Bioresponsive functional nanogels as an emerging platform for cancer therapy

Introduction: Bioresponsive nanogels with a crosslinked three-dimensional structure and an aqueous environment that undergo physical or chemical changes including swelling and dissociation in response to biological signals such as mild acidity, hyperthermia, enzymes, reducing agents, reactive oxygen species (ROS), and adenosine-5?-triphosphate (ATP) present in tumor microenvironments or inside cancer cells have emerged as an appealing platform for targeted drug delivery and cancer therapy.

Areas covered: This review highlights recent designs and development of bioresponsive nanogels for facile loading and triggered release of chemotherapeutics and biotherapeutics. The in vitro and in vivo antitumor performances of drug-loaded nanogels are discussed.

Expert opinion: Bioresponsive nanogels with an excellent stability and safety profile as well as fast response to biological signals are unique systems that mediate efficient and site-specific delivery of anticancer drugs, in particular macromolecular drugs like proteins, siRNA and DNA, leading to significantly enhanced tumor therapy compared with the non-responsive counterparts. Future research has to be directed to the development of simple, tumor-targeted and bioresponsive multifunctional nanogels, which can be either constructed from natural polymers with intrinsic targeting ability or functionalized with targeting ligands. We anticipate that rationally designed nanotherapeutics based on bioresponsive nanogels will become available for future clinical cancer treatment.

Abbreviations: AIE, aggregation-induced emission; ATP, adenosine-5?-triphosphate; ATRP, atom transfer radical polymerization; BSA, bovine serum albumin; CBA, cystamine bisacrylamide; CC, Cytochrome C; CDDP, cisplatin; CT, computed tomography; DC, dendritic cell; DiI, 1,1?-dioctadecyl-3,3,3?,3?-tetramethylindocarbocyanine perchlorate; DOX, doxorubicin; dPG, dendritic polyglycerol; DTT, dithiothreitol; EAMA, 2-(N,N-diethylamino)ethyl methacrylate; EPR, enhanced permeability and retention; GrB, granzyme B; GSH, glutathione tripeptide; HA, hyaluronic acid; HAase, hyaluronidases; HCPT, 10-Hydroxycamptothecin; HEP, heparin; HPMC, hydroxypropylmethylcellulose; LBL, layer-by-layer; MTX, methotrexate; NCA, N-carboxyanhydride; OVA, ovalbumin; PAH, poly(allyl amine hydrochloride); PBA, phenylboronic acid; PCL, polycaprolactone; PDEAEMA, poly(2-diethylaminoethyl methacrylate); PDGF, platelet derived growth factor; PDPA, poly(2-(diisopropylamino)ethyl methacrylate); PDS, pyridyldisulfide; PEG, poly(ethylene glycol); PEGMA, polyethyleneglycol methacrylate; PEI, polyethyleneimine; PHEA, poly(hydroxyethyl acrylate); PHEMA, poly(2-(hydroxyethyl) methacrylate; PNIPAM, poly(N-isopropylacrylamide); PMAA, poly(methacrylic acid); PPDSMA, poly(2-(pyridyldisulfide)ethyl methacrylate); PTX, paclitaxel; PVA, poly(vinyl alcohol); QD, quantum dot; RAFT, reversible addition-fragmentation chain transfer; RGD, Arg-Gly-Asp peptide; ROP, ring-opening polymerization; ROS, reactive oxygen species; TMZ, temozolomide; TRAIL, tumor necrosis factor-related apoptosis inducing ligand; VEGF, vascular endothelial growth factor.     

Recent trends in targeted therapy of cancer using graphene oxide-modified multifunctional nanomedicines

Rapid progresses in nanotechnology fields have led us to use a number of advanced nanomaterials (NMs) for engineering smart multifunctional nanoparticles (NPs)/nanosystems (NSs) for targeted diagnosis and therapy of various diseases including different types of malignancies. For the effective therapy of any type of solid tumor, the treatment modality should ideally solely target the aberrant cancerous cells/tissue with no/trivial impacts on the healthy cells. One approach to achieve such unprecedented impacts can be fulfilled through the use of seamless multimodal NPs/NSs with photoacoustic properties that can be achieved using advanced NMs such as graphene oxide (GO). It is considered as one of the most promising materials that have been used in the development of various NPs/NSs. GO-based targeted NSs can be engineered as programmable drug delivery systems (DDSs) to perform on-demand chemotherapy combined with photonic energy for photothermal therapy (PTT) or photodynamic therapy (PDT). In the current review, we provide important insights on the GO-based NSs and discuss their potentials for the photodynamic/photothermal ablation of cancer in combination with anticancer agents.     

Recent progress of functionalised graphene oxide in cancer therapy

Abstract

In recent years, graphene oxide (GO) nanomaterials have attracted wide attention due to their large surface area, strong light sensitivity and good biocompatibility in cancer treatment. The rich oxygen-containing functional groups on the surface provide it with the opportunity to be modified by many functional molecules to expand biological applications and reduce toxicity. In this review, the properties of GO and the methods of surface modification are presented, and the toxicity of GO is analysed. In addition, the current applications of GO in cancer diagnoses and treatments including biological imaging, drug and gene delivery, phototherapy and imaging-mediated combination therapy are summarised. Finally, the prospects and challenges of GO in cancer treatment are discussed.     

Preparation and use of nanogels as carriers of drugs

Nanogels have high tunability and stability while being able to sense and respond to external stimuli by showing changes in the gel volume, water content, colloidal stability, mechanical strength, and other physical/chemical properties. In this article, advances in the preparation of nanogels will be reviewed. The application potential of nanogels in drug delivery will also be highlighted. It is the objective of this article to present a snapshot of the recent knowledge of nanogel preparation and application for future research in drug delivery.     

Eco-friendly synthesis of isatin-thiazolidine hybrid using graphene oxide catalyst in deep eutectic solvent and further evaluated for antibacterial,anticancer and cytotoxic agents

The utilization of green syntheses is important for reducing environmental pollution. Many synthetic approaches have been developed for the synthesis of isatin-thiazolidine hybrids. However, none of these methods directly address a green methodology for the synthesis of this key organic scaffold. This work deals with the synthesis of isatin-thiazolidine hybrids using graphene oxide (GO) catalyst in deep eutectic solvent (DES) as a green media. Synthesized compounds were evaluated for in-vitro antibacterial, anticancer and cytotoxic activities. The tested compounds exhibited more antibacterial activity against Gram-positive bacteria than Gram-negative bacteria. The compounds were observed to contain electron-withdrawing groups which displayed more bacterial inhibition. In summary, the current study reports that eco-friendly graphene oxide together with deep eutectic solvent catalyzed the synthesis of isatin-thiazolidine hybrids, whereby a high product yield was achieved in a short space of time. Although, newly synthesized compounds could not produce efficient biological activity, cytotoxicity instead.     

Multifunctional core-shell nanoplatforms (gold@graphene oxide) with mediated NIR thermal therapy to promote miRNA delivery

Recent insights into the nanomedicine have revealed that nanoplatforms enhance the efficacy of carrier in therapeutic applications. Here, multifunctional nanoplatforms were utilized in miRNA-101 delivery and NIR thermal therapy to induce apoptosis in breast cancer cells. Au nanorods (NRs) or nanospheres (NSs) covered with graphene oxide (GO) were prepared and functionalized with polyethylene glycol as a stabilizer and poly-L-arginine (P-L-Arg) as a targeting agent. In nanoplatforms, coupling Au@GO prepared stable structures with higher NIR reactivity. P-L-Arg substantially enhanced the cellular uptake and gene retardation of stuffs coated by them. However, rod-shape nanoplatforms indicated better performance in cellular uptake and gene transfection than spherical ones. NIR thermal therapy was implemented to improve gene release and in synergy with miRNA-101 activated the apoptotic pathway and decreased the viability of breast cancer cell (<20%). Briefly, presented delivery systems are potentially efficient in distinguishing cancer cells, miRNA internalization and controlling apoptosis of cancer cells.     

Polymeric micelles for targeted tumor therapy of platinum anticancer drugs

Introduction: Platinum anticancer drugs are effective against a wide range of tumors, though their severe adverse effects and resistance remain unresolved. A breakthrough in these drawbacks could be achieved by using polymeric micelles, i.e. nanoassemblies having a drug loaded core and a protective hydrophilic shell, incorporating platinum drugs for tumor-targeted delivery.

Areas covered: The development of cisplatin- (NC-6004) and DACHPt-loaded micelles (NC-4016) has been reviewed, particularly, from the viewpoint of the effect of their structural features on the tumor-targeting efficacy. We have also described new approaches for molecular targeting by installing ligand moieties on the surface of micelles. Moreover, small platinum drugs and platinum drug-loaded nanocarriers are introduced to explain the context for developing platinum drug-loaded polymeric micelles.

Expert opinion: NC-6004 and NC-4016 micelles meet critical structural and functional requirements for achieving safe and effective tumor targeting, enhancing efficacy even against drug resistant cancer cells, and have been translated into human studies, aiming to be the first-of-their-kind in the clinic. Due to their flexible design, polymeric micelles could readily integrate new features based on the knowledge arising from the human clinical trials toward the development of innovative formulations with superior performance.     

Novel folated and non-folated pullulan bioconjugates for anticancer drug delivery

Two new anticancer polymer therapeutics were designed for tumour cell targeting. The bioconjugates were synthesised by pullulan derivatisation with either doxorubicin or doxorubicin and folic acid. Pullulan was activated by periodate oxidation and functionalised by reductive conjugation with cysteamine and 1.9 kDa PEG(NH₂)₂. The cysteamine thiol groups were conjugated to doxorubicin through a pH-sensitive hydrazone spacer while the pending PEG-NH₂ functions of one derivatised pullulan batch were conjugated to folic acid to obtain one of the two polymer therapeutics. The reaction intermediates and the final products were characterised by mass spectrometry, UV–vis analysis and reverse phase and gel permeation chromatography. The folic acid-free derivative [(NH₂ PEG)-Pull-(Cyst-Dox)] contained 6.3% (w/w) doxorubicin while the folic acid-doxorubicin-coupled derivative [(FA-PEG)-Pull-(Cyst-Dox)] contained 6% (w/w) doxorubicin and 4.3% (w/w) folic acid. Photon correlation spectroscopy showed that (NH₂ PEG)-Pull-(Cyst-Dox) and (FA-PEG)-Pull-(Cyst-Dox) assembled into particles of about 150 and 100 nm diameter, respectively. The two bioconjugates displayed similar drug release profiles either at pH 7.4 buffer or in plasma, where less than 20% of doxorubicin was released within three days. At pH 5.5, both conjugates underwent complete drug release in about 40 h. In vitro studies carried out with KB tumour cells over-expressing folic acid receptor showed that both free doxorubicin and (FA-PEG)-Pull-(Cyst-Dox) were rapidly taken up by the cells, while the internalisation of the non-folated derivative was significantly slower. Cell viability studies did not show relevant difference between the two bioconjugates. After 72 h of incubation with folic acid receptor non-expressing MCF7 cells, the IC₅₀ values of doxorubicin, (NH₂PEG)-Pull-(Cyst-Dox) and (FA-PEG)-Pull-(Cyst-Dox) were 0.3 μM, 1.2 μM and 3.1 μM, respectively. After incubation with KB cells over-expressing folic acid receptor, the IC₅₀ values were 0.4 μM, 1.8 μM and 1.1 μM, respectively. Pharmacokinetic studies showed that 4 h after intravenous administration of the conjugates to Balb/c mice about 40% of the administered drug equivalent dose was present in the bloodstream while in the case of unconjugated doxorubicin, 80% of the drug was cleared within 30 min.These findings suggest that the novel doxorubicin–pullulan bioconjugates possess suitable properties for passive tumour targeting. On the other hand, folic acid conjugation has been found to have limited effect on selective cell up-take.     

Synthesis, in vitro and in vivo evaluation of a delivery system for targeting anticancer drugs to the brain

A 1, 4-dihydropyridine <--> pyridinium salt type redox system is described as a general and flexible method for site-specific and sustained delivery of drugs to the brain. This concept was used in the present investigation as a model to deliver an alkylating antitumor agent into the brain. A bis-(chloroethyl)amine drug was hooked to 1, 4-dihydropyridine chemical delivery system (CDS) through an amide linkage. Five new-target compounds (23-27) of the 1, 4-dihydropyridine CDS type were synthesized through the reduction of five new pyridinium quaternary intermediates (18-22). The synthesized 1, 4-dihydropyridines were subjected to various chemical and biological investigations to evaluate their ability to cross the blood-brain barrier (BBB), and to be oxidized biologically into their corresponding quaternary compounds. The in vitro oxidation studies showed that 1-benzyl-3-[N-[2-bis(2-chloroethyl)aminoethyl]-carbamoyl]-1, 4-dihydropyridine (23) and 1-(4-nitrobenzyl)-3-[N-[2-bis(2-chloroethyl)aminoethyl ]carbamoyl]-1, 4-dihydropyridine (27) could be oxidized into their corresponding quaternary compounds 18 and 22 respectively, at an adequate rate, which ensure the release of the carried anticancer drug. The in vivo studies showed that compound 23 was able to cross the BBB at detectable concentrations. On the other hand, the in vitro alkylation activity studies revealed that 1-(4-nitrobenzyl)-3-[N-[2-bis(2-chloroethyl)aminoethyl]carbamoyl]pyridinium bromide (22) is an alkylating agent with activity comparable to the known drug chlorambucil.     

氧化石墨烯纳米载体的生物相容性研究进展

氧化石墨烯是一种石墨烯的含氧衍生物,作为新型碳纳米材料,氧化石墨烯具有高载药能力、高度可修饰性及独特的光学性质等特性,在药物传递、生物成像及光热治疗等方面表现出了巨大的应用潜力。然而,随着氧化石墨烯在生物医学领域的广泛研究,其生物相容性问题成为了其进入临床应用的主要障碍。基于此,本文系统综述了氧化石墨烯在体外和体内的生物相容性,以及表面修饰如何影响其在体内外的毒性。通过分析氧化石墨烯的理化性质、使用剂量和表面修饰等对细胞和实验动物毒性的影响,为开发高效、安全的新型纳米载体提供参考。     

Disease-directed design of biodegradable polymers: Reactive oxygen species and pH-responsive micellar nanoparticles for anticancer drug delivery

Herein, we report reactive oxygen species (ROS)- and pH-responsive biodegradable polyethylene glycol (PEG)-block-polycarbonate by installing thioether groups onto the polycarbonate and its self-assembled core/shell structured micelles for anticancer drug delivery. Oxidation of thioethers to sulfoxide and subsequently sulfone induces an increase in hydrophilicity, resulting in more hydrophilic micellar core. This phase-change caused the micelles to swell and enhance cargo release. Carboxylic acid groups have also been installed onto thioether-containing polycarbonate to promote loading of amine-containing anticancer doxorubicin through electrostatic interaction. Urea-functionalized thioether-containing PEG-block-polycarbonates were synthesized to mix with the acid-functionalized PEG-block-polycarbonate for stabilizing micelle structure through hydrogen-bonding interaction. The mixed micelles were 50?nm in diameter and had a 25?wt% loading capacity for doxorubicin. Enhanced drug release from the micelles was triggered by low pH and high content of ROS. Drug-encapsulated micelles accumulated in tumors through leaky tumor vasculature in PC-3 human prostate cancer xenograft mouse model.     

Near-infrared light-activated IR780-loaded liposomes for anti-tumor angiogenesis and Photothermal therapy

Tumor angiogenesis is a key step in the process of tumor development, and antitumor angiogenesis has a profound influence on tumor growth. Herein we report a dual-function drug delivery system comprising a Near-infrared (NIR) dye and an anti-angiogenic drug within liposomes (Lip-IR780-Sunitinib) for enhanced antitumor therapy. The hydrophobic NIR dye IR780 was loaded into the liposome phospholipid bilayer, and the bilayer would be disrupted by laser irradiation so that anti-angiogenic drug sunitinib release would be activated remotely at the tumor site. The released hydrophilic sunitinib could potentially target multiple VEGF receptors on the tumor endothelial cell surface to inhibit angiogenesis. Meanwhile, IR780-loaded liposomes kill the cancer cells by photothermal therapy. Lip-IR780-Sunitinib exhibited enhanced anti-tumor and anti-angiogenic effects in vitro and in vivo. This system facilitates easy and controlled release of cargos to achieve anti-tumor angiogenesis and photothermal therapy.     

石墨烯复合材料的抗菌研究进展

由于抗生素过量使用会带来细菌耐药性、变异性等临床问题,越来越多的非抗生素类纳米材料被应用于抗菌的研究。本文综述了基于氧化石墨烯为载体的复合材料构建及其抗菌应用,讨论了此类纳米材料的合成方法及其抗菌性能和抗菌机制。     

Combination therapy: Opportunities and challenges for polymer–drug conjugates as anticancer nanomedicines

The discovery of new molecular targets and the subsequent development of novel anticancer agents are opening new possibilities for drug combination therapy as anticancer treatment. Polymer–drug conjugates are well established for the delivery of a single therapeutic agent, but only in very recent years their use has been extended to the delivery of multi-agent therapy. These early studies revealed the therapeutic potential of this application but raised new challenges (namely, drug loading and drugs ratio, characterisation, and development of suitable carriers) that need to be addressed for a successful optimisation of the system towards clinical applications.     

Targeting necroptosis in anticancer therapy: mechanisms and modulators

Necroptosis, a genetically programmed form of necrotic cell death, serves as an important pathway in human diseases. As a critical cell-killing mechanism, necroptosis is associated with cancer progression, metastasis, and immunosurveillance. Targeting necroptosis pathway by small molecule modulators is emerging as an effective approach in cancer therapy, which has the advantage to bypass the apoptosis-resistance and maintain antitumor immunity. Therefore, a better understanding of the mechanism of necroptosis and necroptosis modulators is necessary to develop novel strategies for cancer therapy. This review will summarize recent progress of the mechanisms and detecting methods of necroptosis. In particular, the relationship between necroptosis and cancer therapy and medicinal chemistry of necroptosis modulators will be focused on.     

Modeling of tumor growth and anticancer effects of combination therapy

Combination therapies are widely used in the treatment of patients with cancer. Selecting synergistic combination strategies is a great challenge during early drug development. Here, we present a pharmacokinetic/pharmacodynamic (PK/PD) model with a smooth nonlinear growth function to characterize and quantify anticancer effect of combination therapies using time-dependent data. To describe the pharmacological effect of combination therapy, an interaction term was introduced into a semi-mechanistic anticancer PK/PD model. This approach enables testing of a pharmacological hypothesis with respect to an anticipated pharmacological synergy of drug combinations, such as an assumed pharmacological synergy of complementary inhibition of a particular signaling pathway. The model was applied to three real data sets derived from preclinical screening experiments using xenograft mice. The suggested model fitted well the observed data from mono- to combination-therapy and allowed physiologically meaningful interpretation of the experiments. The tested drug combinations were assessed for their ability to act as synergistic modulators of tumor growth inhibition by the interaction parameter ψ. The presented approach has practical implications because it can be applied to standard xenograft experiments and may assist in the selection of both optimal drug combinations and administration schedules. The unique feature of the presented approach is the ability to characterize the nature of combined drug interaction as well as to quantify the intensity of such interactions by assessing the time course of combined drug effect.     

The application of graphene oxide in drug delivery

Introduction: As a shining star in material science, graphene oxide (GO) and its derivatives possess potential applications in a variety of areas. Among them, the application of GO to drug delivery has attracted ever-increasing interest in the past few years.

Areas covered: In this article, the authors summarize the latest progress of utilizing GO in the field of drug delivery. In particular, the functionalization of GO, cytotoxicity of GO and its derivatives, in vitro and in vivo drug delivery and the comparison with carbon nanotube-based delivery systems are discussed. Future perspectives and possible challenges in this emerging field are briefly described.

Expert opinion: GO and its derivatives are highly attractive for the application to drug delivery due to their exceptional physiochemical properties and unique planar structure in spite of some existing challenges, such as the reproducibly smart functionalization of GO and the investigation of its long-term toxicology.     

Chitosan-based luminescent/magnetic hybrid nanogels for insulin delivery, cell imaging, and antidiabetic research of dietary supplements

In this work, the chitosan-based luminescent/magnetic (CLM) nanomaterials were synthesized by direct gelation of chitosan, CdTe and superparamagnetic iron oxide into the hybrid nanogels. The morphology, sizes and properties of the nanogels prepared with different chitosan/QD/MNP ratios and under different processing parameters were researched. Fluorescence microscopy, FTIR spectra and TEM images confirmed the success of the preparation of the CLM hybrid nanogels. Spherical CLM hybrid nanogels with appropriate average sizes (<160 nm) were used for insulin loading. The actual loading amount of insulin was approximately 40.1mg/g. Human normal hepatocytes L02 cell line was used to explore the effects of additives, such as mangiferin (MF), (-)-epigallocatechin gallate (EGCG), and (-)-epicatechin gallate (ECG) on the insulin-receptor-mediated cellular uptake using insulin-loaded CLM (ICLM) hybrid nanogels. Above 80% of viability of L02 cells were watched at a nanogels concentration of 500 μg/mL whatever the additives existed or not. The study discovered that the fluorescent signals of the ICLM hybrid nanogels in L02 cells were more intense in the presence of MF, EGCG and ECG in medium than in the absence of these components, respectively. These results demonstrate that MF, EGCG and ECG are potentially able to enhance targeting combination of insulin with L02 cells and improve insulin sensitivity in L02 cells. The hybrid nanogels designed as a targeting carrier can potentially offer an approach for integration of insulin delivery, cell imaging, and antidiabetic investigation of dietary supplements.     

Assessment of the toxic potential of graphene family nanomaterials

Graphene, a single-atom-thick carbon nanosheet, has attracted great interest as a promising nanomaterial for a variety of bioapplications because of its extraordinary properties. However, the potential for widespread human exposure raises safety concerns about graphene and its derivatives, referred to as graphene-family nanomaterials. This review summarizes recent findings on the toxicological effects and the potential toxicity mechanisms of graphene-family nanomaterials in bacteria, mammalian cells, and animal models. Graphene, graphene oxide, and reduced graphene oxide elicit toxic effects both in vitro and in vivo, whereas surface modifications can significantly reduce their toxic interactions with living systems. Standardization of terminology and the fabrication methods of graphene-family nanomaterials are warranted for further investigations designed to decrease their adverse effects and explore their biomedical applications.     

功能化石墨烯负载氯霉素稳定性的研究

目的 通过利用β-环糊精对氧化石墨烯进行功能化改性,合成GO-β-CD杂化复合材料,探索其作为新型纳米载体负载药物的应用.方法 采用透射电子显微镜(TEM)、扫描电子显微镜(SEM)、拉曼光谱仪、傅立叶变换红外检测器(FT-IR)等检测方法对GO-β-CD的形貌和结构进行表征.结果 利用GO-β-CD体系对氯霉素进行负载,载药量高达115％,氯霉素滴眼液加速实验90d后,测得二醇物含量分别为10.13％(市售处方)和7.28％(改进处方)(≤8.0％,符合药典).结论 通过功能化的石墨烯载体对药物进行负载后,氯霉素的稳定性显著提高,并提高了制剂质量.