生物可降解无机介孔纳米材料研究进展

近年来,无机介孔纳米材料由于比表面积大、孔结构有序可控、比孔容大等优秀性质而受到化学、材料、物理、医药等领域科研人员重点关注.但在生物临床诊疗应用中,无机介孔纳米材料在机体内的相对难降解、排泄也是亟待解决的问题.本文将围绕科研领域最受关注的几种无机介孔材料,综述目前最为可行的无机介孔纳米材料的生物可降解性质改造策略.     

共载阿霉素与小干扰RNA的脂质介孔硅纳米粒的制备表征及抗多药耐药肿瘤细胞研究

目的 制备共载阿霉素(DOX)与小干扰RNA(siRNA)的脂质介孔硅纳米粒(CLMSNs-SS-NH₂@DOX/siRNA),并对其进行表征及抗多药耐药肿瘤细胞研究。方法 先以介孔硅纳米粒(MSNs)为基础制备MSNs-SS-NH₂@DOX,并以阳离子脂质体(CLs)对其包覆制得CLMSNs-SS-NH₂@DOX,进一步负载siRNA即得CLMSNs-SS-NH₂@DOX/siRNA。测定该制剂粒径及Zeta电位,观察其微观形态并进行差示扫描量热分析、X射线衍射分析、红外光谱分析、物理吸附分析;测定该制剂在不同pH条件下(pH5.0、pH7.4)及不同谷胱甘肽浓度下(0、2、5、10 mmol/L)DOX的体外释放度;考察该制剂对耐DOX型乳腺癌细胞MCF-7/ADR摄取、迁移、凋亡、周期及P-糖蛋白(P-gp)表达的影响。结果 CLMSNs-SS-NH₂@DOX/siRNA结构清晰,表面脂膜层明显,粒径为(197.63±3.75)nm,Zeta电位为(20.64±0.98)...     

介孔二氧化硅纳米材料的皮肤安全性研究

目的:评价介孔二氧化硅纳米材料(MSNs)的皮肤渗透性、刺激性及过敏性。方法:在体透皮实验中,将分别载不同量(0.75%和3%,W/W)MSNs和氨基修饰的MSNs(NH2-MSNs)的凝胶涂布于大鼠背部皮肤,考察24 h后皮肤中硅含量及在皮肤组织中的分布(n=4);皮肤刺激性实验中,将分别载3%MSNs和NH2-MSNs的凝胶多次(1次/d,共7 d)涂布于家兔完整皮肤及破损皮肤,采用同体左右侧自身对照,给药期间每日观察局部皮肤红斑及水肿情况(n=4);皮肤过敏性实验中,于实验第1、7、14天将载3%MSNs和NH2-MSNs的凝胶、凝胶基质和1%2,4-二硝基氯代苯溶液(阳性对照)分别涂布于豚鼠背部皮肤左侧致敏,于末次致敏后14 d(第28天)同法涂药于右侧激发接触,以是否出现红斑或水肿为指标,观察局部皮肤的过敏反应(n=6)。结果:载0.75%、3%MSNs的凝胶致皮肤中硅含量分别为(10.812±3.963)、(22.050±5.721)μg/g,载0.75%、3%NH2-MSNs的凝胶致皮肤中硅含量分别为(7.799±2.068)、(16.416±3.221)μg/g,透射电镜显示MSNs能跨过皮肤屏障,进入真皮层;完整皮肤和破损皮肤均未出现红斑或水肿现象;与阳性对照比较,载MSNs及NH2-MSNs的凝胶均未导致豚鼠皮肤出现红斑或水肿。结论:MSNs作为局部施药载体具有良好的皮肤安全性。     

载姜黄素的介孔二氧化硅及中空介孔二氧化硅的制备及释药性能研究

目的:制备载姜黄素(Cur)的介孔二氧化硅(MSN)和中空介孔二氧化硅(HMSN),并考察其体外释药行为.方法:采用溶胶-凝胶法、选择性刻蚀法分别制备MSN和HMSN,并采用溶剂挥干法制备载药体系Cur-MSN、Cur-HMSN,以紫外分光光度法测定其载药量.采用差示扫描量热法(DSC)和X射线衍射法(XRD)表征药物...     

介孔二氧化硅和中空介孔二氧化硅载体用于提高难溶性药物溶出度的比较

目的研究介孔二氧化硅(mesoporous silica nanoparticles,MSN)和中空介孔二氧化硅(hollow mesoporous silica nanoparticles,HMSN)两种载体对提高难溶性药物缬沙坦(valsartan,VAL)和尼莫地平(nimodipine,NMP)的载药量以及改善药物溶出度作用的比较。方法采用溶剂挥干法制备VAL-MSN、VAL-HMSN、NMP-MSN和NMP-HMSN四种固体分散体,以紫外分光光度法测定样品的载药量。采用X射线衍射法表征药物的存在状态。以溶出度为评价指标,对原料药、无定型药物以及载药体系的溶出速率进行了比较。结果 VAL-HMSN和NMP-HMSN的载药量分别为(34.76±1.36)%和(38.30±1.38)%,而VAL-MSN和NMP-MSN的载药量分别为(23.54±1.72)%和(22.93±1.08)%。X射线衍射实验表明药物在载体中以非晶体状态存在。溶出实验结果显示无定型药物的溶出度最低,HMSN和MSN载药体系的溶出度均比原料药有所提高。结论 HMSN和MSN相比,HMSN载药体系的载药量更高,但溶出度较MSN载药体系低。     

以介孔硅为基质的固体分散体片剂的制备与性质考察

目的将替米沙坦与介孔硅制备成片剂,并考察片剂的稳定性。方法在处方筛选的基础上,采用粉末直接压片法压制替米沙坦-介孔硅片剂;采用高效液相色谱法测定药物含量;采用示差扫描量热、X-射线衍射和溶出法考察制剂的晶型稳定性。结果替米沙坦-介孔硅分散体66 g、交联聚乙烯吡咯烷酮30 g、微晶纤维素50 g、甘露醇50 g、硬脂酸镁4 g,混合均匀,压制成1 000片,含量均匀度和溶出度符合要求,在12个月内替米沙坦稳定性良好,且一直以无定型状态存在。结论利用自制介孔硅制备固体分散体,介孔硅的孔道使难溶性药物长期以无定型状态存在,故制剂稳定性良好。     

不同粒径的介孔纳米硅材料对小鼠的急性毒性研究

目的介孔二氧化硅纳米粒(mesoporous silica nanoparticles,MSN)是一种新型、潜在的药物纳米载体。为探索其可能存在的毒性,本研究采用小鼠进行急性毒性研究,分析毒性与材料粒径的关系。方法使用上下法主试验,经静脉注射途径将3种不同粒径(80、200、1000 nm)及二氧化硅粉(20 nm)分别给予小鼠,观察动物的毒性反应,存活动物观察14 d,计算半数致死量(LD50)。观察期结束后,取血进行血生化检测,并对其进行大体解剖,摘取心、肝、脾、肺、肾和大脑,称重并计算脏器系数,制片及进行病理组织学检查。结果 MSNs对小鼠有明显的急性毒性,20、80、200、1000 nm给予小鼠静脉注射的LD50范围分别为:(26.3³2.8)、(10032.8)、(100¹25)、(304.7125)、(304.7³81)、(80381)、(80¹00)mg·kg-1;即毒性大小为20 nm>1000 nm>80 nm>200 nm。结论 MSNs会对小鼠造成急性毒性,并且毒性强弱与其粒径密切相关。     

铜掺杂介孔硅载双硫仑抗肠癌活性研究

目的 以铜掺杂介孔硅（Cu/MSNs）为载体包载双硫仑（DSF）制备成纳米粒,研究其对CT.26WT肠癌细胞的体外抑制活性。方法 Stober法制备二氧化硅微粒后对其进行优化,MTT法验证其体外抗肿瘤活性。结果 通过单因素法优化得到在1.5 mL氨水、12.5 mL水和温度85 ℃时具有最佳粒径;MTT法得到DSF、5-Fu和DSF-NPs在48 h下的IC₅₀值分别为7.532、3.359和1.208 μg·mL^-1,72 h的IC50值分别为2.258、1.137和0.985 μg·mL^-1。结论 铜掺杂介孔硅能有效的负载双硫仑并增强其抗肠癌细胞活性,具有优良的抗肠癌潜力。     

介孔二氧化硅纳米粒的研究进展

介孔二氧化硅纳米粒(MSNs)具有良好生物相容性、有序介孔结构、比表面积大、表面易修饰性等特点,在很多生物医药领域显示出了极大的应用前景,尤其是基于MSNs的纳米药物输送体系被广泛用于各种药物的递送。主要介绍MSNs和可降解MSNs的制备,同时介绍了MSNs膜包被及官能团修饰在缓释控释药物中的应用,最后探讨了MSNs递进到中空介孔二氧化硅纳米粒(HMSNs)的更大的应用前景。     

介孔复合硅微球的制备及载药性质

目的制备介孔复合硅(CaO-SiO2-P2O5)微球,考察其作为水难溶性药物载体提高水难溶性药物的分散性及溶出度的优势。方法采用sol-gel方法制备介孔CaO-SiO2-P2O5微球,以扫描电镜及氮气吸附-脱附等方法分析表征载体的外观形貌、比表面积及孔径分布;选取尼莫地平为模型药物,以溶剂浸渍挥干法载药制得药物固体分散体;采用热分析、氮气吸附-脱附曲线分析以及溶出度实验研究药物固体分散体的基本性质。结果制得的复合硅载体的形貌近球状,粒径大小主要分布在3～6μm,载体的比表面积为637.34 m2.g-1,孔容为1.371 8 cm3.g-1,孔径分布主要集中在10～12 nm。当药物和载体的质量比为1:4时,药物能够被包埋分散于载体内部,且以无定型的形式存在,45 min尼莫地平累计溶出达80%。结论介孔CaO-SiO2-P2O5微球有望成为水难溶性药物的优良载体。     

Targeting gold nanocages to cancer cells for photothermal destruction and drug delivery

Importance of the field: Plasmonic nanoparticles provide a new route to treat cancer owing to their ability to convert light into heat effectively for photothermal destruction. Combined with the targeting mechanisms possible with nanoscale materials, this technique has the potential to enable highly targeted therapies to minimize undesirable side effects.

Areas covered in this review: This review discusses the use of gold nanocages, a new class of plasmonic nanoparticles, for photothermal applications. Gold nanocages are hollow, porous structures with compact sizes and precisely controlled plasmonic properties and surface chemistry. Also, a recent study of gold nanocages as drug-release carriers by externally controlling the opening and closing of the pores with a smart polymer whose conformation changes at a specific temperature is discussed. Release of the contents can be initiated remotely through near-infrared irradiation. Together, these topics cover the years from 2002 to 2009.

What the reader will gain: The reader will be exposed to different aspects of gold nanocages, including synthesis, surface modification, in vitro studies, intial in vivo data and perspectives on future studies.

Take home message: Gold nanocages are a promising platform for cancer therapy in terms of both photothermal destruction and drug delivery.     

乌贼墨纳米颗粒制备工艺优化及肿瘤光热治疗应用研究

目的 分离纯化乌贼墨纳米颗粒(squid ink nanoparticles,SINPs),开展材料学表征,考察其肿瘤光热治疗(photothermal therapy,PTT)作用。方法 通过搅拌、超声和离心纯化出SINPs,在近红外激光(Near Infra-Red,NIR)照射下考察其体外光热转化效果,采用CCK-8法测定细胞存活率,通过对小鼠瘤内注射给药的同时给予激光照射研究其体内抑瘤效果。结果 制备的SINPs粒径为(212 ± 1.4) nm,Zeta电位为(-14.5 ± 0.7) mV。测定其光热转化效率为35.5%,说明其可作为一种光热转化剂。800 μg/mL的SINPs在808 nm激光照射下小鼠乳腺癌细胞(4T1)的存活率为67.3%,表明SINPs联合PTT对4T1细胞有一定的细胞毒性,此外,在荷瘤小鼠体内,空白组瘤重为SINPs高+laser组瘤重的2.3倍,说明SINPs联合PTT有一定的抗瘤作用。结论 SINPs联合PTT能显著抑制荷瘤小鼠体内肿瘤组织的生长。作为一种天然纳米材料,SINPs具有良好的肿瘤PTT作用,提示其除传统药理作用外,作为天然、安全的纳米材料或载体,在肿瘤光学治疗领域具有一定应用前景。     

Integrated nanomaterials for non-invasive photothermal therapy of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease that causes swelling, redness, and arthralgia of multiple joints. Despite significant research and development on the treatment modalities for RA, there is still no established effective treatment option for eradicating joint damage and inflammation. In recent years, photothermal therapy (PTT) has emerged as a practical approach to treat RA. In this review, we outline various factors that affect the effective treatment of RA. Moreover, we discuss various PTT-based nanomaterials that can be used to treat RA.     

Construction of iron-mineralized black phosphorene nanosheet to combinate chemodynamic therapy and photothermal therapy

Chemodynamic therapy (CDT) by triggering Fenton reaction or Fenton-like reaction to generate hazardous hydroxyl radical (•OH), is a promising strategy to selectively inhibit tumors with higher H₂O₂ levels and relatively acidic microenvironment. Current Fe-based Fenton nanocatalysts mostly depend on slowly releasing iron ions from Fe or Fe oxide-based nanoparticles, which leads to a limited rate of Fenton reaction. Herein, we employed black phosphorene nanosheets (BPNS), a biocompatible and biodegradable photothermal material, to develop iron-mineralized black phosphorene nanosheet (BPFe) by in situ deposition method for chemodynamic and photothermal combination cancer therapy. This study demonstrated that the BPFe could selectively increase cytotoxic ·OH in tumor cells whereas having no influence on normal cells. The IC₅₀ of BPFe for tested tumor cells was about 3–6 μg/mL, which was at least one order of magnitude lower than previous Fe-based Fenton nanocatalysts. The low H₂O₂ level in normal mammalian cells guaranteed the rare cytotoxicity of BPFe. Moreover, the combination of photothermal therapy (PTT) with CDT based on BPFe was proved to kill tumors more potently with spatiotemporal accuracy, which exhibited excellent anti-tumor effects in xenografted MCF-7 tumor mice models.     

Chidamide stacked in magnetic polypyrrole nano-composites counter thermotolerance and metastasis for visualized cancer photothermal therapy

Photothermal therapy (PTT) has become one of the most promising therapies in cancer treatment as its noninvasiveness, high selectivity, and favorable compliance in clinic. However, tumor thermotolerance and distal metastasis reduce its efficacy, becoming the bottleneck of applying PTT in clinic. In this study, a chidamide-loaded magnetic polypyrrole nanocomposite (CMPP) has been fabricated as a visualized cancer photothermal agent (PTA) to counter tumor thermotolerance and metastasis. The efficacy of CMPP was characterized by in vitro and in vivo assays. As a result, this kind of magnetic polypyrrole nanocomposites were black spherical nanoparticles, possessing a favorable photothermal effect and the suitable particle size of 176.97 ± 1.45 nm with a chidamide loading rate of 12.92 ± 0.45%. Besides, comparing with PTT, CMPP exhibited significantly higher cytotoxicity and cellular apoptosis rate in two tumor cell lines (B16-F10 and HepG2). In vivo study, the mice showed obvious near-infrared (NIR) and magnetic resonance imaging (MRI) dual-modal imaging at tumor sites and sentinel lymph nodes (SLNs); on the other hand, magnetic targeting guided CMPP achieved a cure level on melanoma-bearing mice through preventing metastasis and thermotolerance. Overall, with high loading efficiency of chidamide and strong magnetic targeting to tumor sites and SLNs, CMPP could significantly raise efficiency of PTT by targeting tumor thermotolerance and metastasis, and this strategy may be exploited therapeutically to upgrade PTT with MPP as one of appropriate carriers for histone deacetylase inhibitors (HDACis).     

Charge-reversal nanomedicine based on black phosphorus for the development of A Novel photothermal therapy of oral cancer

Driven by the lifestyle habits of modern people, such as excessive smoking, drinking, and chewing betel nut and other cancer-causing foods, the incidence of oral cancer has increased sharply and has a trend of becoming younger. Given the current mainstream treatment means of surgical resection will cause serious damage to many oral organs, so that patients lose the ability to chew, speak, and so on, it is urgent to develop new oral cancer treatment methods. Based on the strong killing effect of photothermal therapy on exposed superficial tumors, we developed a pH-responsive charge reversal nanomedicine system for oral cancer which is a kind of classic superficial tumor. With excellent photothermal properties of polydopamine (PDA) modified black phosphorus nanosheets (BP NSs) as basal material, then used polyacrylamide hydrochloride-dimethylmaleic acid (PAH-DMMA) charge reversal system for further surface modification, which can be negatively charged at blood circulation, and become a positive surface charge in the tumor site weakly acidic conditions due to the breaking of dimethylmaleic amide. Therefore, the uptake of oral cancer cells was enhanced and the therapeutic effect was improved. It can be proved that this nanomedicine has excellent photothermal properties and tumor enrichment ability, as well as a good killing effect on oral cancer cells through in vitro cytotoxicity test and in vivo photothermal test, which may become a very promising new model of oral cancer treatment.     

Topically applied liposome-in-hydrogels for systematically targeted tumor photothermal therapy

Transdermal drug delivery for local or systemic therapy provides a potential anticancer modality with a high patient compliance. However, the drug delivery efficiency across the skin is highly challenging due to the physiological barriers, which limit the desired therapeutic effects. In this study, we prepared liposome-in-hydrogels containing a tumor targeting photosensitizer IR780 (IR780/lipo/gels) for tumor photothermal therapy (PTT). The formulation effectively delivered IR780 to subcutaneous tumor and deep metastatic sites, while the hydrogels were applied on the skin overlying the tumor or on an area of distant normal skin. The photothermal antitumor activity of topically administered IR780/lipo/gels was evaluated following laser irradiation. We observed significant inhibition of the rate of the tumor growth without any toxicity associated with the topical administration of hydrogels. Collectively, the topical administration of IR780/lipo/gels represents a new noninvasive and safe strategy for targeted tumor PTT.     

Multifunctional liposome for photoacoustic/ultrasound imaging-guided chemo/photothermal retinoblastoma therapy

Retinoblastoma (RB) is a malignant intraocular neoplasm that occurs in children. Diagnosis and therapy are frequently delayed, often leading to metastasis, which necessitates effective imaging and treatment. In recent years, the use of nanoplatforms allowing both imaging and targeted treatment has attracted much attention. Herein, we report a novel nanoplatform folate-receptor (FR) targeted laser-activatable liposome termed FA-DOX-ICG-PFP@Lip, which is loaded with doxorubicin (DOX)/indocyanine green (ICG) and liquid perfluoropentane (PFP) for photoacoustic/ultrasound (PA/US) dual-modal imaging-guided chemo/photothermal RB therapy. The dual-modal imaging capability, photothermal conversion under laser irradiation, biocompatibility, and antitumor ability of these liposomes were appraised. The multifunctional liposome showed a good tumor targeting ability and was efficacious as a dual-modality contrast agent both in vivo and in vitro. When laser-irradiated, the liposome converted light energy to heat. This action caused immediate destruction of tumor cells, while simultaneously initiating PFP phase transformation to release DOX, resulting in both photothermal and chemotherapeutic antitumor effects. Notably, the FA-DOX-ICG-PFP@Lip showed good biocompatibility and no systemic toxicity was observed after laser irradiation in RB tumor-bearing mice. Hence, the FA-DOX-ICG-PFP@Lip shows great promise for dual-modal imaging-guided chemo/photothermal therapy, and may have significant value for diagnosing and treating RB.     

Folic acid-modified and functionalized CuS nanocrystal-based nanoparticles for combined tumor chemo- and photothermal therapy

Recent studies have identified that CuS nanocrystal (CuS NCs) could be used as a new class of promising photo-thermal agents due to their excellent plasmonic absorption abilities in a wide near-infrared (NIR) region. However, most of nanocarriers lack target capacity for combining chemotherapy and photothermal therapy effects. Herein, we reported chitosan (CS)-encapsulated and folic acid (FA)-modified nanoparticles (NPs) simultaneously loading with functionalized CuS NCs and docetaxel (DTX) (FA-DTX-PVP/CuS-NPs). Compared with free DTX, the photothermal agent CuS NCs and DTX not only could be specially targeted to deliver into MCF-7 cancer cells via a receptor-mediated endocytosis pathway, but also could be effectively transferred into tumor tissues of S₁₈₀ tumor-bearing mice in vivo. More important, when combination with NIR laser irradiation, FA-DTX-PVP/CuS-NPs showed a higher antitumor efficacy than the individual therapies. Thus, as a remote and noninvasive tumor therapy strategy, these active targeting NPs may provide a great potential for tumor synergistic therapy.     

One-pot preparation of nanodispersion with readily available components for localized tumor photothermal and photodynamic therapy

Photothermal(PTT) and photodynamic(PDT) combined therapy has been hindered to clinical translation, due to the lack of available biomaterials, difficult designs of functions,and complex chemical synthetic or preparation procedures. To actualize a high-efficiency combination therapy for cancer via a feasible approach, three readily available materials are simply associated together in one-pot, namely the single-walled carbon nanohorns(SWCNH), zinc phthalocyanine(ZnPc), and surfactant TPGS. The es...