Redox and pH dual-responsive biodegradable mesoporous silica nanoparticle as a potential drug carrier for synergistic cancer therapy

Multifunctional mesoporous silica-based nanocarriers able to efficiently encapsulate drugs for stimuli-responsive release and display rapid biodegradation are highly desirable. In this work, we dope disulfide bonds and calcium into silica framework by one step method to obtain a redox and pH dual-responsive biodegradable mesoporous silica nanoparticle (BT-Ca-MSN) as a potential drug carrier for synergistic cancer therapy. TEM and ICP-OES are used to assess the biodegradation behavior of BT-Ca-MSN. The results show that BT-Ca-MSN can significantly biodegrade in a concurrent reductive and acidic environment due to the simultaneous disulfide bonds cleavage and Ca²⁺ release. In addition, BT-Ca-MSN shows efficient drug loading capacity and significant biodegradation-mediated drug release. Moreover, the in-vitro cytotoxicity indicates that BT-Ca-MSN can not only exhibit significant cancer cell killing effect without obvious toxicity on healthy cells via the way of released Ca²⁺-mediated apoptosis, but also can combine with its loaded doxorubicin hydrochloride for synergistic cancer therapy. This work demonstrates that BT-Ca-MSN is a promising platform as drug carrier, providing a paradigm to rationally design biodegradable silica-based carriers for highly efficient cancer therapy.     

Functionalized Reduced Graphene Oxide as a Versatile Tool for Cancer Therapy

Cancer is one of the deadliest diseases in human history with extremely poor prognosis. Although many traditional therapeutic modalities—such as surgery, chemotherapy, and radiation therapy—have proved to be successful in inhibiting the growth of tumor cells, their side effects may vastly limited the actual benefits and patient acceptance. In this context, a nanomedicine approach for cancer therapy using functionalized nanomaterial has been gaining ground recently. Considering the ability to carry various anticancer drugs and to act as a photothermal agent, the use of carbon-based nanomaterials for cancer therapy has advanced rapidly. Within those nanomaterials, reduced graphene oxide (rGO), a graphene family 2D carbon nanomaterial, emerged as a good candidate for cancer photothermal therapy due to its excellent photothermal conversion in the near infrared range, large specific surface area for drug loading, as well as functional groups for functionalization with molecules such as photosensitizers, siRNA, ligands, etc. By unique design, multifunctional nanosystems could be designed based on rGO, which are endowed with promising temperature/pH-dependent drug/gene delivery abilities for multimodal cancer therapy. This could be further augmented by additional advantages offered by functionalized rGO, such as high biocompatibility, targeted delivery, and enhanced photothermal effects. Herewith, we first provide an overview of the most effective reducing agents for rGO synthesis via chemical reduction. This was followed by in-depth review of application of functionalized rGO in different cancer treatment modalities such as chemotherapy, photothermal therapy and/or photodynamic therapy, gene therapy, chemotherapy/phototherapy, and photothermal/immunotherapy.     

Polydopamine-mediated polypyrrole/doxorubicin nanocomplex for chemotherapy-enhanced photothermal therapy in both NIR-I and NIR-II biowindows against tumor cells

Photothermal therapy (PTT) is featured by the desirable spatiotemporal controllability and excellent specificity, which has been identified as one of the important tumor treatment methods. Although promising, the efficacy of PTT is still limited and needs further improvement. In this work, a kind of PPy-PDA-PEG@DOX nanocomplex was designed and constructed for chemotherapy-enhanced PTT in both near-infrared (NIR)-I and NIR-II biowindows against tumor cells, which was integrated by the polypyrrole (PPy) core, polydopamine (PDA) shell, polyethylene glycol (PEG) linkage, and doxorubicin (DOX) payload. This constructed PPy-PDA-PEG@DOX nanocomplex was uniform in size around 56.3 nm, and with the optimized DOX loading content at 37.4%. The photothermal conversion efficiencies of this nanocomplex were calculated to be around 23.1 and 30.8% in NIR-I and NIR-II biowindows, respectively, showing good photothermal capacity and stability. The loaded DOX could be released in stimuli-responsive manners. The therapeutic efficacy was enhanced by PPy-PDA-PEG@DOX nanocomplex, indicating the high effectiveness of chemotherapy-enhanced phototherapy. This developed PPy-PDA-PEG@DOX nanocomplex shows promising applications in tumor treatment applications.     

A Bimetallic Nanozyme with Cascade Effect for Synergistic Therapy of Cancer

Novel nanocomposites were constructed through encapsulation of Au nanoparticles and Ru nanoparticles into dendritic mesoporous silica (DMSN-Au-Ru NPs). These exhibit improved effects due to a cascade catalytic ability for the synergistic therapy of cancer. Au nanoparticles with glucose oxidase-like properties were found to catalyze the oxidation of glucose to produce H₂O₂, while Ru nanoparticles could decompose H₂O₂ and produce toxic ¹O₂ for improved photodynamic therapy (PDT). In addition, the nanocomposites were found to have good photothermal performance under irradiation by near-infrared (NIR) light. Both in vitro and in vivo experiments show that the nanocomposites have good therapeutic effects due to the cascade catalytic effect and synergistic effect. These findings provide an effective way to design a new generation of nanodrugs for highly efficient cancer treatment.     

Multifunctional zinc phthalocyanine-phenolic resin (ZnPc-PFR)@MSN nanocomposite based fluorescent imaging,photothermal therapy,and pH-sensitive drug release

Because of the good fluorescence of zinc phthalocyanine-phenolic resin (ZnPc-PFR) photosensitizer and large specific surface area of mesoporous silica nanoparticles (MSNs), a highly efficient nano-drug carrier system, denoted as ZnPc-PFR@MSN, was constructed for photothermal therapy (PTT) and pH-sensitive drug delivery. The facile hydrothermal reaction was used to synthesize ZnPc-PFR nanoparticles in one-step. After loading the as-synthesized ZnPc-PFR nanoparticles into MSNs, and a good high drug-loading rate (143.7 mg g⁻¹) to the anticancer drug of Adriamycin (DOX) could be obtained. Thus, a novel nanosphere with the merits of good fluorescence, high drug-loading rate (143.7 mg g⁻¹), better sustained-release properties, and photothermal properties (reached 43.23°C within 260 s) was prepared. The as-synthesized multifunctional composites make it a good candidate in fluorescence imaging, PTT, and drug delivery.     

血清白蛋白-铜酞菁纳米粒子用于线粒体靶向光疗

铜酞菁是一类具有优异光物理性质和良好光热稳定性的染料,在印染、太阳能电池、传感器等领域中应用广泛。血清白蛋白作为血液中主要的转运蛋白,常用于小分子和药物的负载和运输。通过牛血清白蛋白（BSA）和铜酞菁类染料（LGS-CuPc）的自组装,构建了LGS-CuPc-BSA纳米粒子（LGS-CuPc-BSA NPs）,研究了其作为光动力和光热一体化试剂在光疗中的作用。在671 nm光照下（800 mW·cm^-2）,LGS-CuPc-BSA NPs活性氧产率达到23.3%,光热转换效率为36.8%。与LGS-CuPc比较,LGS-CuPc-BSA NPs光动力和光热治疗效果明显提升,且表现出较低的细胞毒性、良好的生物相容性以及在肿瘤细胞线粒体的定位能力,实现对肿瘤细胞的有效杀伤。     

F3-functionalized nanoscale metal–organic frameworks for tumor-targeting combined chemotherapy and chemodynamic therapy

Nanoscale metal–organic frameworks (nMOFs) have attracted much attention as emerging porous materials as drug delivery carriers. Appropriate surface modification of them can greatly improve stability and introduce biocompatibility and cancer targeting functionality into drug delivery systems. Herein, we prepared nano-sized MIL-101(Fe)-N₃ and loaded anticancer drug doxorubicin (DOX) into it. The synthetic polymer layer Alkyne-PLA-PEG was then attached to the F3 peptide (labeled as Alkyne-PLA-PEG-F3), and the surface of DOX/MIL-101(Fe)-N₃ was covalently modified with it to obtain DOX/MIL-101-PLA-PEG-F3. Nano-sized MIL-101(Fe)-N₃ has high drug loading capacity and the modification of MIL-101(Fe)-N₃ by polymer Alkyne-PLA-PEG not only improved the dispersion, but also avoided the sudden release of the drugs and increased the biocompatibility of nanocarriers. The F3 peptide introduced into the nanocarriers also enabled it to specifically target tumor tissues and achieved active targeted drug delivery. As a nucleolin-mediated endocytosis drug delivery system, DOX/MIL-101-PLA-PEG-F3 can not only deliver anticancer drugs to tumors accurately, but also participate in Fenton-like reaction to generate hydroxyl radicals (•OH) for chemodynamic therapy (CDT), thus enabling combination therapy. It holds great promise as drug candidates to reduce systemic toxicity and improve the efficacy of cancer treatment.     

Targeted Delivery of Drugs and Genes Using Polymer Nanocarriers for Cancer Therapy

Cancer is one of the primary causes of worldwide human deaths. Most cancer patients receive chemotherapy and radiotherapy, but these treatments are usually only partially efficacious and lead to a variety of serious side effects. Therefore, it is necessary to develop new therapeutic strategies. The emergence of nanotechnology has had a profound impact on general clinical treatment. The application of nanotechnology has facilitated the development of nano-drug delivery systems (NDDSs) that are highly tumor selective and allow for the slow release of active anticancer drugs. In recent years, vehicles such as liposomes, dendrimers and polymer nanomaterials have been considered promising carriers for tumor-specific drug delivery, reducing toxicity and improving biocompatibility. Among them, polymer nanoparticles (NPs) are one of the most innovative methods of non-invasive drug delivery. Here, we review the application of polymer NPs in drug delivery, gene therapy, and early diagnostics for cancer therapy.     

Dopamine-Modified Zero-Valent Iron Nanoparticles for Dual-Modality Photothermal and Photodynamic Breast Cancer Therapy

Phototherapy has the advantages of minimal invasion, few side effects, and improved accuracy for cancer therapy. The application of a polydopamine (PDA)-modified nano zero-valent iron (nZVI@PDA) as a new synergistic agent in combination with photodynamic/photothermal (PD/PT) therapy to kill cancer cells is discussed here. The nZVI@PDA offered high light-to-heat conversion and ROS generation efficiency under near-infrared (NIR) irradiation (808 nm), thus leading to irreversible damage to nZVI@PDA-treated MCF-7 cells at low concentration, without inducing apoptosis in normal cells. Irradiation of nZVI@PDA using an NIR laser converted the energy of the photons to heat and ROS. Our results showed that modification of the PDA on the surface of nZVI can improve the biocompatibility of the nZVI@PDA. This work integrated the PD and PT effects into a single nanodevice to afford a highly efficient cancer treatment. Meanwhile, nZVI@PDA, which combines the advantages of PDA and nZVI, displayed excellent biocompatibility and tumoricidal ability, thus suggesting its huge potential for future clinical research in cancer therapy.     

Synthesis of hollow maghemite (-Fe2O3) particles for magnetic field and pH-responsive drug delivery and lung cancer treatment

The development of smart stimuli-responsive materials for drug delivery offers new opportunities for precise drug release and cancer chemotherapy. A combination of more than one stimuli is highly desirable to further maximize the therapy by taking the advantages of various unique merits. Herein, we employed polyethylene glycol (PEG) functionalized γ-Fe₂O₃ particles (γ-Fe₂O₃/PEG) as a novel magnetic drug carrier for doxorubicin (DOX) delivery. The results showed that the γ-Fe₂O₃/PEG exhibited excellent thermal effects under alternating magnetic field (AMF), high magneto-thermal stability, and large DOX loading capacity. Furthermore, the effects of pH and AMF on the DOX drug release were studied. It was discovered that DOX loaded γ-Fe₂O₃/PEG carriers were highly responsive to both AMF and pH, resulting in significantly improved cancer cell killing capability over a single stimulus. The magnetic and pH responsive drug delivery system provided a new opportunity to minimize the side effects and maximize the therapeutic efficiency of lung cancer treatment.     

Supramolecular Nanodrugs Based on Covalent Assembly of Therapeutic Peptides toward In Vitro Synergistic Anticancer Therapy

Therapeutic peptides have attracted significant attention in clinical applications due to their advantages in biological origination and good biocompatibility. However, the therapeutic performance of peptides is usually hindered by their short half-lives in blood and inferior activity. Herein, supramolecular nanodrugs of therapeutic peptides are constructed by covalent assembly of chemotherapeutic peptides through genipin cross-linking. The resulting nanodrugs have intense absorbance in the near-infrared region and high photothermal conversion efficiencies, leading to the possibility of photothermal therapy. The combination of photothermal therapy and chemotherapy using the nanodrugs shows synergistic therapeutic effects on cancer cells. Hence, covalent assembly not only maintains the chemotherapeutic activities of the peptides but also triggers supramolecular photothermal effects, demonstrating that the covalent assembly of therapeutic peptides through genipin cross-linking is an efficient approach in constructing supramolecular nanodrugs toward synergistic anticancer therapy.     

Nanocarrier-Based Drug Delivery for Melanoma Therapeutics

Melanoma, as a tumor cell derived from melanocyte transformation, has the characteristics of malignant proliferation, high metastasis, rapid recurrence, and a low survival rate. Traditional therapy has many shortcomings, including drug side effects and poor patient compliance, and so on. Therefore, the development of an effective treatment is necessary. Currently, nanotechnologies are a promising oncology treatment strategy because of their ability to effectively deliver drugs and other bioactive molecules to targeted tissues with low toxicity, thereby improving the clinical efficacy of cancer therapy. In this review, the application of nanotechnology in the treatment of melanoma is reviewed and discussed. First, the pathogenesis and molecular targets of melanoma are elucidated, and the current clinical treatment strategies and deficiencies of melanoma are then introduced. Following this, we discuss the main features of developing efficient nanosystems and introduce the latest reports in the literature on nanoparticles for the treatment of melanoma. Subsequently, we review and discuss the application of nanoparticles in chemotherapeutic agents, immunotherapy, mRNA vaccines, and photothermal therapy, as well as the potential of nanotechnology in the early diagnosis of melanoma.     

Injectable Ovalbumin-Based Composite Implant for Photothermal Tumor Therapy

Polymeric hydrogels with three-dimensional network structures have found tremendous applications in biomedicine. Herein, we report the synthesis of a multifunctional implant based on ovalbumin (OVA) as a carrier capable of synergistically delivering a photothermal transducing agent (polydopamine, PDA) to tumors. The formation of PDA was achieved by utilizing the basicity of OVA, whereas the formation of the hydrogel implant was achieved through the in vitro/in vivo near-infrared (NIR) laser-induced hyperthermia of PDA. The as-prepared PDA@OVA implant exhibits high photothermal conversion efficiency (38.7 %). Once implanted in vivo, the OVA-based implant shows great versatility in the treatment of malignant tumors. Furthermore, a chemotherapeutic (doxorubicin, DOX) and a contrast agent (iohexol), dispersed in the OVA solution in advance, can also be firmly entrapped in the hydrogel along with the hydrogel formation. It is anticipated that the multifunctional OVA-based implant, not showing any obvious toxicity to healthy tissue, could be a promising system for synergistic cancer treatment.     

NIR light-triggered gelling in situ of porous silicon nanoparticles/PEGDA hybrid hydrogels for localized combinatorial therapy of cancer cells

Porous silicon-based nanocomposite hydrogels were readily constructed with the gelation of poly(ethylene glycol) double acrylates (PEGDA) macromers, due to the initiation of singlet oxygen photosensitized with porous silicon nanoparticles (PSiNPs) under near-infrared (NIR) light irradiation. Multifunctional PSiNPs/PEGDA nanocomposite hydrogels showed strong fluorescence, excellent biodegradability, significant photothermal effect, and sustained drug release with high efficiency (>80%). Finally, in situ growth of PSiNPs/PEGDA hybrid hydrogels on cancer cells was also achieved by NIR light, and then their biodegradation, drug release and synergistic chemo-phototherapeutic efficacy were further demonstrated, which could provide a significant localized inhibition for the viability, adherence, and migration of cancer cells in vitro. Thus, we suggested that these resultant hybrid hydrogels would have important potential on local cancer therapy in future clinical practice. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47443.     

Acid‐sensitive reactive oxygen species triggered dual‐drug delivery systems for chemo‐photodynamic therapy to overcome multidrug resistance

In clinical treatment, multidrug resistance (MDR) is one of the major obstacles resulting in the failure of chemotherapy. It is still a challenge to overcome MDR. Herein, we fabricated intelligent dextran‐based dual‐drug delivery systems histidine modified dextran conjugated doxorubicin/zinc porphyrin/paclitaxel (DHTD/Zn‐TPP/PTX) via supramolecular metallo‐coordination for synergistic chemo‐photodynamic therapy to overcome cancer drug resistance. In this designed DHTD/Zn‐TPP/PTX, one anticancer drug (doxorubicin, DOX) was conjugated on the dextran backbone through a reactive oxygen species sensitive linker and the other drug PTX was encapsulated into the acid responsive supramolecular micelles formed by the photosensitizer Zn‐TPP and histidine grafted on dextran. DHTD/Zn‐TPP/PTX with excellent stability could be effectively internalized by tumour cells. In the acidic tumour environment, the loaded PTX and Zn‐TPP as photosensitizer could be released; moreover, when irradiated with light the conjugated DOX could be specifically released because the linker broke. As the obtained data indicate, DHTD/Zn‐TPP/PTX exhibited not only an enhanced anticancer therapeutic effect but also significant growth inhibition for drug‐resistant MCF‐7/ADR cells to reverse MDR, having great potential for synergistic treatments of cancer to overcome MDR. © 2020 Society of Chemical Industry     

Co‐delivery of methotrexate and doxorubicin via nanocarriers of star‐like poly(DMAEMA‐block‐HEMA‐block‐AAc) terpolymers

Combined therapy is a promising strategy for clinical cancer treatment with synergistic effects. The purpose of the work reported was to evaluate a smart nanocarrier for co‐delivery of doxorubicin (DOX) and methotrexate (MTX). Since star‐like nanocarriers can load a high dose of drugs with various properties, we developed star polymer nanomicelles based on poly[(2,2‐dimethylaminoethyl methacrylate)‐block‐(2‐hydroxyethyl methacrylate)‐block‐(acrylic acid)] having potential for multi‐drug delivery. The nanomicelles demonstrated high encapsulation efficiency, i.e. 97.1% for DOX and 79.5% for MTX. To this end, the star‐like terpolymers were synthesized via atom transfer radical polymerization with pentaerythritol as an initiator. The micellar properties and dual stimuli‐responsive behaviour of the terpolymers were investigated using transmission electron microscopy, field emission scanning electron microscopy and dynamic light scattering measurements, concluding that this co‐therapy offers a promising approach for cancer treatment. © 2019 Society of Chemical Industry     

Rational design and synthesis of upconversion luminescence-based optomagnetic multifunctional nanorattles for drug delivery

Optomagnetic multifunctional composite based on upconversion luminescence nanomaterial is regarded as a promising strategy for bioimaging,disease diagnosis and targeted delivery of drugs.To explore a mesoporous nanostructure with excellent water dispersibility and high drug-loading capacity,a novel nanorattle-structured Fe3O4@SiO2@NaYF4∶Yb,Er magnetic upconversion nanorattle (MUCNR) was suc-cessfully designed by using Fe3O4 as core and NaYF4∶Yb,Er nanocrystals as shell.The microstructures and crystal phase of the as-prepared MUCNRs were evaluated by transmission electron microscopy,X-ray powder diffraction and N2 adsorption/desorption isotherms.The Kirkendall effect was adapted to explain the formation mechanism of the MUCNRs.The loading content and encapsulation efficiency of doxorubicin hydrochloride (DOX) could reach as high as 18.2％ and 60.7％,respectively.Moreover,the DOX loading MUCNR (DOX-MUCNR) system showed excellent sustained drug release and strong pH-dependent performance,which was conducive to drug release at the slightly acidic microenvironment of tumor.Microcalorimetry was used to quantify the interactions between the carrier structure and drug release rate directly.The heat release rates in the heat-flow diagrams are basically consistent with the DOX release rate,thereby showing that microcalorimetry assay not only provides a unique thermody-namic explanation for the structure-activity relationship of Fe3O4@SiO2@NaYF4∶Yb,Er MUCNRs but also provides powerful guidance to avoid the blind selection or design of drug carriers.Therefore,our work firmly provided a comprehensive perspective for using Fe3O4@SiO2@NaYF4∶Yb,Er MUCNRs as a remark-able magnetic targeted drug carrier.     

构建pH响应性中空介孔硅纳米复合材料用于肿瘤联合治疗

以正硅酸四乙酯为原料,合成直径约为100 nm的中空介孔二氧化硅纳米颗粒(HMSN)作为药物载体,采用物理包埋法和原位还原KMnO4生成二氧化锰的方法实现对化疗药物阿霉素(DOX)和MnO2的有效负载.此外,利用肿瘤靶向性功能肽(PEG-R7-RGDS)末端的氨基与醛基修饰的HMSN(HMSN-CHO)形成席夫碱,合成pH响应性纳米载药系统(DOX/MnO2@HMSN-imide-PEG-R7-RGDS).通过TEM、激光粒度仪、FTIR和XRD对合成材料形貌、粒径、结构和组成等进行表征.结果表明,合成的HMSN呈球形中空结构.DOX/MnO2@HMSN-imide-PEG-R7-RGDS在模拟的肿瘤酸性环境(pH 5.0)中具有明显快于在模拟生理环境(pH 7.4)下的药物释放行为.此外,体外细胞实验结果表明,DOX/MnO2@HMSN-imide-PEG-R7-RGDS可以靶向进入宫颈癌细胞(HeLa)并快速释放DOX.与此同时,纳米载药颗粒中的MnO2和肿瘤细胞中高浓度谷胱甘肽(GSH)反应产生具有类芬顿反应效果的Mn2+.Mn2+与肿瘤细胞内过表达的H2O2反应生成?OH,发挥增强的化学动力学治疗.细胞毒性实验证明,化学动力学治疗与化疗相结合能对HeLa细胞产生很高的细胞毒性.     

A magnetic polypeptide nanocomposite with pH and near-infrared dual responsiveness for cancer therapy

A magnetic polypeptide nanocomposite with pH and near-infrared (NIR) dual responsiveness was developed as a drug carrier for cancer therapy, which was prepared through the self-assembly of Fe₃O₄ superparamagnetic nanoparticles, poly(aspartic acid) derivative (mPEG-g-PDAEAIM) and doxorubicin (DOX) in water. Fe₃O₄ nanoparticles were prepared to provide the superparamagnetic core of nanocomposites for tumor targeting via chemical co-precipitation. The protonable imidazole groups of mPEG-g-PDAEAIM with a pKa of ~7 were accountable for the pH-responsiveness of nanocomposites. The photothermal effect of nanocomposites under the irradiation of NIR laser was induced via the interactions between dopamine groups of mPEG-g-PDAEAIM and Fe₃O₄ superparamagnetic nanoparticles to trigger the drug release. NMR, FT-IR, TEM, hysteresis loop analysis and MRI were utilized to characterize the materials. The DOX loaded nanocomposites exhibited pH-responsive and NIR dependent on/off switchable release profiles. The nanocomposites without drug loading (Fe₃O₄@mPEG-g-PDAEAIM) showed excellent biocompatibility while DOX loaded nanocomposites caused MCF-7 cells’ apoptosis due to the photothermal/chemotherapy combination effects. Overall, the pH and near-infrared dual responsive magnetic nanocomposite had a great potential for cancer therapy.     

pH响应的二氧化硅纳米粒子载运阿霉素进行癌症化疗

对所制备的二氧化硅纳米粒子(MS NPs)的载药性能、生物相容性和pH响应的药物释放性能进行了系统研究。实验结果显示,该MS NPs对化疗药物阿霉素(Dox)的负载量可达30μg·mg~(-1),具有很好的药物载运能力。此外,这种MS NPs具有pH响应性,能够对肿瘤微环境发生响应并精准释放药物对肿瘤细胞进行治疗。细胞MTT实验结果表明,所制得的MS NPs具有良好的生物相容性以及载药后很好的抗肿瘤能力,72h后可杀灭约82%的肿瘤细胞。因此,所制备的MS NPs在抗肿瘤领域有着巨大的应用潜力。