Preparation of a mesoporous silica-based nano-vehicle for dual DOX/CPT pH-triggered delivery

A dual doxorubicin/camptothecin (DOX/CPT) pH-triggered drug delivery mesoporous silica nanoparticle (MSN)-based nano-vehicle has been prepared. In this drug-delivery system (DDS), CPT is loaded inside the pores of the MSNs, while DOX is covalently attached to the surface of an aldehyde-functionalized MSN through a dihydrazide–polyethylene glycol chain. Thus, DOX and the linker act as pH-sensitive gatekeeper. The system is versatile and easy to assemble, not requiring the chemical modification of the drugs. While at physiological conditions the release of the drugs is negligible, at acidic pH a burst release of DOX and a gradual release of CPT take place. In vitro cytotoxicity tests have demonstrated that this DDS can deliver efficiently DOX and CPT for combination therapy.     

Controlled synthesis and size effects of multifunctional mesoporous silica nanosystem for precise cancer therapy

Nanomaterials-based drug delivery systems display potent applications in cancer therapy, owing to the enhanced permeability and retention effect and diversified chemical modification. In this study, we have tailored and synthesized different sized mesoporous silica nanoparticles (MSNs) through reactant control to investigate the relevancy of nanoparticle size toward anticancer efficacy and suppressing cancer multidrug resistance. The different sized MSNs loaded with anticancer ruthenium complex (RuPOP) and conjugated with folate acid (FA) to enhance the selectivity between cancer and normal cells. The nanosystem (Ru@MSNs) can specifically recognize HepG2 hepatocellular carcinoma cells, thus enhance accumulation and selective cellular uptake. The smaller sized (20?nm) Ru@MSNs exhibit higher anticancer activity against HepG2 cells, while the larger sized (80?nm) Ru@MSNs exhibit higher inhibitory effect against DOX-resistant hepatocellular carcinoma cells (R-HepG2). Moreover, Ru@MSNs induced ROS overproduction in cancer cells, leading to DNA damage and p53 phosphorylation, consequently promoting cancer cells apoptosis. Ru@MSNs (80?nm) also inhibited ABCB1 and ABCG2 expression in R-HepG2 cells to prevent drug efflux, thus overcome multidrug resistance. Ru@MSNs also inhibited tumor growth in vivo without obvious toxicity in major organs of tumor-bearing nude mice. Taken together, these results verify the size effects of MSNs nanosystem for precise cancer therapy.     

多功能介孔二氧化硅纳米粒在肿瘤治疗中的研究进展

介孔二氧化硅纳米粒由于较高的物理化学稳定性、易于官能化、低毒性以及对许多不同类型治疗剂的巨大负载能力,涉及了化学药物治疗、光热治疗、光动力治疗以及联合治疗,在肿瘤治疗方面受到极大的关注和广泛的研究探索。本文介绍了近年来基于介孔二氧化硅纳米粒作为载体在肿瘤治疗方面的一些研究报道,这些智能化的多功能性已经促使介孔二氧化硅纳米粒成为将来用于临床的非常有前途的药物纳米载体。     

刺激响应型纳米共给药系统的研究进展

纳米技术的进步对基于纳米载体构建的给药系统的发展产生了革命性影响。由于癌症机制的复杂性，单一药物治疗并不能取得满意的疗效，通过纳米载体同时负载作用机制不同的药物可以从多个通路杀伤癌细胞。除了化疗药物联用外，将药物与基因、抗体、蛋白或siRNA联用已成为近来的研究热点。利用肿瘤微环境内源性的刺激例如低pH值、强还原性、过表达的酶等，以及外部刺激如磁场、光、热、超声等，设计具有相应刺激响应性的纳米载体可以实现药物在病灶部位快速释放。本文将重点介绍刺激响应性纳米载体用于共同递送小分子化疗药物或生物分子的研究进展。     

Nanoparticle-mediated co-delivery of chemotherapeutic agent and siRNA for combination cancer therapy

Introduction: Cancer is the leading cause of death worldwide. Current cancer treatments in the clinic mainly include chemotherapy, radiotherapy and surgery, with chemotherapy being the most common.

Areas covered: Cancer treatments based on the single ‘magic-bullet’ concept are often associated with limited therapeutic efficacy, unwanted adverse effects, and drug resistance. The combination of multiple drugs is a promising strategy for effective cancer treatment due to the synergistic or additive effects. Small interfering RNA (siRNA) has the ability to knock down the expression of carcinogenic genes or drug efflux transporter genes, paving the way for cancer treatment. Treatment with both a chemotherapeutic agent and siRNA based on nanoparticle (NP)-mediated co-delivery is a promising approach for combination cancer therapy.

Expert opinion: The combination of chemotherapeutic agents and siRNAs for cancer treatment offers the potential to enhance therapeutic efficacy, decrease side effects, and overcome drug resistance. Co-delivery of chemical drug and siRNA in the same NP would be much more effective in cancer therapy than application of chemical agent or siRNA alone. With the development of material science, NPs have come to be the most widely used platform for co-delivery of chemotherapeutic drugs and siRNAs.     

A comparison of mesoporous silica nanoparticles and mesoporous organosilica nanoparticles as drug vehicles for cancer therapy

Mesoporous silica nanoparticles (MSNs) are promising drug carriers for use in cancer treatment owing to their excellent biocompatibility and drug‐loading capacity. However, MSN's incomplete drug release and toxic bioaccumulation phenomena limit their clinical application. Recently, researchers have presented redox responsive mesoporous organosilica nanoparticles containing disulfide (S–S) bridges (ss‐MONs). These nanoparticles retained their ability to undergo structural degradation and increased their local release activity when exposed to reducing agents. Disulfide‐based mesoporous organosilica nanoparticles offer researchers a better option for loading chemotherapeutic drugs due to their effective biodegradability through the reduction of glutathione. Although the potential of ss‐MONs in cancer theranostics has been studied, few researchers have systematically compared ss‐MONs with MSNs with regard to endocytosis, drug release, cytotoxicity, and therapeutic effect. In this work, ss‐MONs and MSNs with equal morphology and size were designed and used to payload doxorubicin hydrochloride (DOX) for liver cancer chemotherapy. The ss‐MONs showed considerable degradability in the presence of glutathione and performed comparably to MSNs on biocompatibility measures, including cytotoxicity and endocytosis, as well as in drug‐loading capacity. Notably, DOX‐loaded ss‐MONs exhibited higher intracellular drug release in cancer cells and better anticancer effects in comparison with DOX‐loaded MSNs. Hence, the ss‐MONs may be more desirable carriers for a highly efficient and safe treatment of cancer.     

Berberine‐loaded Janus nanocarriers for magnetic field‐enhanced therapy against hepatocellular carcinoma

Berberine, an bioactive isoquinolin alkaloid from traditional Chinese herbs, is considered to be a promising agent based on its remarkable activity against hepatocellular carcinoma. However, the clinical application of this nature compound had been hampered owing to its properties such as poor aqueous solubility, low gastrointestinal absorption, and reduced bioavailability. Therefore, we developed Janus magnetic mesoporous silica nanoparticles (Fe₃O₄‐mSiO₂ NPs) consisting of a Fe₃O₄ head for magnetic targeting and a mesoporous SiO₂ body for berberine delivery. A pH‐sensitive group was introduced on the surface of mesoporous silica for berberine loading to develop a tumor microenvironment‐responsive nanocarrier, which exhibited uniform morphology, good superparamagnetic properties, high drug‐loading amounts, superior endocytic ability, and low cytotoxicity. Berberine‐loaded Fe₃O₄‐mSiO₂ NPs exerted extraordinarily high specificity for hepatocellular carcinoma cells, which was due to the pH‐responsive berberine release, as well as higher endocytosis capacity in hepatocellular carcinoma cells rather than normal liver cells. More importantly, an external magnetic field could significantly improve antitumor activity of Ber‐loaded Fe₃O₄‐mSiO₂ NPs through enhancing berberine internalization. Taken together, our results suggest that Janus nanocarriers driven by the magnetic field may provide an effective and safe way to facilitate clinical use of berberine against hepatocellular carcinoma.     

Transferrin- and folate-modified,double-targeted nanocarriers for gene delivery

Context: Surface modification of nanocarriers with specific ligands defines a new biological identity, which assist in targeting and internalization of the nanocarriers to specific cell populations, such as cancers and disease organs.

Objective: This study aimed to develop systemically administrable dual ligands modified nanocarriers, which could target the cells through receptor-mediated pathways to increase the nuclear uptake of genetic materials.

Materials and methods: In the present work, transferrin (Tf) and folate (Fa) were linked onto polyethylene glycol-phosphatidylethanolamine (PEG-PE) separately to get transferrin-PEG-PE (T-PEG-PE) and folate-PEG-PE (F-PEG-PE) ligands for the surface modification of carriers. The in vivo transfection efficiency of the novel dual ligands modified (D-modified) vectors were evaluated in tumor-bearing animal models.

Results: D-Modified solid lipid nanoparticles/enhanced green fluorescence protein plasmid (D-SLN/pEGFP) has a particle size of 226?nm and a gene-loading quantity of 90%. D-SLN/pEGFP displayed over 30% higher transfection efficiency than unmodified SLN/pEGFP and single ligand modified particles in HepG2 cells.

Conclusion: It could be concluded that Tf and Fa could function as excellent active targeting ligands to improve the cell-targeting ability of the carriers and the resulting dual ligands modified vectors could be applied as a promising active targeting gene delivery system.     

Nano-drug co-delivery system of natural active ingredients and chemotherapy drugs for cancer treatment: a review

Chemotherapy drugs have been used for a long time in the treatment of cancer, but serious side effects are caused by the inability of the drug to be solely delivered to the tumor when treating cancer with chemotherapy. Natural products have attracted more and more attention due to the antitumor effect in multiple ways, abundant resources and less side effects. Therefore, the combination of natural active ingredients and chemotherapy drugs may be an effective antitumor strategy, which can inhibit the growth of tumor and multidrug resistance, reduce side effects of chemotherapy drugs. Nano-drug co-delivery system (NDCDS) can play an important role in the combination of natural active ingredients and chemotherapy drugs. This review provides a comprehensive summary of the research status and application prospect of nano-delivery strategies for the combination of natural active ingredients and chemotherapy drugs, aiming to provide a basis for the development of anti-tumor drugs.     

Anti-miRNA21 and resveratrol-loaded polysaccharide-based mesoporous silica nanoparticle for synergistic activity in gastric carcinoma

Abstract

Anti-miR21 and resveratrol (RSV)-loaded mesoporous silica nanoparticles (MSNs) conjugated with hyaluronic acid (HA) were developed to enhance therapeutic efficacy in gastric carcinoma. The surface conjugation of HA, which acts as a targeting ligand to the overexpressed CD44 receptor on gastric cancer cells, was clearly identified by the presence of a greyish shell on the dark MSNs. Confocal laser-scanning microscopy and flow cytometry analysis showed higher cellular internalisation of HA/RSVmirNP compared to RSVmirNP. In vitro cytotoxicity and apoptosis assays confirmed the superior anticancer effect of the optimised formulation and synergistic effects of anti-miR21 and RSV in gastric cancer cells. Importantly, HA/RSVmirNP showed significant (p?<?.001) reductions in the tumour burden compared to the other group. Indeed, HA/RSVmirNP showed a threefold higher tumour regression effect compared to that of free RSV and a twofold tumour regression effect compared to that of RSVmirNP, indicating its anticancer efficacy. The percentage of TUNEL-positive cells was significantly higher in HA/RSVmirNP-treated cells compared to any other group, indicating that the mechanism underlying the superior anticancer efficacy of HA/RSVmirNP included apoptosis and cell necrosis. Thus, a combination of anti-miR21 and RSV in a targeted nanocarrier might be a promising drug delivery system for gastric cancer therapy.     

An understanding of mitochondria and its role in targeting nanocarriers for diagnosis and treatment of cancer

Nanotechnology has changed the entire paradigm of drug targeting and has shown tremendous potential in the area of cancer therapy due to its specificity. In cancer, several targets have been explored which could be utilized for the better treatment of disease. Mitochondria, the so-called powerhouse of cell, portrays significant role in the survival and death of cells, and has emerged as potential target for cancer therapy. Direct targeting and nanotechnology based approaches can be tailor-made to target mitochondria and thus improve the survival rate of patients suffering from cancer. With this backdrop, in present review, we have reemphasized the role of mitochondria in cancer progression and inhibition, highlighting the different targets that can be explored for targeting of disease. Moreover, we have also summarized different nanoparticulate systems that have been used for treatment of cancer via mitochondrial targeting.     

Advances in mesoporous silica nanoparticles for targeted stimuli-responsive drug delivery: an update

Introduction: Mesoporous silica nanoparticles (MSNs) are outstanding nanoplatforms for drug delivery. Herein, the most recent advances to turn MSN-based carriers into minimal side effect drug delivery agents are covered.

Areas covered: This review summarizes the scientific advances dealing with MSNs for targeted and stimuli-responsive drug delivery since 2015. Delivery aspects to diseased tissues together with approaches to obtain smart MSNs able to respond to internal or external stimuli and their applications are here described. Special emphasis is done on the combination of two or more stimuli on the same nanoplatform and on combined drug therapy.

Expert opinion: The use of MSNs in nanomedicine is a promising research field because they are outstanding platforms for treating different pathologies. This is possible thanks to their structural, chemical, physical and biological properties. However, there are certain issues that should be overcome to improve the suitability of MSNs for clinical applications. All materials must be properly characterized prior to their in vivo evaluation; furthermore, preclinical in vivo studies need to be standardized to demonstrate the MSNs clinical translation potential.     

克服肿瘤多药耐药的药物共递送纳米载体的设计及研究新方向

多药耐药（multidrug resistance,MDR）是肿瘤治疗成功的主要障碍,药物共递送纳米载体因其肿瘤靶向、控制释放、一致的药动学曲线而被认为是克服MDR的有效策略。本综述总结了当前克服MDR的药物共递送纳米载体的设计思路,并分析了具有前景的研究方向,包括精确药物负载纳米载体、呈时序释放的纳米载体和对肿瘤微环境设计纳米载体,这些新兴策略为临床肿瘤治疗提供了新颖且更好的定制组合方案。     

Self-assembled polymeric nanocarrier-mediated co-delivery of metformin and doxorubicin for melanoma therapy

Malignant melanoma is a life-threatening form of skin cancer with a low response rate to single-agent chemotherapy. Although combined therapies of metformin (MET) and doxorubicin (DOX) are effective in treating a variety of cancers, including breast cancer, their different physicochemical properties and administration routines reduce the effective co-accumulation of both drugs in tumors. Nanoparticles (NPs) have been demonstrated to potentially improve drug delivery efficiency in cancer therapy of, for example, liver and lung cancers. Hence, in this study, we prepared pH-sensitive, biocompatible, tumor-targeting NPs based on the conjugation of biomaterials, including sodium alginate, cholesterol, and folic acid (FCA). As expected, since cholesterol and folic acid are two essentials, but insufficient, substrates for melanoma growth, we observed that the FCA NPs specifically and highly effectively accumulated in xenograft melanoma tumors. Taking advantage of the FCA NP system, we successfully co-delivered a combination of MET and DOX into melanoma tumors to trigger pyroptosis, apoptosis, and necroptosis (PANoptosis) of the melanoma cells, thus blocking melanoma progression. Combined, the establishment of such an FCA NP system provides a promising vector for effective drug delivery into melanoma and increases the possibility and efficiency of drug combinations for cancer treatment.     

Polydopamine and peptide decorated doxorubicin-loaded mesoporous silica nanoparticles as a targeted drug delivery system for bladder cancer therapy

We reported a simple polydopamine (PDA)-based surface modification method to prepare novel targeted doxorubicin-loaded mesoporous silica nanoparticles and peptide CSNRDARRC conjugation (DOX-loaded MSNs@PDA-PEP) for enhancing the therapeutic effects on bladder cancer. Drug-loaded NPs were characterized in terms of size, size distribution, zeta potential, transmission electron microscopy (TEM), Brunauer–Emmett–Teller (BET) surface area and drug loading content. In vitro drug release indicated that DOX-loaded MSNs@PDA and MSNs@PDA-PEP had similar release kinetic profiles of DOX. The PDA coating well controlled DOX release and was highly sensitive to pH value. Confocal laser scanning microscopy (CLSM) showed that drug-loaded MSNs could be internalized by human bladder cancer cell line HT-1376, and DOX-loaded MSNs@PDA-PEP had the highest cellular uptake efficiency due to ligand–receptor recognition. The antitumor effects of DOX-loaded nanoparticles were evaluated by the MTT assay in vitro and by a xenograft tumor model in vivo, demonstrating that targeted nanocarriers DOX-loaded MSNs@PDA-PEP were significantly superior to free DOX and DOX-loaded MSNs@PDA. The novel DOX-loaded MSNs@PDA-PEP, which specifically recognized HT-1376 cells, can be used as a potential targeted drug delivery system for bladder cancer therapy.     

Cancer prevention and treatment using combination therapy with natural compounds

ABSTRACT

Introduction: Naturally occurring compounds play an essential role in the prevention and treatment of various cancers. There are more than 100 plant and animal based natural compounds currently in clinical use.

Areas covered: 1) The importance of natural products combinations in the prevention and treatment of cancer, 2) the need to maximize efficacy while minimizing side effects when using natural product combinations, and 3) specifics related to plant and animal derived natural products, as well as agents derived from natural products. Therapies using natural compounds that have been investigated, their rationale, mechanism of action and findings are reviewed. When the data warrant it, combined interventions that appear to increase efficacy (compared with monotherapy) while minimizing toxicity have been highlighted. Pubmed was used to search for relevant publications.

Expert opinion: Combination therapy with natural compounds has the potential to be more effective than single agent therapy. Similar to pharmacologic agents, the goal is to maximize efficacy while mimimizing potential side effects. There is an increasing research focus on the development of agents derived from natural products, with notable successes already achieved from the effort.     

Metal nanoparticles as a promising technology in targeted cancer treatment

Traditional anticancer treatments have several limitations, but cancer is still one of the deadliest diseases. As a result, new anticancer drugs are required for the treatment of cancer. The use of metal nanoparticles (NPs) as alternative chemotherapeutic drugs is on the rise in cancer research. Metal NPs have the potential for use in a wide range of applications. Natural or surface-induced anticancer effects can be found in metals. The focus of this review is on the therapeutic potential of metal-based NPs. The potential of various types of metal NPs for tumor targeting will be discussed for cancer treatment. The in vivo application of metal NPs for solid tumors will be reviewed. Risk factors involved in the clinical application of metal NPs will also be summarized.     

Star polyester-based folate acid-targeting nanoparticles for doxorubicin and curcumin co-delivery to combat multidrug-resistant breast cancer

Chemotherapeutic treatments are indispensable in the treatment of breast cancer. However, the emergence of multidrug-resistance, strong cell toxicity, and poor targeting selection has inhibited their clinical application. In this study, two synergistic drugs, doxorubicin (DOX) and curcumin (CUR), were co-administered to overcome multidrug resistance (MDR). Based on the characteristics of the tumor microenvironment, we developed folic acid-modified nanoparticles ((DOX + CUR)-FA-NPs) based on a star-shaped polyester (FA-TRI-CL) to enhance the tumor targeting selectivity and drug loading (DL) capacity. The (DOX + CUR)-FA-NPs displayed a characteristic spheroid morphology with an ideal diameter (186.52 nm), polydispersity index (0.024), zeta potential (–18.87 mV), and good entrapment efficiency (97.64%/78.13%, DOX/CUR) and DL (20.27%/11.29%, DOX/CUR) values. In vitro pharmacokinetic and pharmacodynamic experiments demonstrated that the (DOX + CUR)-FA-NPs were gradually released, and they displayed the highest cell apoptosis and cellular uptake in MCF-7/ADR cells. Additionally, in vivo results illustrated that (DOX + CUR)-FA-NPs not only displayed significant tumor targeting and anticancer efficacy, but also induced less pathological damage to the normal tissue. In summary, co-administered DOX and CUR appeared to reverse MDR, and this targeted combinational nanoscale delivery system could thus be a promising carrier for tumor therapies in the future.