水中的稳定性。用于制备SLNs的脂类材料包括甘油三酯（例如，三硬脂酸甘油酯、软脂酸甘油酯、三肉豆蔻酸甘油酯和甘油三月桂酸酯）、部分甘油酯（例如，苯乙酸甘油酯、硬脂酸甘油酯和棕榈酸甘油酯）、脂肪酸（例如，硬脂酸、棕榈酸和没食子酸）、类固醇（例如，胆固醇）和蜡类。常用的表面活性剂有泊洛沙姆、卵磷脂、甘胆酸钠、聚山梨酸酯、山梨醇酯和及其混合物[16]。尽管SLNs的制备可以使用多种脂类和表面活性剂，但核心脂类和表面活性剂的正确选择是至关重要的，因为它们会影响SLNs的尺寸、电荷、储存稳定性、载药量和药物释放情况[38]。通过融合聚合物纳米粒、脂质体和微乳的所有优势，SLNs扩大了药物输送的范围。作为一种药物输送工具，SLNs的主要优势包括生产简单且无有机溶剂，可灵活地同时包裹高载药量的疏水和亲水分子，提高储存期间和生理环境中的稳定性，可大规模制备和灭菌，调控药物释放，以及降低细胞毒性[39]。许多基于SLN的制剂已经显示出提高各种肿瘤的疗效[40]。以十六烷基酯、十六烷基棕榈酸酯或肉豆蔻醇为原料，以Pluronic®F68为表面活性剂，制备了含有芳樟醇的SLN制剂[41]。其形状为球形，平均粒径为90-130nm，粒径分布窄，Zeta电位近中性（即−4.0 mV），包封率高（80%以上）。基于SLN所开发的制剂，尤其是肉豆蔻酸酯的SLN，对HepG2人肝癌细胞和A549人肺腺癌细胞具有良好的体外杀伤活性，且呈剂量依赖关系。同样，SLN包裹的姜黄素对SKBR3人乳腺癌细胞显示出比游离药物更高的细胞毒性[42]。与脂质体一样，SLNs也与肿瘤特异性配体偶联，以实现主动靶向。精氨酸-甘氨酸-天冬氨酸（RGD）多肽修饰的pH敏感的阿霉素SLN制剂被用于克服乳腺癌的多药耐药[43]。得到的纳米载流子尺寸为96.3 nm，粒径分布窄，Zeta电位为35.6 mV。载药量为9.8%，包封率为98.5%。在pH为5的条件下，阿霉素的体外释药呈双相释放，8h内药物的释放量为39%，随后持续释放至96h，而在生理pH（pH 7.4）或更高的pH（PH 9）条件下，药物释放速率较低。此外，RGD修饰的阿霉素SLN制剂的AUC是阿霉素溶液的5.58倍。最重要的是，阿霉素靶向SLNs显示出比游离阿霉素和非靶向阿霉素SLNs更强的肿瘤抑制作用。2.1.3 纳米脂质载体（NLCS）NLCs是第二代脂质纳米粒，是为了克服SLN的缺点而开发的，这些缺点包括载药量低、多晶性转变、脂质随时间结晶和储存过程中药物泄漏[39，44]。通常，NLCs由固体和液体脂类、表面活性剂和其他成分组成，包括助表面活性剂和反离子[45]。将固体脂基质加入液体脂相中。液体脂质的加入导致固体脂质基质从高度有序的晶相转变为中间态晶格，从而提高了药物载药量并防止药物泄漏[46，47]。像SLNs一样，NLCS中最常用的固体脂质是甘油三酯、部分甘油酯、脂肪酸、类固醇和蜡类[48]。常用的液态脂包括可消化的天然油（如玉米油、大豆油、红花油、橄榄油、椰子油和棕榈油）、中链甘油三酯（如三癸酸甘油酯和三辛酸甘油酯）、脂肪酸（如油酸、亚油酸和没食子酸）、Cetiol® V、Miglyol 812、石蜡油、肉豆蔻酸异丙酯、三十碳六烯和维生素[45，48]。为了提高NLC在水相中的稳定性，人们使用了多种表面活性剂及其混合物。然而，常用的表面活性剂是吐温（例如吐温20、吐温40和吐温80）、泊洛沙姆（例如Pluronic F68和Pluronic F127），Solutol HS15，聚乙烯醇，油酸、脱氧胆酸和乙醇酸的钠盐，聚甘油葡萄糖双硬脂酸酯、TegoCare 450、蛋黄卵磷脂和大豆卵磷脂[45]。据报道，表面活性剂种类对NLCs的稳定性、结晶度和毒性有很大影响[49]。一项研究比较了包裹阿霉素的NLCs和脂质体对4T1乳腺癌动物模型的抗肿瘤效果[50]。脂质体包裹的和游离的阿霉素对平均肿瘤体积的影响没有差异；然而，NLC包裹的阿霉素在减少肿瘤进展方面最有效。此外，NLCs和脂质体都显示了延缓肿瘤肺转移的能力。最近，NLCs作为一种潜在的癌症治疗药物输送工具受到越来越多的关注[16，51]。白藜芦醇是一种天然的非黄酮类多酚，通过与P53、MAPK、caspase-3、7、8、9、VEGF和MMP2等分子靶点相互作用，抑制多种癌细胞的增殖、转移和入侵[52]。然而，由于白藜芦醇的水溶性低、光稳定性差和大量的首过代谢，限制了其在体内的应用。开发了一种基于NLC的白藜芦醇静脉注射制剂，可有效地将其输送到乳腺癌细胞[53]。优化后的白藜芦醇纳米粒（RSV-NLCS）粒径为88.3±3.1 nm，包封率为88.0±2.6%。将优化后的NLC与叶酸偶联，靶向乳腺癌细胞中高表达的叶酸受体。叶酸修饰的NLCS（RSV-FA-NLCS）对MCF-7叶酸受体阳性的人乳腺癌细胞的毒性显著高于未修饰的NLC和游离白藜芦醇（图3）。在几乎没有叶酸受体表达的A549细胞中，其细胞毒作用不明显。有趣的是，与未修饰的NLCs（T1/2：10.38h，AUC：27.11±3.92µg/mL.h）和游离白藜芦醇（T1/2：0.98h，AUC：6.37±1.16µg/mL.h）相比，叶酸偶联的NLCs显示出更好的药动学曲线（t1/2：12.04h，AUC：57.92µg/mL.h）。表1列举了主动靶向脂类制剂及其靶向配体的简要清单。2.2 无机纳米载体无机纳米载体由金属（如金和银）、金属氧化物（如氧化铁、氧化钛、氧化铜和氧化锌）、介孔二氧化硅、氧化石墨烯、碳纳米管和黑磷组成[64-66]。这些纳米载体可以以纳米壳、纳米棒、纳米笼、纳米星和纳米球的形式存在。与有机材料相比，无机纳米颗粒的主要优势是它们的稳定性高[67]。它们可以克服脂基纳米载体的不稳定问题，如易氧化和水解。此外，药物分子容易从脂基纳米载体中泄漏，使无机纳米载体成为药物输送的潜在替代品[65]。无机纳米载体的其他显著优势包括多样化的表面化学、可控的结构以及独特的磁性、电性和光学性质[68，69]。因此，除了它们的药物输送能力外，许多无机纳米颗粒还被用于光动力疗法、光热疗法和热疗[70]。尽管它们有许多潜在优势，但它们通常存在生物相容性差和生物降解性低的问题。在各种无机纳米载体中，铁纳米颗粒（FeNPs）、金纳米颗粒（AuNPs）、碳纳米管（CNTs）、介孔二氧化硅纳米颗粒（MSN）和氧化石墨烯纳米颗粒已被广泛研究用于癌症诊断和治疗。2.2.1纳米铁（FeNPs）多年来，铁纳米颗粒（FeNPs）已被广泛研究用于诊断、治疗和治疗诊断学目的。FeNPs可以通过物理、化学和生物技术合成，但化学方法，特别是共沉淀法，是最常用的步骤[71-73]。氧化铁的超顺磁性使其成为核磁共振成像和磁粒子成像（MPI）的造影剂[74]。而FeNPs的治疗应用包括补铁、磁热、巨噬细胞极化和磁性药物靶向[72]。然而，FeNPs的组成和形态对其磁性影响很大。因此，选择合适的合成方法是制备尺寸、形状和结晶度合适的FeNPs的关键。磁性纳米颗粒的一些潜在缺点与其药物输送相关，包括去除外部磁场后难以在靶组织中维持疗效。此外，由于纳米粒子的三维结构，其体内条件下有效的肿瘤分布是具有挑战性的[75]。阿霉素是一种拓扑异构酶Ⅱ抑制剂，对多种肿瘤具有细胞毒作用。然而，阿霉素治疗多形性胶质母细胞瘤（GBM）的有效性受到限制，主要是因为它在穿过血脑屏障时的分布不均匀。因此，制备了载阿霉素的三甲氧基硅丙基乙二胺三乙酸（EDT）稳定的生物相容性FeNPs，以增强其对GBM的疗效[76]。阿霉素体外4d内可释放完毕，酸性条件下药物释放较快。纳米粒包裹的阿霉素在U251人恶性胶质瘤细胞中的摄取率是游离阿霉素的2.8倍，具有更好的体外细胞毒性。最重要的是，外加磁场进一步增强了多耐药蛋白1基因转染犬肾细胞（MDCK-MDR1）-U251共培养模型中纳米粒的通透性和细胞毒性。较高的表面能、较强的静电作用以及对氧的敏感性使得裸露的超顺磁性氧化铁纳米颗粒（SPION）容易自团聚，限制其体内性能。基于表面活性剂的SPION表面修饰是提高其体系稳定性的潜在策略之一。然而，在纳米颗粒中添加过多的表面活性剂可能会通过电荷中和和桥联导致颗粒团聚。为了避免纳米粒子的桥联和不稳定，必须精确地调整表面活性剂的用量，以达到调节粒子尺寸和增强分散性的目的。此外，快速调控和随后的RES清除是SPION在体内发挥作用的另一个障碍。许多材料，如聚乙二醇[77]、聚乳酸（PLA）[78]、聚乳酸-乙醇酸（PLGA）[79]、壳聚糖[80]、酪蛋白[81]和聚己内酯[82]，已经被用来包裹FeNPs，这些FeNPs具有隐形特性并使纳米颗粒无法被免疫系统识别。一些研究表明，酪氨酸激酶样孤儿素受体1 （ROR1）在三阴性乳腺癌（TNBC）细胞中过度表达，并与肿瘤细胞增殖增加有关[83，84]。因此，以小干扰RNA（SiRNA）为基础的针对ROR1的基因治疗可能成为治疗TNBC的一种潜在策略。然而，系统性的siRNA传递是一个巨大的挑战，因为它在生理条件下很容易被降解。在过去，基因传递主要是通过病毒载体实现的，这与免疫原性、炎症和插入诱变等多重不利影响有关[85]。因此，目前各种基于脂质、聚合物和金属的非病毒递送系统被开发用于靶向基因治疗。FeNPs的超顺磁性可以通过在外部施加磁场来实现器官特异性递送。最近合成了丝胶包裹的FeNPs（SS-FeNPs），用于肿瘤靶向递送ROR1 siRNA以治疗TNBC[86]。丝胶包裹可降低FeNPs引起的先天毒性和免疫反应。用聚乙烯亚胺（PEI）包裹SS-FeNPs，使其表面带正电荷，进行siRNA偶联。细胞凋亡研究显示，ROR1-siRNA-FeNPs处理组的细胞凋亡率明显高于对照组和游离的ROR1 siRNA组。磁场引导下，BALB/c小鼠乳腺肿瘤区FeNP明显积聚。此外，与对照组相比，用ROR1-siRNA-FENPs治疗的小鼠肿瘤生长减少，同时肿瘤坏死增加。FeNPs还可以与其他纳米平台整合，以实现其治疗诊断学应用。为此，设计了一种单分散介孔二氧化硅包裹多功能FeNPs纳米平台（DOX@MMSN-SS-PEI-cit），用于诊断和治疗癌症[87]。首先将单分散介孔二氧化硅纳米颗粒（MMSN）通过二硫键与支化的PEI偶联，然后再将柠檬酸酐偶联到PEI上。阿霉素通过与PEI的相互作用被固定在介孔纳米粒中。在生理条件下（pH 7.4），这些纳米载体具有负的表面电荷，这有助于避免不必要的血清蛋白吸附和随后的RES清除。在弱酸性的TME中，由于酰胺键的水解，发生了从负到正的电荷反转，这促进了所产生的纳米载体的内在体逃逸（图4A）。MMSN和PEI之间的二硫键可以在癌细胞的高度还原环境中断裂，导致药物快速释放。体外释放研究表明，阿霉素在10 mM谷胱甘肽（GSH）存在的介质中72 h内释放率为98.1±2.22%，而在1 mM GSH存在时只有42.4±1.21%的药物释放，在不含GSH的介质中甚至下降到15.3±0.54%（图4B）。与pH 7.4相比，4T1细胞在pH 6.5时对DOX@MMSN-SS-PEI-cit的摄取更高。DOX@MMSN-SS-PEI-Cit纳米载体不仅有助于肿瘤组织的MRI成像，而且改善了阿霉素的肿瘤靶向输送，比游离阿霉素更好地抑制肿瘤生长。除了药物递送的潜力外，无药物的FeNPs还可以广泛用于癌症治疗，因为它们通过铁死亡通路（一种非凋亡机制）杀死细胞。铁死亡的诱发因素，如细胞中铁的积累，直接或间接影响谷胱甘肽过氧化物酶，导致其抗氧化能力降低，加重细胞内脂质ROS，最终导致细胞氧化死亡[88]。包裹没食子酸和聚丙烯酸的FeNPs对U87 MG和U373 MG人胶质母细胞瘤细胞系、HT1080人纤维肉瘤细胞系、IMR32人神经母细胞瘤细胞系和HT22小鼠海马神经细胞系[89]具有细胞毒作用。一些研究表明，铁死亡增加了癌细胞对化疗药物的敏感性，特别是对化疗药物耐药癌细胞的敏感性[90]。2.2.2 纳米金粒子（AuNPs）由于其独特的物理化学、光学和电学性质，AuNPs已被广泛研究用于癌症诊断和治疗[91]。作为药物载体的AuNPs的其他优点包括其良好的生物安全性、可控的分散性、较强的稳定性、较高的载药表面积以及易于表面功能化[92]。此外，它们可以被设计成不同形状，如纳米棒、纳米笼、空心球、纳米线、纳米盒和纳米星，每一种都有独特的属性、行为和应用。AuNPs可以由纯金制成，与其他材料结合，或掺入其他金属，制成新型杂化材料，可以进一步包封、功能化或与药物或生物分子结合，用于细胞靶向给药[93]。已有许多化学、热、物理、电化学、生物或混合方法用于合成AuNP[94，95]。最广泛使用的是Turkevich法，使用还原剂（例如，单宁酸、抗坏血酸或柠檬酸盐）还原水介质中的[AuCl4][96]。另一方面，最常用的物理方法包括辐射和激光消融[95]。通常，微波、紫外线或γ辐射为AuNP合成过程提供加热和还原条件。相比之下，激光消融会发出特定的波长，诱导金纳米粒子的产生。物理和化学的AuNPs生产过程都依赖于高温、压力和暴露在有毒化学品中，由于增加了不良反应的可能性而限制其应用 [97]。因此，如今的研究人员选择利用微藻、细菌、真菌和植物等生物方法将金属盐还原成稳定的、生物相容的金属[98]。金纳米颗粒独特的光学性质使其能够有效地吸收和散射光。金属纳米粒子受到电磁辐射后，其表面的传导电子由于与输入电磁场的共振作用而发生集体振荡，称为表面等离子激元共振（SPR）。AuNPs的SPR效应总是比相同尺寸的非等离子体纳米颗粒的SPR效应更大[99]。金纳米颗粒的SPR效应强烈地取决于它们的尺寸、形状、组成和含量[99]。在某些情况下，特殊形状的AuNPs可以捕获比光热染料高出数倍的光子，使它们成为PTT的合适候选物。此外，AuNPs的共振频率可以通过改变其大小和形状进行控制，这使得研究人员可以使用对血液和其他组织影响最小的“生物窗口（650-1100 nm）”内的波长[100]。近红外光谱因其较强的组织穿透性而被频繁地用于PTT介导性组织消融。据报道，AuNPs的近红外吸收能力对其PTT疗效，特别是对深层组织癌的疗效有很大影响 [101]。然而，AuNPs的尺寸必须大于100 nm才能获得对NIR的较强吸收能力，NIR由于排泄量低可能在体内积累而出现毒性 [102]。为了避免这种情况，TME响应型AuNPs制剂拥有小尺寸，在低pH值下聚集，提供更大的颗粒以获得更好的近红外吸收，并在生理pH下分解[103]。通过在AuNPs表面添加一层单链DNA（SsDNA）和细胞色素C来实现对pH的响应。金纳米颗粒、单链DNA和细胞色素的最适比例分别为1：400：1000。结果表明，在pH为5.5的条件下，CytC/ssDNA-AuNPs以聚集的方式形成簇，与癌细胞的pH相似。PH降低导致CytC/ssDNA-AuNPs的Zeta电位降低，通过静电聚集增大了纳米粒子的尺寸。这种聚集可以通过将纳米颗粒暴露在类似于生理条件的PH7.4中来解聚。低pH诱导的AuNPs的聚集导致等离子体吸收峰红移，在酸性pH下比在生理pH下产生更大的光热效应。结果表明，含有细胞色素C/sSNAAuNPs的细胞培养液在pH5.5的条件下，在近红外辐射下温度升高30℃或更多，而在pH 7.4的培养液中，温度只升高9-12℃。体外PTT研究表明，CytC/ssDNA-AuNPs对B16F10黑色素瘤的细胞毒性强于非pH响应性颗粒，且不影响健康细胞。利用近红外激活的氟尿嘧啶-金纳米复合体也实现了纳米颗粒介导的PTT，这在结肠癌腹膜转移中显示出显著的抗肿瘤效果[104]。AuNPs还被广泛用作药物输送平台，因为它们的表面性质可以很容易地与各种治疗药物结合，从而提高肿瘤的靶向性。例如，丁香酚偶联的AuNPs研究用于潜在的癌症治疗[105]。丁香酚偶联的AuNPs对人PC-3前列腺癌和人PANC-1胰腺导管癌细胞的毒性高于游离丁香酚，表明将丁香植物化学物质包埋在AuNPs中可以提高其药理潜力和生物利用度。在另一项研究中，透明质酸结合的树枝状大分子包裹的AuNPs被用于阿霉素肿瘤靶向传递[106]。纳米阿霉素对人SK-OV-3卵巢癌细胞移植瘤的生长抑制率是游离阿霉素的4倍。此外，AuNPs可用于同时输送化疗药物和siRNA。评估了多柔比星和Bcl2 siRNA负载的AuNPs（Dox-Bcl2-AuNPs）对TNBC细胞的抗肿瘤效果[107]。Bcl2siRNA的3’端通过硫醇偶联连接到AuNPs表面，而阿霉素通过插层直接连接到siRNA上。当与50 nM的siRNA孵育时，结肠型纳米载体使Bcl-2的表达降低40%。与游离阿霉素相比，Dox-Bcl2-AuNPs不仅显著抑制了细胞的增殖，而且抑制了细胞的迁移。2.2.3 介孔二氧化硅纳米颗粒（MSN）MSN作为多功能纳米载体用于癌症治疗，因为它们具有控制药物释放的能力、可控制的孔径、生物相容性以及将结晶型药物转化为无定形状态的能力[108,109]。MSN具有刚性的骨架和较大的内部孔道，可以包裹大量的化疗药物、生物大分子和多种金属。例如，紫杉醇和喜树碱往往因为水中的溶解性很差在体内的应用受到限制。采用MSN作为药物载体，显著提高了紫杉醇和喜树碱的溶解度，最终使紫杉醇对HepG2细胞的细胞毒性增加了4.3倍，喜树碱对人胰腺癌细胞Capan-1的细胞毒性增加了约86%[110,111]。此外，许多配体分子可以连接到MSN表面进行主动靶向。通过二硫键将抗碳酸氢酶IX抗体（CAIX）偶联到MSN表面，设计了一种抗体靶向和氧化还原响应型的MSN药物传递系统（DOX@MSNS-CAIX）[112]。与健康组织相比，CAIX在实体肿瘤组织中高表达，如肺、食道、头部、乳腺、膀胱癌、子宫颈和肾脏。因此，用抗CAIX抗体功能化的MSNS，以提高其对4T1细胞的肿瘤靶向性。在体外条件下，DOX@MSNS-CAIX在GSH存在下表现出氧化还原响应药物释放，这是由于MSNS中二硫键连接子的裂解。此外，随着释放介质pH的降低，药物的释放量也增加。DOX@MSNS-CAIX在4T1荷瘤小鼠中显示出高效的肿瘤聚集和较强的抗肿瘤效果（图5）。类似地，pH响应的叶酸修饰的MSNPs（MSN-COOH-Tet-HBP-FA）用于化疗药物青藤碱的肿瘤特异性给药[113]。端氨基超支化聚合物的使用给该体系赋予了pH的响应特性。在普通的生理环境中，MSN-COOH-Tet-HBP-FA的药物释放曲线具有pH依赖性，20h内释药可忽略不计。此外，合成的纳米颗粒具有更高的摄取量，对HeLa和A549细胞有较高的细胞毒作用。2.2.4碳纳米管（CNTs）自从1991年Sumio Iijima发现碳纳米管以来，碳纳米管为研究打开了一扇新的大门[114]。碳纳米管由单个或多个同心石墨烯薄片组成，包裹在直径为0.4-100nm的圆柱体中，尽管它们的长度可以达到几微米。根据石墨烯片层的不同，碳纳米管可分为单壁碳纳米管（SWCNTs）和多壁碳纳米管（MWCNTs）。碳纳米管优良的结构特性使其适合用于各种行业，包括生物、制药、电气和材料行业。单壁碳纳米管体积更小、更灵活，并提供成像功能。相比之下，多壁碳纳米管由多个石墨烯薄片组成，形成复杂的石墨烯圆柱体网络，并提供适合高效载药的高比表面积[118]。由于其亲脂性，未修饰的碳纳米管在水介质中很难分散，并且具有很高的毒性，限制了其在体内的应用。然而，碳纳米管可以很容易地通过几种共价和非共价修饰来功能化，以提高其在水溶性和生物利用度[119-121]。碳纳米管的表面聚乙二醇化是改善其生物相容性和生物半衰期的一种很有前途的策略。赵等人[115]设计了肿瘤靶向细胞内触发阿霉素释放的聚乙二醇化多壁碳纳米管制剂。较长的原始多壁碳纳米管显示出明显的细胞毒性，而聚乙二醇化的多壁碳纳米管（尺寸为≤300 nm）显示出更好的细胞相容性。优化后的聚乙二醇化多壁碳纳米管具有较高的载药量和对HepG2细胞的杀伤活性。酸性功能化多壁碳纳米管被开发用于乳腺癌的治疗[122]。酸性功能化多壁碳纳米管和局部热疗的联合治疗完全根除了EMT6荷瘤小鼠的肿瘤，且在50天的研究期间没有动物死亡。高热处理组小鼠HSP70表达增强，联合治疗组肿瘤部位的免疫反应增强。多壁碳纳米管还与Pgp特异性抗体偶联，选择性地针对耐药细胞，然后用光照射进行局部肿瘤消除[123]。在另一项研究中，合成了Cy7和IGF-1R抗体偶联的单壁碳纳米管（SWNT-Cy7-IGF1-Ra），使其能够在成像引导下靶向输送到IGF-1R受体高表达的胰腺癌细胞[124]。尾静脉注射SWNT-Cy7-IGF1-Ra在BXPC-3荷瘤小鼠体内的生物分布，并与SWNT-Cy7和Cy7纳米探针进行比较。用IVIS光谱小动物成像仪记录多个时间点的Cy7相关的近红外（NIR）荧光强度。SWNT-Cy7-IGF1-Ra纳米探针最初分布于全身，仅在肿瘤部位保留了较长一段时间，即使在注射后48小时，肿瘤内仍可见相关的荧光（图6A）。在注射后24小时，进一步定量评价各种纳米探针在组织中的生物分布。肾脏主要代谢游离的Cy7染料，而SWNT-Cy7-IGF-1Ra和SWNT-Cy7主要由肝脏和肠道代谢（图6B，D）。然而，SWNT-Cy7-IGF1-Ra在整个过程中显示出比其他纳米探针更高的肿瘤积累（图6C）。有趣的是，纳米管追踪显示SWNT-Cy7-IGF1-Ra在肿瘤上大量积聚（绿点），但在正常组织中没有积聚（图6e）。2.2.5 氧化石墨烯纳米颗粒（GONP）石墨烯是一种不同石墨化材料的关键成分，它可以堆积成球形结构（0D富勒烯），缠绕成一维结构（碳纳米管），或堆叠成三维层状结构（石墨）[125,126]。它具有平面结构，其中sp2杂化碳原子连接在一起形成六方晶格。石墨烯及其衍生物具有许多诱人的性质，包括高载药量、良好的生物相容性、可调节的两亲性以及可调节的大小和形状，使其适合于各种与癌症相关的应用（例如，包括生物传感、药物传输和光热治疗）[126,127]。石墨烯还具有高比表面积、极好的导热性和导电性、最大的强度质量比和优异的抗拉强度[128,129]。氧化石墨烯（GO）是石墨烯的一种氧化形式，由于其易于生产、稳定性更高、水溶性更好和光学性能优异，在生物医学应用中具有明显的优势。因此，许多基于氧化石墨烯的纳米材料被设计成将氧化石墨烯或其衍生物，与化疗药物、抗体和纳米材料结合在一起[128,130,131]。例如，多功能生物相容GO-Fe3O4结合物被开发用于双重MRI/荧光成像和磁靶向[132]。GO-Fe3O4结合物可以通过非共价络合方式包裹大量的阿霉素，其平均粒径为260 nm。癌细胞有效地结合了这些偶联物，显示出比游离阿霉素好2.5倍的疗效。因此，即使在游离阿霉素剂量的八分之一的情况下，这些结合物也可以产生类似的细胞毒性。开发具有更好的生物降解性的肿瘤靶向递送平台对于成功的化疗是H很重要的。在一项研究中，将GONPs与N甲酰-甲硫基-亮氨酰苯丙氨酸偶联，以靶向甲酰肽受体过表达的癌细胞，包括宫颈癌细胞[133]。合成的杂化纳米载体在人髓过氧化物酶的作用下表现出良好的生物降解性。混合纳米材料本身，而不是原始的氧化石墨烯，不需要任何激活而诱导中性粒细胞脱颗粒。此外，杂化纳米材料可以更快地在人HeLa宫颈癌细胞中传递阿霉素，并诱导更大程度的凋亡。线粒体是参与三磷酸腺苷合成的重要亚细胞器，在生物合成、代谢、信号传递、蛋白质合成和细胞死亡等过程中起着关键作用。因此，线粒体与肿瘤发生的每一步，包括从肿瘤的起始、进展、存活到转移都有关系。因此，线粒体已成为癌症治疗的新靶点。然而，靶向癌细胞内的线粒体仍然是一个巨大的挑战。为了解决这一问题，合成了含有顺铂和拓扑替康的PEI包衣自组装GONPs（PEI-GTC-NP）[134]。孵育6小时后，纳米颗粒有效地积聚在HeLa细胞的线粒体中，在线粒体外膜上产生过渡孔。PEI-GTC-NP诱导线粒体损伤，产生ROS，最终产生癌细胞。2.3 聚合物纳米颗粒聚合物纳米载体已成为肿瘤靶向输送化疗药物的有力工具。作为药物载体，它们提供了几个优势，包括包封率高、稳定性较好、易于表面功能化、易于放大，以及可在GMP条件下制备 [135,136]。聚合物的组成和摩尔比也可以改变，以实现最佳的降解率，调控药物释放，并增加细胞摄取[137]。此外，聚合物纳米颗粒具有显著的灵活性，可以包裹疏水和亲水分子、小分子到大分子、蛋白质、DNA和RNA[138-140]。药物分子可以通过吸附、包裹和结合的方式被装载到纳米颗粒中[141]。基于纳米颗粒制剂工艺，制备的聚合物纳米颗粒将药物包裹在整个聚合物基质中或颗粒的核心中。常用的纳米粒子制备聚合物包括PLGA、聚乳酸、聚乙醇酸（PGA）、PCL、PLGA-PEG，以及一些天然聚合物，如海藻酸盐、壳聚糖、明胶和白蛋白。PLGA是FDA批准被广泛研究用于生物医学应用的聚合物[142]。它由不同比例合成的乳酸和乙醇酸的共聚物组成[143]。由于其生物相容性、生物降解性、低毒和缓释特性，已有多项研究使用PLGA纳米颗粒作为药物载体[144]。包裹多西紫杉醇和LY294002（PI3K/AKT信号转导抑制剂）的PLGA纳米粒可控制治疗药物的释放和在肿瘤部位的蓄积性增强[145]。该纳米颗粒对异种移植和原位小鼠胃癌模型均显示出较好的抗癌活性。不幸的是，PLGA纳米颗粒不能直接与癌细胞上过度表达的特定受体或细胞表面标记物相互作用，从而阻止药物在肿瘤组织中积累。因此，PLGA纳米颗粒通常被修饰用于靶向癌细胞表面过度表达受体的配体分子。为此，开发了RGD-PLGA纳米粒（RGD-PLGA纳米粒），用于控制和靶向递送顺铂和上转换纳米粒治疗肺癌[146]。这些纳米粒可控制药物释放长达72小时。RGD偶联纳米粒的AUC是市面上销售的Ciszest-50注射剂的6.3倍。此外，RGD-PLGA纳米粒的肺组织损伤小，生物相容性强，全身毒性可忽略不计。PLGA纳米颗粒的另一个缺点是突释很高，这可能是潜在的危险。几种包衣剂，包括壳聚糖（CS）和海藻酸盐，已经被用来将突释问题降到最低。例如，多西紫杉醇PLGA纳米颗粒被壳聚糖和叶酸包裹，以增强多西紫杉醇对癌细胞的输送，并改善其药物释放情况[147]。多西紫杉醇的体外释放与叶酸、壳聚糖的用量和释放介质的pH呈负相关。与游离药物相比，纳米颗粒增强了多西紫杉醇的细胞毒作用。壳聚糖因其良好的生物相容性、生物降解性、无毒性和低免疫原性而被广泛应用于生物医学领域，尤其是癌症治疗领域。它的主干上含有许多可质子化的氨基，因为氨基是质子化的，所以在酸性环境中更易溶解。可以对这些氨基进行化学修饰，以提高其溶解性、生物相容性和靶向性[148,149]。壳聚糖纳米粒被设计用于在乳腺肿瘤微环境中持续释放阿霉素[150]。纳米粒子表面进行了聚乙二醇化处理，以改善血液循环时间。将聚乙二醇化的纳米颗粒进一步功能化，以提高肿瘤的靶向性。与游离阿霉素相比，抗体偶联的聚乙二醇化纳米粒对MCF-7细胞具有更好的细胞毒作用。在另一项研究中，制备了叶酸和2-甲基丙烯酸二异丙胺乙酯（DPA）双官能化三甲基壳聚糖纳米粒（FTD NPs），用于共传递阿霉素和Survivin shRNA表达载体（ISur PDNA）或Survivin CRISPR/Cas9表达载体（SgSurvivin PDNA）[151]。叶酸修饰改善了纳米颗粒对癌细胞的输送（图7）。由于DPA偶联纳米粒的pH敏感性，阿霉素在酸性条件下可以快速释放。CRISPR/Cas9纳米粒与RNA载药纳米粒的抗癌效果相当。然而，阿霉素和sgSurvivin PDNA纳米粒比单用阿霉素或sgSurvivin PDNA更有效，与阿霉素和iSur PDNA纳米粒相当。聚合物胶束是聚合物纳米颗粒的另一个成员，由两亲性嵌段共聚物在水溶液中自组装产生的疏水核心和亲水外壳组成。内部疏水核心作为难溶或疏水物质的增溶库，提高了它们的生物利用度。亲水性壳有两个功能：延长血液循环时间和增加血液稳定性。可以将肿瘤特异性配体添加到聚合物胶束中，以增加肿瘤聚集。因此，聚合物胶束可以在输送用于癌症治疗的疏水性药物方面发挥重要作用[152]。研制了一种由PLGA-聚乙二醇维A酸（RA）组成的聚合物胶束，用于将伊立替康靶向输送到人结肠癌细胞HT-29和人肝癌细胞HepG2[153]。与非靶向纳米胶束和游离药物相比，靶向纳米胶束对HepG2和HT-29细胞株具有显著的细胞毒作用。同样，合成了聚乙二醇聚（β-氨基酯）（PBAE）-聚乙二醇三嵌段共聚物胶束，用于水不溶性抗癌药物维替帕芬的pH依赖性给药[154]。胶束形态也可通过改变共聚物的核心PBAE嵌段的疏水性来控制，以避免巨噬细胞的吸收。胶束制剂显示出对人TNBC和小细胞肺癌细胞有效的抗癌活性。纳米载体的聚乙二醇化通过阻止它们的光学离解而增加了纳米载体的循环时间。然而，聚乙二醇化往往会阻碍细胞对纳米载体的摄取。为此，合成了聚乙二醇聚L赖氨酸嵌段共聚物（PEGPLL）为载体的cRGD多肽配体修饰聚合物胶束。通过静电络合，将抗血管生成的质粒DNA引入到聚合物胶束的中心核中。由此产生的纳米载体通过增强肿瘤细胞的摄取而显示出显著的转染率。体内治疗表明，该制剂有效地抑制了BxPC3肿瘤的生长[155]。癌蛋白，如转录因子，也使用抗体加载的聚合物胶束作为抗肿瘤活性的靶点。包裹抗c-Myc抗体的pH响应性聚合物胶束能够从高酸化的癌细胞内切/溶酶体中逃逸，同时阻止其从健康细胞的内体中释放。因此，抗体胶束有效地抑制了肿瘤组织中的c-myc，从而抑制了肿瘤的生长[156]。树枝状大分子是一类独特的聚合物，也经常用于癌症纳米医学。它们是高度有序的支化聚合物大分子，具有明显且统一的大小和形状[157]。它的基本结构由三个主要部分组成：中心核心、重复分支单元和提供可调表面特征的端基。化疗药物可以通过包裹到树枝状大分子核心或结合到表面来负载到树枝状大分子上[158,159]。许多外周功能基团提高了装载和输送治疗物质的能力。此外，树状大分子的分子量和化学成分可以通过调节其产生来严格控制，使可预测的药代动力学和生物相容性调整成为可能。树枝状大分子几乎可以建立在任何形式的化学物质上，这种化学物质的性质极大地影响了它的溶解性、降解性和生物活性[159]。聚酰胺（（PAMAM）[160]、多聚-L-赖氨酸（PLL） [161]、聚酰胺（多肽）[162]、聚（丙烯亚胺）[163]和碳水化合物[164]是生物应用中最常用的树枝状大分子形式。然而，PAMAM树枝状大分子是最流行的树枝状大分子支架，市面销售的具有广泛的代数和表面性质。制备了N-乙酰-D-氨基葡萄糖（NAG）偶联的PAMAM树状大分子，以增强喜树碱对表达凝集素受体和葡萄糖转运体的A549细胞的转运[165]。NAG偶联的树枝状大分子对A549细胞的毒性是游离药物的4.5倍。不幸的是，在生理环境下，这些阳离子胺基对细胞是有害的，限制了PAMAM在体内的应用。聚乙二醇化一直是控制PAMAM表面以提高生物相容性和体循环时间的最简单和最广泛使用的方法[166,167]。开发了一种自组装的两亲性树状大分子，它产生了具有较大空隙面积的超分子胶束[168]。这种设计具有更高的载药量和更高的包封率。所制备的纳米胶束可以通过促进细胞摄取和最大限度地减少细胞毒物质的外流来提高药效并中和耐药性。2.4 生物纳米载体自1990年以来，人们对合成纳米载体，如无机、脂类和聚合物纳米材料进行了广泛的研究，以提高化疗药物的疗效。然而，在许多情况下，由于由于刺激了宿主对这些纳米载体的免疫反应，导致了被迫提前终止治疗。生物载体，如外切体，可以作为纳米平台克服传统给药系统的缺点，并通过增强的药物靶向能力成功的实现药物输送。外切体是膜结合的细胞外囊泡，大小从40 nm到150 nm[169]。它们由健康细胞和癌细胞释放，存在于不同的体液中，如牛奶、血浆、羊水、唾液、尿液、脑脊液、痰和腹水[170]。外切体以信号分子的形式携带有关其母细胞的关键信息，使它们成为癌症和其他炎症性疾病的早期诊断和预后的有希望的生物标记物[171-173]。例如，从乳腺癌患者血清中分离的外切体已被证明表达CD24，表明外切体CD24可能作为乳腺癌的潜在标记物[174]。外切体通过表面受体相互作用、膜融合、受体介导的内吞作用、吞噬作用和/或微胞吞作用向靶细胞传递指令。这些策略有效地允许外切体将治疗药物输送到靶向组织和细胞。已经探索了几种技术，包括电穿孔、转染法、孵育、挤压、超声、热冲击、冻融循环、低渗透析和pH梯度法，以将不同的化疗药物和其他生物活性物质负载到外切体上[175]。例如，外切体包埋紫杉醇（ExoPTX）被评估为克服癌细胞中的多药耐药[176]。RAW 264.7小鼠巨噬细胞来源的外切体通过室温孵育、电穿孔或温和超声负载紫杉醇，并通过尺寸排除层析将游离药物从exoPTX中去除。用多药耐药的MDCK-MDR1细胞及其敏感的野生型细胞（MDCK-WT）研究了exoPTX制剂的抗癌作用。用多药耐药的MDCK-MDR1细胞及其敏感的野生型细胞（MDCK-WT）研究了exoPTX制剂的抗癌作用。与游离紫杉醇或紫杉醇相比，exoPTX制剂对耐药细胞和敏感细胞显示出更大的细胞毒性。不出所料，MDCK-MDR1细胞比敏感的MDCK-WT细胞更容易受到外源性PTX的影响。采用小鼠Lewis肺癌肺转移模型进一步评价了exoPTX的抗癌活性。与未经处理的对照组和紫杉醇处理的动物相比，使用exoPTX的治疗显示出显著的肿瘤生长抑制（p<0.05）（图8）。在最近的一项研究中，一个基于外切体的生物平台被开发出来，以重新编程TME并提高对胰腺导管腺癌（PDAC）的抗癌效果[177]。首先通过电穿孔方法将Galectin-9 siRNA负载于骨髓间充质干细胞（BM-MSC）来源的外切体，然后通过马来酰亚胺-硫醇偶联反应将奥沙利铂-马来酰亚胺偶联到负载siRNA的外切体表面。BM-MSC外切体的肿瘤归巢能力导致治疗药物在PDAC组织中积累增加，同时将全身毒性降至最低。此外，外切体介导的联合治疗通过肿瘤抑制巨噬细胞极化、细胞毒性T淋巴细胞增长和调节性T细胞下调而显示出有效的抗肿瘤免疫，并在ANC-02荷瘤小鼠中实现了有效的抗癌效果。MSC衍生的外切体还被用于联合癌症热疗和胞嘧啶脱氨酶（CD）/5-氟胞嘧啶（5-FC）前药基因治疗[178]。CD/5-FC系统是一种成熟的基因导向酶/前药疗法，可以将无毒的5-FC转化为细胞毒性的5-FU[179]。从V enofer标记的MSCs和表达Cd：：uracil磷酸核糖基转移酶自杀融合基因的酵母（yCD：：UPRT-MSCs）中分离FeNP外切体（即糖包被的氧化铁纳米颗粒）。在交变磁场作用下，MSCs和yCd：：UPRT-MSCs外切体均能有效地被肿瘤细胞内化，并表现出高温诱导的细胞凋亡。当AMF暴露的存活肿瘤细胞在5-FC存在的情况下接受yCD：：UPRT-MSCs治疗时，细胞毒性进一步改善。与其他纳米载体一样，外切体的肿瘤靶向能力也可以通过使用肿瘤特异性配体进行功能化来提高。为此，负载的阿霉素乳外切体（MEXO）被透明质酸功能化，以便于将它们运送到CD44高表达的癌细胞[180]。首次将透明质酸（HA）偶联到两亲性DSPE-PEG2000上，合成了DSPE-PEG2000-HA偶联物。包载阿霉素的mExos（Mexo-Dox）与DSPE-PEG2000-HA结合物共同孵育，可以将透明质酸包埋在Mexo的磷脂双层上。透明质酸功能化的Mexo-Dox显示有选择性地将阿霉素传递给CD44过表达的癌细胞，并显著的促进细胞凋亡。除了药物输送潜力外，外切体还可以用作治疗平台。开发了一种基于外体的治疗工具，用于成像和将奥拉帕利输送到缺氧肿瘤区域[181]。MDAMB-231细胞在常氧或低氧条件下，及在有或无辐射照射的条件下，获得了四种不同类型的外切体。这些外切体被3，30-二十八烷氧碳菁高氯酸盐（Dio）荧光染料标记，以评估它们被缺氧癌细胞摄取。随后，将超顺磁性氧化铁纳米颗粒和奥拉帕利负载到外体中。随后，将超顺磁性氧化铁纳米颗粒和奥拉帕利负载到外体中。据报道，与其他外切体相比，低氧细胞优先摄取由低氧细胞产生的外切体。此外，还利用MPI显示了氧化铁标记的外切体的生物分布。最后，较高的细胞凋亡率和较慢的肿瘤进展证实了负载奥拉帕利布的外切体的治疗效果。3.肿瘤纳米药物的研究现状目前的癌症治疗主要局限于手术、放疗和化疗。这三种方法都受到癌症组织切除不彻底和损害健康组织的风险的限制。纳米技术为精确和直接针对癌细胞的化疗提供了工具，指导外科肿瘤切除，并提高基于放射和其他现有治疗方式的治疗效果。这可能降低患者的风险，提高生存机会。美国FDA批准的第一种基于纳米技术的抗癌药物是1995年上市的聚乙二醇化阿霉素脂质体（Doxil®/Caelyx®）。自那以后，在开发纳米治疗制剂方面取得了重大进展，几种纳米药物已被FDA和其他监管机构批准用于癌症治疗。脂质体（聚乙二醇化或非聚乙二醇化），以及其他基于脂质的纳米颗粒，继续在市场上的纳米疗法中占据相当大的比例。然而，许多其他纳米平台，如聚合物、金属或蛋白质纳米颗粒，也已被批准用于癌症治疗。尽管多年来在基于配体的主动肿瘤靶向方面取得了重大进展，但大多数临床阶段的纳米制剂，仍然依赖于基于EPR的肿瘤蓄积。表2总结了已批准的癌症纳米疗法及其活性药物成分、制造商和授权用途。除了批准的纳米药物外，FDA近年来还批准了多项纳米制剂的研究新药申请，允许进行肺癌、乳腺癌、妇科、胃、胰腺癌、淋巴瘤、中枢神经系统和泌尿生殖系统癌症治疗的临床研究（表3）。这些试验中的大多数使用了具有先前建立的纳米平台的传统化疗药物。4.挑战与未来展望在过去的几十年里，我们看到了纳米技术的巨大发展，我们对纳米粒子理化性质及其与生物系统相互作用的机制的科学理解也有了很大的进步。然而，考虑到纳米技术研究的速度和范围，纳米技术用于癌症诊断和治疗仍处于开发阶段。纳米颗粒的开发面临着几个挑战，极大地限制了它们在临床环境中的成功。首先，所有上市的癌症纳米药物都依赖EPR效应进行被动的肿瘤靶向。然而，EPR效应本身受到肿瘤异质性的影响，导致患者之间甚至患者内部的差异。最重要的是，一些研究表明，EPR效应在较小的动物中比在人类中更显著，这可能导致关于特定疗法疗效的数据不准确。为了克服第一代纳米药物（即基于EPR的药物）所面临的问题，人们开发了具有先进的肿瘤靶向潜力的纳米载体，希望获得更好的临床结果。例如，目前正在进行临床测试的几种纳米制剂寻求通过主动靶向（例如，BIND-014：PSM定向多西紫杉醇纳米粒）和刺激响应性药物释放（例如，ThermoDox：溶热敏感脂质体阿霉素）来提高癌症治疗的有效性。其次，纳米载体涵盖了广泛的材料，并不是所有的材料都在人体上进行了广泛的测试。因此，确定生物相容性可能是主要挑战之一。我们的大部分毒性研究适用于散装材料。然而，纳米颗粒的性质与相应的块状物质有很大的不同；因此，标准的毒理学图谱可能不足以衡量或评估其毒性。尽管初步结果显示纳米载体是无毒和可生物降解的，但对使用纳米载体的长期影响的担忧仍然未知。此外，纳米颗粒在特定的器官中积累的浓度更高，如肝脏、脾和肺。因此，在进行纳米药物的临床试验之前，纳米载体的长期毒性研究是必不可少的。第三，严格评估纳米颗粒和纳米制剂中的无菌和内毒素具有重要意义，因为大多数纳米颗粒用于静脉注射治疗癌症。这些因素在发展的早期阶段被忽视，这可能导致临床前评估过程中的各种困难。内毒素可能来自制造纳米颗粒时使用的材料，而无菌问题可能源于配方过程中使用的机器或设备。第四，根据纳米材料的类型以及所需的纳米载体的特性，可以使用多种方法来合成纳米载体。然而，最常用的实验室技术包括纳米沉淀法、离子凝胶法、超声波法、超临界流体技术、高压均化技术、乳化溶剂挥发技术、膜挤压技术、微流控技术、共沉淀技术、光刻技术等[182]。这些技术中许多都需要密切监测各种工艺参数，以实现纳米制剂的可重复性，因为这些参数的细微变化可能会显著改变纳米载体的特性。在这些技术中，超临界流体技术、高压均质技术、膜挤压技术和微流化器技术具有较好的放大能力。然而，这些技术在大规模制备多功能（如表面功能化或TME响应型）纳米载体方面的应用仍然值得怀疑。此外，在载药能力和重复性方面还需要更多的改进。最后但同样重要的是，纳米药物的临床转化受到极大的阻碍，因为实验动物肿瘤模型不能准确地模拟人类临床癌症中的肿瘤。他们构建的可用于评估纳米药物的药代动力学和疗效的实验模型必须仔细选择，使其与人类肿瘤非常相似。因此，必须根据所关注的包括生产成本、安全性和纳米制剂的复杂性的问题来评估纳米药物的潜在益处。一些纳米药物由于其成本和生产需求，它们的临床转化可能永远不会实现，即使它们的治疗益处方面优于传统配方。根据处方和复杂性的不同，纳米药物的生产成本可能显著高于传统药物。商业生产对环境的影响正变得越来越重要，不仅考虑到纳米材料本身，还考虑到工业废物和能源支出。5.结论癌症纳米医学旨在解决传统癌症化疗的内在局限性。人们对使用纳米技术治疗癌症的兴趣与日俱增，主要是因为它有潜力改善现有的治疗方法，增强靶向能力，增加局部药物疗效，最大限度地减少全身毒性，控制药物释放，提高诊断灵敏度，增强成像，并完善放射治疗[183-185]。此外，纳米载体可以有效地运输各种类型的新型抗癌药物，如核酸、分子靶向药物和免疫治疗药物。鼻腔纳米药物的发展为有效跟踪药物动力学和治疗药物的累积以及疾病进展提供了一种很有前途的策略。同样，大量体内研究表明，使用单一纳米制剂联合传递多种治疗药物有效地绕过了耐药机制，从而显示出较强的肿瘤抑制作用。最近，除了化疗外，纳米技术在癌症免疫治疗领域变得更加流行。综上所述，纳米医学的未来似乎很有希望，先进的技术增强了治疗和诊断，机器学习节省大量的时间和成本。通过跨学科的方法，基于纳米载体的治疗在未来是可以预见的。然而，必须在合适的动物模型中对纳米载体的有效性和毒性进行详细的研究，以确保更高的临床转化率。参考文献1. 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免疫疗法临床研究
100 项与 盐酸多柔比星脂质体(Imunon) 相关的药物交易
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 肝细胞癌 | 临床3期 | 中国 | 2014-06-01 | |
| 不可切除的肝细胞癌 | 临床3期 | 美国 | 2008-05-01 | |
| 不可切除的肝细胞癌 | 临床3期 | 中国 | 2008-05-01 | |
| 不可切除的肝细胞癌 | 临床3期 | 日本 | 2008-05-01 | |
| 不可切除的肝细胞癌 | 临床3期 | 加拿大 | 2008-05-01 | |
| 不可切除的肝细胞癌 | 临床3期 | 中国香港 | 2008-05-01 | |
| 不可切除的肝细胞癌 | 临床3期 | 意大利 | 2008-05-01 | |
| 不可切除的肝细胞癌 | 临床3期 | 马来西亚 | 2008-05-01 | |
| 不可切除的肝细胞癌 | 临床3期 | 菲律宾 | 2008-05-01 | |
| 不可切除的肝细胞癌 | 临床3期 | 中国台湾 | 2008-05-01 |
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| 研究 | 分期 | 人群特征 | 评价人数 | 分组 | 结果 | 评价 | 发布日期 |
|---|
临床3期 | 554 | (ThermoDox 50 mg/m2) | 蓋觸糧齋壓憲顧選醖鬱(築顧餘顧廠鏇積構餘選) = 憲觸積鑰顧鏇繭鹹簾夢 網壓壓願獵獵膚鑰簾醖 (積獵夢淵夢遞鬱膚顧獵, 襯製鹹窪鏇壓鏇鏇蓋襯 ~ 餘遞築遞鹽築窪鹹繭蓋) 更多 | - | 2024-08-20 | ||
Dummy infusion (Dummy Infusion) | 蓋觸糧齋壓憲顧選醖鬱(築顧餘顧廠鏇積構餘選) = 鏇憲齋襯窪築餘遞積蓋 網壓壓願獵獵膚鑰簾醖 (積獵夢淵夢遞鬱膚顧獵, 壓窪簾襯餘鏇鹽夢鏇觸 ~ 糧夢憲遞憲鏇窪獵簾鏇) 更多 | ||||||
临床2期 | 2 | 5% Dextrose Solution+Lyso-Thermosensitive Liposomal Doxorubicin | 遞簾艱願製壓簾憲壓構(構糧廠蓋構夢糧鹹遞遞) = 壓範醖鏇艱簾觸選構選 選襯齋選壓獵艱構鹽糧 (構淵窪範積齋構製築艱, 壓獵構範選構鹽簾廠餘 ~ 範鹹鬱廠鬱構壓襯積鑰) 更多 | - | 2022-10-13 | ||
临床3期 | 701 | (ThermoDox + RFA) | 窪遞蓋鹽範製獵鏇築築 = 餘積膚構廠願選積顧壓 鑰製顧觸積鏇膚觸夢襯 (鹽夢壓夢膚築膚窪鹽衊, 繭鏇糧範蓋鹹醖襯積鬱 ~ 鑰製範網製鹽壓膚鏇壓) 更多 | - | 2017-03-24 | ||
5% Dextrose Solution (Sham + RFA) | 窪遞蓋鹽範製獵鏇築築 = 遞繭遞艱範遞艱鹹糧顧 鑰製顧觸積鏇膚觸夢襯 (鹽夢壓夢膚築膚窪鹽衊, 願範鹽壓鏇鬱製鑰顧簾 ~ 襯遞淵築憲簾糧淵夢構) 更多 | ||||||
临床1期 | 29 | Low temperature liposomal doxorubicin (LTLD) | 窪簾壓築蓋網廠繭製製(簾網構鬱餘夢願築糧鑰) = 範襯壓夢鹽窪憲齋積膚 鬱築簾範鬱選艱壓願顧 (觸淵簾積壓獵窪艱壓繭 ) 更多 | 积极 | 2014-08-01 |
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