新兴的纳米技术为克服传统化学治疗(化疗)药物作用非特异性和非选择性损伤机体组织的瓶颈问题提供了好的手段,在提高化疗药物治疗效果、降低不良反应等方面显示出独特的优势[1]。多功能纳米载体作为一个极具发展前景的工具,一方面能够利用肿瘤组织和正常组织的差异选择性传输治疗药物,增强药物渗透与滞留效应(enhanced permeability and retention effect,EPR效应),并有特异性高表达分子标记[2],另一方面可以利用肿瘤微环境产生的一系列独特的物理化学性质,例如弱酸性、还原环境、异常温度梯度、过表达蛋白和酶、缺氧等,调控纳米载体对负载药物的释放[3]。其中智能纳米凝胶体系在抗癌药物有效装载、肿瘤细胞和组织特异性富集、控制释放和高效传递中取得了长足进展,这些特点为实现抗肿瘤药物的有效治疗提供纳米技术平台[4]。笔者在本文中重点介绍基于肿瘤微环境响应的调控型和靶向型纳米凝胶体系在肿瘤药物传输中的研究进展和发展前景。
YALLAPU MM,JAGGIM,CHAUHAN SC.Design and engineering of nanogels for cancer treatment[J].Drug Discov Today,2011,16(9):457-463.
Here, we provide a comprehensive insight into current advances in the use of nanogel-mediated chemotherapy for cancer treatment. Nanogels are composed of cross-linked three-dimensional polymer chain networks that are formed via covalent linkages or self-assembly processes. The porosity between the cross-linked networks of nanogels not only provides an ideal reservoir for loading drugs, oligonucleotides and imaging agents, but also protects them from environmental degradation and hazards. Here, we focus mainly on novel synthetic strategies and key considerations in the design of nanogel-based drug delivery systems for controlled and targeted cancer therapeutic applications.
JAIN RK,STYLIANOPOULOST.Delivering nanomedicine to solid tumors[J].Nat Rev Clin Oncol,2010,7(11):653-664.
Recent advances in nanotechnology have offered new hope for cancer detection, prevention, and treatment. While the enhanced permeability and retention effect has served as a key rationale for using nanoparticles to treat solid tumors, it does not enable uniform delivery of these particles to all regions of tumors in sufficient quantities. This heterogeneous distribution of therapeutics is a result of physiological barriers presented by the abnormal tumor vasculature and interstitial matrix. These barriers are likely to be responsible for the modest survival benefit offered by many FDA-approved nanotherapeutics and must be overcome for the promise of nanomedicine in patients to be realized. Here, we review these barriers to the delivery of cancer therapeutics and summarize strategies that have been developed to overcome these barriers. Finally, we discuss design considerations for optimizing the delivery of nanoparticles to tumors.
VASIEVICH EA,HUANGL.The Suppressive tumor micro-environment:a challenge in cancer immunotherapy[J].Mol Pharm,2011,8(3):635-641.
Abstract In this review, we introduce the changing public perception of vaccines and immunotherapy in cancer treatments. We discuss the roles that different immunosuppressive cells play in the tumor microenvironment. Tumor associated macrophages (TAMs) and M1 and M2 macrophage phenotypes are discussed in depth. Additionally, the role that myeloid derived suppressor cells (MDSC) and T regulatory cells (Tregs) play in the tumor microenvironment is addressed. Highlighted are examples of therapies used against each suppressive cell type, which vary from the hypothetical to the ineffective; the inefficient to the successful. A variety of treatments have been tried to combat this fundamental problem, indeed the cause that allows cancerous mutated cells to survive, multiply and overtake the body. Efficient methods to disable each particular suppressive type of cell have been introduced; this review summarizes the discussion with a table to guide future development. We see gene therapy as the most innovative and flexible method to lead the charge to specifically modifying the tumor microenvironment.
DANHIERF,FERONO,PREATV.To exploit the tumor microenvironment:passive and active tumor targeting of nanocarriers for drug delivery[J].J Control Release,2010,148:135-146.
Because of the particular characteristics of the tumor microenvironment and tumor angiogenesis, it is possible to design drug delivery systems that specifically target anti-cancer drugs to tumors. Most of the conventional chemotherapeutic agents have poor pharmacokinetics profiles and are distributed non-specifically in the body leading to systemic toxicity associated with serious side effects. Therefore, the development of drug delivery systems able to target the tumor site is becoming a real challenge that is currently addressed. Nanomedicine can reach tumor passively through the leaky vasculature surrounding the tumors by the Enhanced Permeability and Retention effect whereas ligands grafted at the surface of nanocarriers allow active targeting by binding to the receptors overexpressed by cancer cells or angiogenic endothelial cells. This review is divided into two parts: the first one describes the tumor microenvironment and the second one focuses on the exploitation and the understanding of these characteristics to design new drug delivery systems targeting the tumor. Delivery of conventional chemotherapeutic anti-cancer drugs is mainly discussed.
SCHROEDERA,HELLER DA,WINSLOW MM,et al.Treating metastatic cancer with nanotechnology[J].Nat Rev Cancer,2012,12:39-50.
Metastasis accounts for the vast majority of cancer deaths. The unique challenges for treating metastases include their small size, high multiplicity and dispersion to diverse organ environments. Nanoparticles have many potential benefits for diagnosing and treating metastatic cancer, including the ability to transport complex molecular cargoes to the major sites of metastasis, such as the lungs, liver and lymph nodes, as well as targeting to specific cell populations within these organs. This Review highlights the research, opportunities and challenges for integrating engineering sciences with cancer biology and medicine to develop nanotechnology-based tools for treating metastatic disease.
TORTORELLAS,KARAGIANNIS TC.Transferrin receptor-mediated endocytosis:a useful target for cancer therapy[J].J Membr Biol,2014,247(4):291-307.
Current management strategies fail to adequately treat with multivariable dose-restricting factors such as systemic toxicity and multi-drug resistance limiting therapeutic benefit, quality of life and complete long-term remission rates. The targeted delivery of a therapeutic compound aims to enhance its and cellular uptake, decrease systemic toxicity and improve therapeutic benefit with disease specificity. The , its receptor and their biological significance, has been widely characterised and vastly relevant when applied to targeting strategies. Utilising knowledge about the physiological function of the -receptor complex and the efficiency of its provides rationale to continue the of -targeted anticancer modalities. Furthermore, multiple studies report an upregulation in expression of the receptor on metastatic and drug resistant , highlighting its selectivity to . Due to the increased expression of the receptor in brain , the successful delivery of anticancer compounds to the site and the ability to cross the blood brain barrier has shown to be an important discovery. Its significance in the of -specific therapies is shown to be important by direct and immunotoxin studies which use and anti-receptor antibodies as the targeting moiety. Such conjugates have demonstrated enhanced cellular uptake via -mediated mechanisms and increased selective cytotoxicity in a number of cell lines and xenograft animal models. In addition, incubation of chemotherapy-insensitive cells with -targeted conjugates in vitro has resulted in a reversal of their drug resistance. immunotoxins have also shown similar promise, with a toxin mutant covalently bound to (Tf-CRM107) currently involved in clinical trials for the treatment of . Despite this, the inability to translate preliminary research into a clinical setting has compelled research into novel targeting strategies including the use of nanoparticulate theory in the design of drug delivery systems. The main objective of this review is to evaluate the importance of the -receptor complex as a target for therapy through extensive knowledge of both the physiological and pathological interactions between the complex and different cell types. In addition, this review serves as a summary to date of direct and immunotoxin studies, with an emphasis on as an important targeting moiety in the directed delivery of anticancer therapeutic compounds.
VLASHIE,KELDERHOUSE LE,STURGIS JE,et al.Effect of folate-targeted nanoparticle size on their rates of penetration into solid tumors[J].Acs Nano,2013,7(10):8573-8582.
Targeted therapies are emerging as a preferred strategy for the treatment of cancer and other diseases. To evaluate the impact of a high affinity targeting ligand on the rate and extent of tumor penetration of different sized nanomedicines, we have used intravital multiphoton microscopy to quantitate the kinetics of tumor accumulation of a homologous series of folate-PEG-rhodamine conjugates prepared with polyethylene glycols (PEG) of different molecular weights. We demonstrate that increasing the size of the folate-PEG-rhodamine conjugates results in both longer circulation times and slower tumor penetration rates. Although a “binding site barrier” is observed with the folate-linked polymers in folate receptor expressing tumors, ligand targeting eventually leads to increased tumor accumulation, with endocytosis of the targeted nanocarriers contributing to their enhanced tumor retention. Because the effects of nanocarrier size, shape, chemistry, and targeting ligand are interconnected and complex, we sugg...
CHOJ,KUSHIROK,TERAMURAY,et al.Lectin-tagged fluorescent polymeric nanoparticls for targeting of sialic acid on the living cells[J].Biomacromolecules,2014,15(6):2012-2018.
In this study, we fabricated lectin-tagged fluorescent polymeric nanoparticles approximately 35 nm in diameter using biocompatible polymers conjugated with lectins for the purpose of detecting sialic acid on a living cell surface, which is one of the most important biomarkers for cancer diagnosis. Through cellular experiments, we successfully detected sialic acid overexpression on cancerous cells with high specificity. These fluorescent polymeric nanoparticles can be useful as a potential bioimaging probe for detecting diseased cells.
WANGY,ZHOUJ,QIUL,et al.Cisplatin-alginate conju-gate liposomes for targeted delivery to EGFT-positive ovarian cancer cells[J].Biomaterials,2014,35(14):4297-4309.
Systemic side effects and low aqueous solubility have limited the clinical use of cisplatin (CDDP) in ovarian carcinoma and have contributed to failures in developing effective drug delivery systems. In order to develop a novel drug delivery system with enhanced efficacy and minimal adverse effects, we exploited the properties of sodium alginate (SA) to synthesize CDDP-SA conjugate (CS), which is highly soluble and readily incorporated into liposomes (CS-PEG-Lip). Epidermal growth factor receptor (EGFR) is overexpressed in many ovarian cancers, therefore we modified EGF on the liposomes (CS-EGF-Lip) to specifically target EGFR-expressing tumors, thereby increasing the bioavailability and efficacy of CDDP. In vitro experiments confirmed that EGF-Lip selectively recognized EGFR-positive SKOV3 cells and effectively penetrated tumor spheroids. We demonstrated that CS-EGF-Lip possessed satisfactory size distribution and exhibited significantly improved encapsulation and loading efficiency. Furthermore, CS-EGF-Lip sustained release of COOP in vitro, suggesting that CS-EGF-Lip may retain the antitumor activity of COOP. Inhibition of proliferation and migration was also greater with CS-EGF-Lip compared to CDDP. In vivo xenograft experiments revealed that administration of CS-EGF-Lip enhanced delivery of CDDP into ovarian tumor tissues and improved the antitumor efficacy of CDDP, while reducing nephrotoxicity and body weight loss in mice. These results suggest that CS-EGF-Lip may offer a promising strategy for CDDP delivery in the treatment of EGFR-positive ovarian carcinoma or similar tumors, with enhanced efficacy and fewer adverse effects. (C) 2014 Elsevier Ltd. All rights reserved.
BERTRANDN,WUJ,XU XY,et al.Cancer nanotechno-logy:the impact of passive and active targeting in the era of modern cancer biology[J].Adv Drug Del Rev,2014,66:2-25.
Cancer nanotherapeutics are progressing at a steady rate; research and development in the field has experienced an exponential growth since early 2000's. The path to the commercialization of oncology drugs is long and carries significant risk; however, there is considerable excitement that nanoparticle technologies may contribute to the success of cancer drug development. The pace at which pharmaceutical companies have formed partnerships to use proprietary nanoparticle technologies has considerably accelerated. It is now recognized that by enhancing the efficacy and/or tolerability of new drug candidates, nanotechnology can meaningfully contribute to create differentiated products and improve clinical outcome. This review describes the lessons learned since the commercialization of the first-generation nanomedicines including DOXIL03; and Abraxane03;. It explores our current understanding of targeted and non-targeted nanoparticles that are under various stages of development, including BIND-014 and MM-398. It highlights the opportunities and challenges faced by nanomedicines in contemporary oncology, where personalized medicine is increasingly the mainstay of cancer therapy. We revisit the fundamental concepts of enhanced permeability and retention effect (EPR) and explore the mechanisms proposed to enhance preferential “retention” in the tumor, whether using active targeting of nanoparticles, binding of drugs to their tumoral targets or the presence of tumor associated macrophages. The overall objective of this review is to enhance our understanding in the design and development of therapeutic nanoparticles for treatment of cancers.
GLANGEHAI LC,CALDORERA MM,SHIL.Nanoimprint lithography based fabrication of shape-specific,enzymatically-triggered smart nanoparticles[J].J Controlled Rel,2008,125(3):263-272.
Abstract Our ability to precisely manipulate size, shape and composition of nanoscale carriers is essential for controlling their in-vivo transport, bio-distribution and drug release mechanism. Shape-specific, "smart" nanoparticles that deliver drugs or imaging agents to target tissues primarily in response to disease-specific or physiological signals could significantly improve therapeutic care of complex diseases. Current methods in nanoparticle synthesis do not allow such simultaneous control over particle size, shape and environmentally-triggered drug release, especially at the sub 100 nm range. We report here a high-throughput nanofabrication technique using synthetic and biological macromers (peptides) to produce highly monodisperse, enzymatically-triggered nanoparticles of precise sizes and shapes. Particles as small as 50 nm were fabricated on silicon wafers and harvested directly into aqueous buffers using a biocompatible, one-step release technique. We further demonstrate successful encapsulation and precisely controlled enzyme-triggered release of antibodies and nucleic acids from these nanoparticles, thus providing a potential means for disease-controlled delivery of biomolecules.
NATALIAV,NUKOLOVA,TATIANAK.LHRH-targeted nanogels as a delivery system for cisplatin to ovarian cancer[J].Mol Pharmaceutics,2013,10(10):3913-3921.
Targeted drug delivery using multifunctional polymeric nanocarriers is a modern approach for cancer therapy. Our purpose was to prepare targeted nanogels for selective delivery of chemotherapeutic agent cisplatin to luteinizing hormone-releasing hormone (LHRH) receptor overexpressing tumor in vivo. Building blocks of such delivery systems consisted of innovative soft block copolymer nanogels with ionic cores serving as a reservoir for cisplatin (loading 35%) and a synthetic analogue of LHRH conjugated to the nanogels via poly(ethylene glycol) spacer. Covalent attachment of (d-Lys6)-LHRH to nanogels was shown to be possible without loss in either the ligand binding affinity or the nanogel drug incorporation ability. LHRH-nanogel accumulation was specific to the LHRH-receptor positive A2780 ovarian cancer cells and not toward LHRH-receptor negative SKOV-3 cells. The LHRH-nanogel cisplatin formulation was more effective and less toxic than equimolar doses of free cisplatin or untargeted nanogels in the treat...
SU SS,WANGH,et al.NIE G J.iRGD-coupled responsive fluorescent nanogel for targeted drug delivery[J].Biomaterials ,2013,34(13):3523-3533.
In this investigation, we have designed and synthesized a multifunctional nanogel for anti-tumor drug delivery. Thermo- and pH-responsive poly (N-isopropyl acrylamide-co-acrylic acid) nanogels (NGs) were synthesized by free radical precipitation polymerization. Positive charged chemotherapeutic drug doxorubicin (DOX) was introduced into the negatively charged swollen NGs by electrostatic adsorption at pH 7.4. Fluorescent bovine serum albumin (BSA) encapsulated gold nanoclusters (AuNCs) were conjugated onto the surface of NGs, followed by functionalization of tumor targeting peptide iRGD onto the BSA for tumor targeting. Interestingly, the DOX-encapsulated iRGD-decorated NGs maintain both thermo- and PH-responsive properties, which are favorable for achieving a controlled drug release in tumor tissues. Stable red fluorescent emission, derived from AuNCs, was used to detect and track the NGs in vitro. As expected, the iRGD motif mediated specific targeting to tumor and endothelial cells and enhanced cellular uptake of the NGs, as demonstrated by flow cytometry and confocal microscopy assays. In vitro cytotoxicity studies proved that the presence of iRGD enhanced the cytotoxic efficiency of DOX to the targeted cells. All together, our current study indicates that the NGs drug-carriers can deliver chemotherapeutic drug specifically to the tumor and endothelial cells with enhanced anti-tumor efficacy and controlled drug release. (C) 2013 Elsevier Ltd. All rights reserved.
MAYAS,SARMENTOB,NAIRA,et al.Smart stimuli sen-sitive nanogels in cancer drug delivery and imaging:a review[J].Curr Pharmaceutical Des,2013,41(19):7203-7218.
Nanogels are nanosized hydrogel particles formed by physical or chemical cross-linked polymer networks. The advantageous properties of nanogels related to the ability of retaining considerable amount of water, the biocompatibility of the polymers used, the ability to encapsulate and protect a large quantity of payload drugs within the nanogel matrix, the high stability in aqueous media, their stimuli responsively behavior potential, and the versatility in release drugs in a controlled manner make them very attractive for use in the area of drug delivery. The materials used for the preparation of nanogels ranged from natural polymers like ovalbumin, pullulan, hyaluronic acid, methacrylated chondroitin sulfate and chitosan, to synthetic polymers like poly (N-isopropylacrylamide), poly (Nisopropylacrylamide- co-acrylic acid) and poly (ethylene glycol)-b-poly (methacrylic acid). The porous nanogels have been finding application as anti-cancer drug and imaging agent reservoirs. Smart nanogels responding to external stimuli such as temperature, pH etc can be designed for diverse therapeutic and diagnostic applications. The nanogels have also been surface functionalized with specific ligands aiding in targeted drug delivery. This review focus on stimuli-sensitive, multi-responsive, magnetic and targeted nanogels providing a brief insight on the application of nanogels in cancer drug delivery and imaging in detail.
NAK,BAE YH.Self-assembled hydrogel nanoparticles res-ponsive to tumor extracellular pH from pullulan derivative/sulfonamide conjugate:characterization,aggregation,and adriamycin release in vitro[J].Pharmaceutical Res,2002,19(5):681-688.
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NAK,LEE ES,BAEH.Self-organized nanogels responding to tumor extracellular pH:pH-dependent drug release and in vitro cytotoxicity against MCF-7 cells[J].Bioconjugate Chem,2007,18(5):1568-1574.
The principal objective of this study was to fabricate doxorubicin-loaded self-organized nanogels composed of hydrophobized pullulan(PUL)-N_(alpha)-Boc-L-histidine(bHis)conjugates.Their responses to tumor extracellular pH(pHe)were determined,and they were also evaluated with regard to their anticancer efficacy against breast cancer cell lines(MCF-7).bHis was grafted to a PUL-deoxycholic acid(DO)conjugate(PUL-DO)via an ester linkage.PUL-DO/bHis conjugates with two different degrees of bHis substitutions(PUL-DO/bHis36 and PUL-DO/bHis78)were synthesized.PUL-DO/bHis nanogels formed via dialysis at a pH of 8.5 evidenced larger particle sizes(<140 nm)and lower critical aggregation concentrations(CACs)than did the PUL-DO nanogels(90 nm).The pH-dependent CAC of PUL-DO/bHis78 changed dramatically,from 1.2 mu g/mL at pH 8.5,to 10 at 7.0,and to 660 at 6.2.A similar tendency in pH-dependent size was also noted.The ionization of the imidazole ring in bHis is principally responsible for pH dependency.The bHis moieties function as a switching tool responding to external pH.Doxorubicin(DOX)-loaded nanogels were assessed for pH-dependent releasing kinetics.The release rate of DOX from the PUL-DO/bHis78 nanogels increased significantly with reductions in pH.This resulted in increased cytotoxicity(30% cell viability at a dose of 10 mu g/mL DOX equivalent)against sensitive MCF-7 cells at a pH of 6.8 and,low cytotoxicity at pH 7.4(65% cell viability at an identical dose).The results show that PUL-DO/bHis nanogels may potentially be employed as anti-tumor drug carriers.
DU JZ,SUN TM,SONG WJ,et al.A tumor-acidity-acti-vated charge-conversional nanogel as an intelligent vehicle for promoted tumoral-cell uptake and drug delivery[J].Angew Chem Int Ed Engl,2010,49(21):3621-3626.
ABSTRACT Cerebral dopamine (DA) transmission is thought to be an important modulator for the development and occurrence of aggressive behavior. However, the link between aggression and DA transmission in humans has not been investigated using molecular imaging and standardized behavioral tasks. We investigated aggression as a function of DA transmission in a group of (N = 21) healthy male volunteers undergoing 6-[(18)F]-fluoro-l-DOPA (FDOPA)-positron emission tomography (PET) and a modified version of the Point Subtraction Aggression Paradigm (PSAP). This task measures aggressive behavior during a monetary reward-related paradigm, where a putative adversary habitually tries to cheat. The participant can react in three ways (i.e., money substraction of the putative opponent [aggressive punishment], pressing a defense button, or continuing his money-making behavior). FDOPA-PET was analyzed using a steady-state model yielding estimates of the DA-synthesis capacity (K), the turnover of tracer DA formed in living brain (kloss), and the tracer distribution volume (Vd), which is an index of DA storage capacity. Significant negative correlations between PSAP aggressive responses and the DA-synthesis capacity were present in several regions, most prominently in the midbrain (r = -0.640; p = 0.002). Lower degrees of aggressive responses were associated with higher DA storage capacity in the striatum and midbrain. Additionally, there was a significant positive correlation between the investment into monetary incentive responses on the PSAP and DA-synthesis capacity, notably in the midbrain (r = +0.618, p = 0.003). The results suggest that individuals with low DA transmission capacity are more vulnerable to reactive/impulsive aggression in response to provocation.
MOGHADAM MN,KOLESOVV,VOGELA,et al.Contro-lled release from a mechanically-stimulated thermosensitive self-heating composite hydrogel[J].Biomaterials,2014,35(1):450-455.
Temperature has been extensively explored as a trigger to control the delivery of a payload from environment-sensitive polymers. The need for an external heat source only allows limited spatiotemporal control over the delivery process. We propose a new approach by using the dissipative properties of a hydrogel matrix as an internal heat source when the material is mechanically loaded. The system is comprised of a highly dissipative hydrogel matrix and thermo-sensitive nanoparticles that shrink upon an increase in temperature. Exposing the hydrogel to a cyclic mechanical loading for a period of 5 min leads to an increase of temperature of the nanoparticles. The concomitant decrease in the volume of the nanoparticles increases the permeability of the hydrogel network facilitating the release of its payload. As a proof-of-concept, we showed that the payload of the hydrogel is released after 5-8 min following the initiation of the mechanical loading. This delivery method would be particularly suited for the release of growth factor as it has been shown that cell receptor to growth factor is activated 5-20 min following a mechanical loading. (C) 2013 Elsevier Ltd. All rights reserved.
JU CY,MOR,XUE JW,et al.Sequential intra-inter-cellular nanoparticle delivery system for deep tumor penetration[J].Angew Chem Int Edit,2014,53(24):6253-6258.
To achieve deep tumor penetration of large-sized nanoparticles (NPs), we have developed a reversible swelling-shrinking nanogel in response to pH variation for a sequential intra-intercellular NP delivery. The nanogel had a crosslinked polyelectrolyte core, consisting of N-lysinal-N'-succinyl chitosan and poly(N-isopropylacrylamide), and a crosslinked bovine serum albumin shell, which was able to swell in an acidic environment and shrink back under neutral conditions. The swelling resulted in a rapid release of the encapsulated chemotherapeutics in the cancer cells for efficient cytotoxicity. After being liberated from the dead cells, the contractive nanogel could infect neighboring cancer cells closer to the center of the tumor tissue.
PARKKM,LEE DW,SARKARB,et al.Reduction-sen-sitive,robust vesicles with a non-covalently modifiable surface as a multifunctional drug-delivery platform[J].Small,2010,6(13):1430-1441.
The design and synthesis of a novel reduction-sensitive, robust, and biocompatible vesicle (SSCB[6]VC) are reported, which is self-assembled from an amphiphilic cucurbit[6]uril (CB[6]) derivative that contains disulfide bonds between hexaethylene glycol units and a CB[6] core. The remarkable features of SSCB[6]VC include: 1) facile, non-destructive, non-covalent, and modular surface modification using exceptionally strong host-guest chemistry; 2) high structural stability; 3) facile internalization into targeted cells by receptor-mediated endocytosis, and 4) efficient triggered release of entrapped drugs in a reducing environment such as cytoplasm. Furthermore, a significantly increased cytotoxicity of the anticancer drug doxorubicin to cancer cells is demonstrated using doxorubicin-loaded SSCB[6]VC, the surface of which is decorated with functional moieties such as a folate-spermidine conjugate and fluorescein isothiocyanate-spermidine conjugate as targeting ligand and fluorescence imaging probe, respectively. SSCB[6]VC with such unique features can be used as a highly versatile multifunctional platform for targeted drug delivery, which may find useful applications in cancer therapy. This novel strategy based on supramolecular chemistry and the unique properties of CB[6] can be extended to design smart multifunctional materials for biomedical applications including gene delivery.
RYU JH,CHACKO RT,JIWPANICHS,et al.Self-dross-linked polymer nanogels:a versatile nanoscopic drug delivery platform[J].J Am Chem Soc,2010,132(48):17227-17235.
Nanoscopic vehicles that stably encapsulate drug molecules and release them in response to a specific trigger are of great interest due to implications in therapeutic applications, especially for cancer therapy. For this purpose, we have synthesized highly stable polymeric nanogels, in which the kinetics of guest molecule release can be fine-tuned by control over cross-linking density. The polymer nanogel precursor is based on a random copolymer that contains oligoethyleneglycol (OEG) and pyridyldisulfide (PDS) units as side-chain functionalities. By introducing variations into the precursor polymer, such as molecular weight and the relative percentages of hydrophilic OEG units and hydrophobic PDS functionalities, we have achieved significant control over nanogel size. We show that the noncovalently encapsulated guest molecules can be released in response to a redox trigger, glutathione (GSH). Stability of dye encapsulation inside the nanogels and tunability in the release of guest molecules have been dem...
MACIELD,FIGUERIRAP,XIAO SL,et al.Redox-res-ponsive alginate nanogels with enhanced anticancer cytotoxicity[J].Biomacromolecules,2013,14(9):3140-3146
Although doxorubicin (Dox) has been widely used in the treatment of different types of cancer, its insufficient cellular uptake and intracellular release is still a limitation. Herein, we report an easy process for the preparation of redox-sensitive nanogels that were shown to be highly efficient in the intracellular delivery of Dox. The nanogels (AG/Cys) were obtained through in situ crosslinking of alginate (AG) using cystamine (Cys) as a crosslinker via a miniemulsion method. Dox was loaded into the AG/Cys nanogels by simply mixing it in aqueous solution with the nanogels, that is, by the establishment of electrostatic interactions between the anionic AG and the cationic Dox. The results demonstrated that the AG/Cys nanogels are cytocompatible, have a high drug encapsulation efficiency (95.2 +/- 4.7%), show an in vitro accelerated release of Dox in conditions that mimic the intracellular reductive conditions, and can quickly be taken up by CAL-72 cells (an osteosarcoma cell line), resulting in higher Dox intracellular accumulation and a remarkable cell death extension when compared with free Dox. The developed nanogels can be used as a tool to overcome the problem of Dox resistance in anticancer treatments and possibly be used for the delivery of other cationic drugs in applications beyond cancer.
QIAO ZY,ZHANGR,DU FS,et al.Multi-responsive nanogel containing motifs of orthoester,oligo(ethylene glycol)and disulfide linkage as carriers of hydrophobic anti-cancer drugs[J].J Control Rel,2011,152(1):57-66.
A family of multi-responsive nanogels with different compositions and crosslinking degrees have been prepared by the miniemulsion copolymerization of monomethyl oligo(ethylene glycol) acrylate (OEGA) and an ortho ester-containing acrylic monomer, 2-(5,5-dimethyl-1,3-dioxan-2-yloxy) ethyl acrylate (DMDEA), with bis(2-acryloyloxyethyl) disulfide (BADS) as a crosslinker. These nanogels are thermoresponsive and labile in the weakly acidic or reductive environments. The thermoresponsive behaviors, acid-triggered hydrolysis, and reduction-induced degradation of these nanogels were studied by means of dynamic light scattering (DLS), transmission electron microscopy (TEM) and atomic force microscopy (AFM). The results indicate that the volume phase transition temperature (VPTT), thermally induced deswelling ratio, and acid-triggered swelling ratio of the nanogels are closely relevant to their compositions and crosslinking degrees. Although these nanogels could be reductively disrupted by dithiothreitol (DTT), single polymer chains with sizes smaller than 20 nm were not detected by DLS. This is probably due to the existence of some unbreakable linkages formed by chain transfer to the disulfide bond during the radical polymerization. These nanogels are capable of encapsulating hydrophobic compounds. The loading capability of the nanogels for Nile Red (NR), paclitaxel (PTX), and doxorubicin (DOX), and the release behaviors of the drug-loaded nanogels were investigated by UV-vis spectrometry and HPLC. As expected, drug release can be greatly accelerated by a cooperative effect of both acid-triggered hydrolysis and DTT-induced degradation. Finally, the PTX-loaded nanogels exhibit a concentration-dependent toxicity to MCF-7 cells while the intact unloaded nanogels are non-toxic, thereby they may be used as potential carriers for hydrophobic anticancer drugs.
, 叶孟原, 彭晏, 蔡萌, 祝红达
