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.     

Functional poly(p-phenylene)s as targeting and drug carrier materials

Polymers have a substantial attention in drug delivery systems owing to the diverse intrinsic advantages. It is important to carry the drug to the target site and release to exert its effects. Herein, poly(p-phenylene)s with amino and poly(ethylene glycol) substituents (PPP-NH₂-g-PEG) were used as a carrier for doxorubicin (DOX), an anticancer drug, and haloperidol, a sigma receptor targeting ligand. Both human cervix adenocarcinoma cell line (HeLa) and human keratinocyte cell line (HaCaT) having different Sigma receptor 1 (SigmaR1) expression levels were compared. HeLa was found to express twofold SigmaR1 compared to HaCaT cells. Cell imaging studies showed that, DOX cell uptake was higher in HeLa cells when targeted with haloperidol.     

Hyaluronic acid conjugated graphene oxide for targeted drug delivery

Nano-sized graphene oxide (GO) is functionalized with adipic acid dihydrazide to introduce amine groups, and then hyaluronic acid (HA) is covalently conjugated to GO by the formation of amide bonds. The resulting HA-grafted GO (GO–HA) has negligible hemolytic activity and very low cytotoxicity towards HeLa and L929 cells, and it can be effectively taken up by cancer cells through receptor-mediated endocytosis. The histological, hematological and biochemical analysis results suggest no perceptible toxicity of GO–HA in mice at a high exposure level of 10 mg kg⁻¹ and at an exposure time of up to 10 days. Doxorubicin (DOX) can be efficiently loaded on the GO–HA, and the resulting GO–HA/DOX exhibits notable cytotoxicity to HeLa cells. The in vivo drug delivery capability of GO–HA is demonstrated by following the tumor growth in mice after intravenous administration of GO–HA/DOX. The results indicate that GO–HA can efficaciously deliver DOX to the tumors and suppress tumor growth.     

Mesoporous silica nanoparticles loading doxorubicin reverse multidrug resistance: performance and mechanism

Multidrug resistance (MDR) is one of the major obstacles for successful chemotherapy in cancer. One of the effective approaches to overcome MDR is to use nanoparticle-mediated drug delivery to increase drug accumulation in drug resistant cancer cells. In this work, we first report that the performance and mechanism of an inorganic engineered delivery system based on mesoporous silica nanoparticles (MSNs) loading doxorubicin (DMNs) to overcome the MDR of MCF-7/ADR (a DOX-resistant and P-glycoprotein (P-gp) over-expression cancer cell line). The experimental results showed that DMNs could enhance the cellular uptake of doxorubicin (DOX) and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells. The IC(50) of DMNs against MCF-7/ADR cells was 8-fold lower than that of free DOX. However, an improved effect of DOX in DMNs against MCF-7 cells (a DOX-sensitive cancer cell line) was not found. The increased cellular uptake and nuclear accumulation of DOX delivered by DMNs in MCF-7/ADR cells was confirmed by confocal laser scanning microscopy, and could result from the down-regulation of P-gp and bypassing the efflux action by MSNs themselves. The cellular uptake mechanism of DMNs indicated that the macropinocytosis was one of the pathways for the uptake of DMNs by MCF-7/ADR cells. The in vivo biodistribution showed that DMNs induced a higher accumulation of DOX in drug resistant tumors than free DOX. These results suggested that MSNs could be an effective delivery system to overcome multidrug resistance.     

Self‐assembled nanoparticles from folate‐decorated maleilated pullulan–doxorubicin conjugate for improved drug delivery to cancer cells

The goal of this study was to develop doxorubicin conjugate nanoparticles with increased antitumor effects, reduced side effects and the ability to overcome multidrug resistance (MDR). In this regard, folate‐decorated maleilated pullulan–doxorubicin conjugate nanoparticles were developed as carriers for co‐delivery of pyrrolidinedithiocarbamate and doxorubicin (FA‐MP‐DOX/PDTC + DOX NPs). The resultant nanoparticles showed spherical geometry, with an average diameter of 152 nm. The two drugs were released from the nanoparticles in a slow, pH‐dependent sustained release. To test the efficacy of these nanoparticles, in vitro tests including cell viability and folate receptor‐mediated endocytosis were conducted against both A2780 cells and A2780/DOX^R cells. Compared to free DOX, the FA‐MP‐DOX/PDTC + DOX NPs showed effective but less potent cytotoxicity against A2780 cells. For A2780/DOX^R cells, they showed enhanced cellular uptake, increased targeting capacity and cytotoxicity. These results suggest that co‐delivery of PDTC and DOX may further overcome MDR by transporting an increased amount of DOX within cells in addition to the folate receptor‐mediated endocytosis process. © 2012 Society of Chemical Industry     

Simultaneous synthesis and functionalization of water-soluble up-conversion nanoparticles for in-vitro cell and nude mouse imaging

Water-solubility and biocompatibility are prerequisites for rare-earth up-converting nanophosphors applied to biological imaging. In this work, we have developed a facile and one-step synthesis technique, through which water-soluble NaYF(4): Yb(3+), Er(3+) nanoparticles (NPs) with functional groups including 3-mercaptopropionic acid, 6-aminocaproic acid and poly(ethylene glycol)methyl ether on their surface can be directly prepared without any further surface treatment. Some inorganic salts will be selected as starting materials, water and some low toxic organic agents have been used as reaction media, which differs from earlier works. Structural and up-converting fluorescence are characterized by a variety of techniques. Cell uptake and in-vitro imaging of the as-synthesized NPs have been investigated using a multiphoton con-focal laser scanning microscope with a near-infrared excitation source. Internalization of the bare and functionalized NPs in human lung carcinoma A549 and human cervical carcinoma HeLa cells are studied at a nanoparticle loading of 10 μg mL(-1) over an exposure period from 30 min to 24 h. The cytotoxicity of modified NPs in HeLa cells is found to be low. In addition, the feasibility of the NPs in animal imaging has been demonstrated by subcutaneously injecting these NPs into nude mouse. The results indicated that our directly synthesized NPs coated with various functional groups are promising as bio-imaging agents due to their easy uptake, long lasting, low cytotoxicity, emissive in various human carcinoma cell lines and small animals through up-conversion with near-infrared excitation.     

Both FA- and mPEG-conjugated chitosan nanoparticles for targeted cellular uptake and enhanced tumor tissue distribution

Both folic acid (FA)- and methoxypoly(ethylene glycol) (mPEG)-conjugated chitosan nanoparticles (NPs) had been designed for targeted and prolong anticancer drug delivery system. The chitosan NPs were prepared with combination of ionic gelation and chemical cross-linking method, followed by conjugation with both FA and mPEG, respectively. FA-mPEG-NPs were compared with either NPs or mPEG-/FA-NPs in terms of their size, targeting cellular efficiency and tumor tissue distribution. The specificity of the mPEG-FA-NPs targeting cancerous cells was demonstrated by comparative intracellular uptake of NPs and mPEG-/FA-NPs by human adenocarcinoma HeLa cells. Mitomycin C (MMC), as a model drug, was loaded to the mPEG-FA-NPs. Results show that the chitosan NPs presented a narrow-size distribution with an average diameter about 200 nm regardless of the type of functional group. In addition, MMC was easily loaded to the mPEG-FA-NPs with drug-loading content of 9.1%, and the drug releases were biphasic with an initial burst release, followed by a subsequent slower release. Laser confocal scanning imaging proved that both mPEG-FA-NPs and FA-NPs could greatly enhance uptake by HeLa cells. In vivo animal experiments, using a nude mice xenograft model, demonstrated that an increased amount of mPEG-FA-NPs or FA-NPs were accumulated in the tumor tissue relative to the mPEG-NPs or NPs alone. These results suggest that both FA- and mPEG-conjugated chitosan NPs are potentially prolonged drug delivery system for tumor cell-selective targeting treatments.     

Intelligent self-assembly prodrug micelles loading doxorubicin in response to tumor microenvironment for targeted tumors therapy

Compared with physical drug-loaded nanocarriers, polymeric prodrug micelles have many advantages such as high drug loading and enhanced stability in blood, so they have great potential in cancer therapy. However, these micelles have a big disadvantage, which cannot achieve long-term circulation in vivo and high absorption of tumor cells simultaneously, resulting in low administration efficiency and poor therapeutic effect on cancer. To solve problems of traditional polymeric prodrug micelles, novel polymeric micelles with tumor microenvironment response were designed in this work. The prodrug formed by covalently linking D-α-tocopherol polyethylene glycol succinate (TPGS₃₃₅₀), peptide (Pep), and doxorubicin (DOX) (TPGS₃₃₅₀-Pep-DOX) was self-assembled into micelles by encapsulating DOX physically. When the micelles entered the tumor tissue, the long-chain polyethylene glycol (PEG) was sensitively cut by the matrix metalloproteinase 2/9 (MMP2/9) enzyme, exposing the targeting molecule folate, then it entered the cell through the endocytic pathway mediated by the folate receptor. The drug loading content, encapsulation efficiency, critical micelle concentration, and invitro release of the micelles invented in this study were measured to characterize their properties. The particle size and zeta potential of micelles were characterized by dynamic light scattering. Images were scanned by transmission electron microscopes. In vitro cytotoxicity, cellular uptake, and in vivo antitumor effect evaluation experiments were measured to show that smart micelles have made much progress in material chemistry and drug delivery, making it possible to apply a stimulus-response carrier drug delivery system in clinical application.     

CD44 Receptor-Mediated/Reactive Oxygen Species-Sensitive Delivery of Nanophotosensitizers against Cervical Cancer Cells

Stimulus-sensitive, nanomedicine-based photosensitizer delivery has an opportunity to target tumor tissues since oxidative stress and the expression of molecular proteins, such as CD44 receptors, are elevated in the tumor microenvironment. The aim of this study is to investigate the CD44 receptor- and reactive oxygen species (ROS)-sensitive delivery of nanophotosensitizers of chlorin e6 (Ce6)-conjugated hyaluronic acid (HA) against HeLa human cervical cancer cells. For the synthesis of nanophotosensitizers, thioketal diamine was conjugated with the carboxyl group in HA and then the amine end group of HA-thioketal amine conjugates was conjugated again with Ce6 (Abbreviated as HAthCe6). The HAthCe6 nanophotosensitizers were of small diameter, with sizes less than 200. Their morphology was round-shaped in the observations using a transmission electron microscope (TEM). The HAthCe6 nanophotosensitizers responded to oxidative stress-induced changes in size distribution when H₂O₂ was added to the nanophotosensitizer aqueous solution, i.e., their monomodal distribution pattern at 0 mM H₂O₂ was changed to dual- and/or multi-modal distribution patterns at higher concentrations of H₂O₂. Furthermore, the oxidative stress induced by the H₂O₂ addition contributed to the disintegration of HAthCe6 nanophotosensitizers in morphology, and this phenomenon accelerated the release rate of Ce6 from nanophotosensitizers. In a cell culture study using HeLa cells, nanophotosensitizers increased Ce6 uptake ratio, ROS generation and PDT efficacy compared to free Ce6. Since HA specifically bonds with the CD44 receptor of cancer cells, the pretreatment of free HA against HeLa cells decreased the Ce6 uptake ratio, ROS generation and PDT efficacy of HAthCe6 nanophotosensitizers. These results indicated that intracellular delivery of HAthCe6 nanophotosensitizers can be controlled by the CD44 receptor-mediated pathway. Furthermore, these phenomena induced CD44 receptor-controllable ROS generation and PDT efficacy by HAthCe6 nanophotosensitizers. During in vivo tumor imaging using HeLa cells, nanophotosensitizer administration showed that the fluorescence intensity of tumor tissues was relatively higher than that of other organs. When free HA was pretreated, the fluorescence intensity of tumor tissue was relatively lower than those of other organs, indicating that HAthCe6 nanophotosensitizers have CD44 receptor sensitivity and that they can be delivered by receptor-specific manner. We suggest that HAthCe6 nanophotosensitizers are promising candidates for PDT in cervical cancer.     

Novel NGR anchored pullulan micelles for controlled and targeted delivery of doxorubicin to HeLa cancerous cells

Doxorubicin (DOX) is used to treat different kinds of cancers, including cervix carcinoma. However, it has various side effects such as cardiotoxicity. Nano-sized controlled releasing carriers such as polymeric micelles are of interesting approaches to overcome these side effects of doxorubicin in cancer chemotherapy. Regarding the up-regulation of CD13/APN receptors on the cervix carcinoma cells, which can bind to peptide sequences specially NGR (asparagine–glycine–arginine) with high affinity, peptide sequence (NGR) targeted micelles would lead to effective treatment of this carcinoma. In this study, the NGR peptide sequence was synthesized using the solution-phase strategy from asparagine, glycine, and arginine residues. The pullulan–retinoic acid conjugate and pullulan–retinoic acid–NGR conjugate were prepared by the amide and ester bond formation between the hydroxyl groups of pullulan and carboxylic acid groups of retinoic acid and peptide sequence. Pullulan–retinoic acid–NGR micelles were prepared by the direct dissolution method. The optimized micelles, according to their particle size (124.5 nm), zeta potential (? 3.65 mV), entrapment efficiency (85%), and release of DOX (70%, within 72 h) were assessed for their cytotoxicity on HeLa cells using MTT assay. NGR-targeted pullulan/retinoic acid micelles had higher cytotoxicity than the free DOX in cell culture studies on the HeLa cell line, and this can be a promising result in the treatment of cervix carcinoma.     

Fluorescent Silica Nanoparticles Targeting Mitochondria: Trafficking in Myeloid Cells and Application as Doxorubicin Delivery System in Breast Cancer Cells

Fluorescent silica nanoparticles (SiNPs) appear to be a promising imaging platform, showing a specific subcellular localization. In the present study, we first investigated their preferential mitochondrial targeting in myeloid cells, by flow cytometry, confocal microscopy and TEM on both cells and isolated mitochondria, to acquire knowledge in imaging combined with therapeutic applications. Then, we conjugated SiNPs to one of the most used anticancer drugs, doxorubicin (DOX). As an anticancer agent, DOX has high efficacy but also an elevated systemic toxicity, causing multiple side effects. Nanostructures are usually employed to increase the drug circulation time and accumulation in target tissues, reducing undesired cytotoxicity. We tested these functionalized SiNPs (DOX-NPs) on breast cancer cell line MCF-7. We evaluated DOX-NP cytotoxicity, the effect on the cell cycle and on the expression of CD44 antigen, a molecule involved in adhesion and in tumor invasion, comparing DOX-NP to free DOX and stand-alone SiNPs. We found a specific ability to release a minor amount of CD44+ extracellular vesicles (EVs), from both CD81 negative and CD81 positive pools. Modulating the levels of CD44 at the cell surface in cancer cells is thus of great importance for disrupting the signaling pathways that favor tumor progression.     

Surface modified cellulose nanocrystalline hybrids actualizing efficient and precise delivery of doxorubicin into nucleus with: In vitro and in vivo evaluation

Rod-like-shape nanomedicines with the ability of lysosomal pH-controlled drug release can precisely deliver doxorubicin (DOX) into its target, nucleus, and can fully exert its anticancer effect. Taking advantage of their large specific surface area, cellulose nanocrystals (CNCs) were used to fabricate pH-responsive DOX-loaded rod-like shaped hybrids nanomedicines: cis-aconityl-doxorubicin (CAD)@polyethylenimine (PEI)@CNCs (CAD@PEI@CNCs) via layer-by-layer (LbL) assembly. In vitro, CAD@PEI@CNCs hybrids displayed rod-like shape, high drug loading content, lysosomal pH-controlled drug release, efficient and precise doxorubicin (DOX) delivering into the nucleus. Moreover, the cellular uptake of CAD@PEI@CNCs hybrids was 20.9 folds higher than that of DOX·HCl against A549 cells. The cytotoxicity of CAD@PEI@CNCs hybrids was much higher than that of DOX·HCl and the pH-irresponsive hybrids against A549 cell. In vivo, CAD@PEI@CNCs hybrids exhibited good antitumor effect: (42.0 ± 6)% inhibition rate and few harms to the nude mice. Altogether, rod-like shaped pH-responsive CAD@PEI@CNCs hybrids nanomedicines could efficiently overcome the vascular and tumor barriers, and precisely deliver DOX to nucleus to convert DOX antitumor effects. These results indicate that CAD@PEI@CNCs have great potential to act as advanced nanomedicines with enhanced delivery efficiency and therapeutic efficiency.     

Preparation and efficacy of tumor vasculature‐targeted doxorubicin cationic liposomes coated by N‐trimethyl chitosan

Cationic liposomes (CLs) can accumulate in tumor vascular endothelial cells (VECs) to show high selective targeting ability. Therefore, chemotherapeutic agent‐loaded CLs are considered as new therapeutic vehicles to enhance the treatment efficacy. This study investigated the effect of N‐trimethyl chitosan (TMC), one of derivatives of chitosan with positive charge determined by its degree of quaternization (DQ), on preparing doxorubicin (DOX)‐loaded CLs. TMCs with various DQ, i.e., 20% (TMC20), 40% (TMC40), and 60% (TMC60) were synthesized and characterized by ¹HNMR. DOX‐loaded liposomes (DOXL) were prepared by ammonium sulfate gradients followed by TMC‐coating to obtain TMC‐coated DOXL with various positive surface charges. The morphology, size, ζ‐potential and drug release in vitro of TMC‐coated DOXL were studied compared with those of DOXL. Human umbilical vein endothelial cells (HUVECs) as cell model, the vascular targeting ability of TMC‐coated DOXL was evaluated in vitro. A solid tumor, formed by implantationmurine hepatoma cells (H₂₂) into mice, as tumor model, the tumor inhibition rate and tumor histological sections stained by HE of TMC‐coated DOXL group were researched compared with those of free DOX and DOXL group. It was found that with the increase of TMC's DQ, the positive surface charge of TMC‐coated DOXL was enhanced accordingly, which had little effect on DOX release in vitro while led to the significant increase of DOX uptake by HUVECs in vitro and the treatment effect on solid tumor in vivo. Especially, TMC‐coated DOXL showed better targeting ability to the nuclei compared with free DOX and DOXL, which could further enhance the efficacy of DOX in vivo. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Enhanced loading of doxorubicin into polymeric micelles by a combination of ionic bonding and hydrophobic effect,and the pH-sensitive and ligand-mediated delivery of loaded drug

Folate-conjugated micelles were fabricated from amphiphilic diblock copolymers with poly(ethylene glycol) as the hydrophilic block and a random copolymer of n-butyl methacrylate and methacrylic acid as the hydrophobic block. Doxorubicin (DOX), a model drug that contains an amine group and hydrophobic moiety, was loaded with a high loading capacity into micelles by a combination of ionic bonding and hydrophobic effect. The combined interactions imparted a pH-sensitive delivery property to the system. The release rate of loaded DOX was slow at pH 7.4 (i.e., mimicking the plasma environment) but increased significantly at acidic pH (i.e., mimicking endosome/lysosome conditions). Acid-triggered drug release resulted from the carboxylate protonation of poly(methacrylic acid), which dissociated the ionic bonding between the micelles and DOX. Cellular uptake by folate receptor-overexpressing HeLa cells of the DOX-loaded folate-conjugated micelles was higher than that of micelles without folate conjugation. Thus, the DOX-loaded folate-conjugated micelles displayed higher cytotoxicity to HeLa cells.     

Surface modification of TPGS-b-(PCL-ran-PGA) nanoparticles with polyethyleneimine as a co-delivery system of TRAIL and endostatin for cervical cancer gene therapy

The efficient delivery of therapeutic genes into cells of interest is a critical challenge to broad application of non-viral vector systems. In this research, a novel TPGS-b-(PCL-ran-PGA) nanoparticle modified with polyethyleneimine was applied to be a vector of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and endostatin for cervical cancer gene therapy. Firstly, a novel biodegradable copolymer, TPGS-b-(PCL-ran-PGA), was synthesized and characterized. The nanoparticles were fabricated by an emulsion/solvent evaporation method and then further modified with polyethyleneimine (PEI) carrying TRAIL and/or endostatin genes. The uptake of pIRES2-EGFP and/or pDsRED nanoparticles by HeLa cells were observed by fluorescence microscopy and confocal laser scanning microscopy. The cell viability of TRAIL/endostatin-loaded nanoparticles in HeLa cells was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Severe combined immunodeficient mice carrying HeLa tumor xenografts were treated in groups of six including phosphate-buffered saline control, blank TPGS-b-(PCL-ran-PGA) nanoparticles, blank TPGS-b-(PCL-ran-PGA)/PEI nanoparticles, and three types of gene nanoparticles. The activity was assessed using average increase in survival time, body weight, and solid tumor volume. All the specimens were then prepared as formalin-fixed and paraffin-embedded tissue sections for hematoxylin-eosin staining. The data showed that the nanoparticles could efficiently deliver plasmids into HeLa cells. The cytotoxicity of the HeLa cells was significantly increased by TRAIL/endostatin-loaded nanoparticles when compared with control groups. The use of TPGS in combination with TRAIL and endostatin had synergistic antitumor effects. In conclusion, the TRAIL/endostatin-loaded nanoparticles offer considerable potential as an ideal candidate for in vivo cancer gene delivery.     

Clostridium neurotoxin fragments as potential targeting moieties for liposomal gene delivery to the CNS

Targeted transfection of the CNS with synthetic, nonviral vectors represents a huge technical challenge. The approach explored here attempts to combine self-assembly ABCD nanoparticles (Kostarelos and Miller, Chem. Soc. Rev. 2005, 34, 970), with the potential of Clostridium neurotoxin fragments to effect receptor-mediated transfection of neuronal cells. Cationic liposome-plasmid DNA complexes were first modified with a PEG stealth layer, before the addition of C-terminal fragments of tetanus toxin (TH(C)), botulinum toxin (BH(C)) or the truncated C-terminal domain of TH(C) as biological "targeting" ligands. First-generation nanoparticles were identified for the transfection of two neuronal cell lines (human SH-5YSY and rat/mouse hybrid N18-RE105); control studies were also performed with HeLa cells. ABCD nanoparticle transfections of the neuronal cell lines were up to 30-fold higher than corresponding control transfections with nanoparticles that lacked the protein ligand. We also demonstrate apparent receptor-mediated uptake by means of competition-binding and real-time confocal experiments. By contrast, nanoparticle transfection of HeLa cells appeared to involve alternative nonspecific enhanced cellular uptake mechanism(s). Receptor-mediated and nonspecific mechanisms appear to be in competition, potentially harming the capacity of receptor-mediated delivery to effect proper targeted delivery of nucleic acids to cells ex vivo and in vivo.     

An FGFR1-Binding Peptide Modified Liposome for siRNA Delivery in Lung Cancer

Liposome modification by targeting ligands has been used to mediate specific interactions and drug delivery to target cells. In this study, a new peptide ligand, CP7, was found to be able to effectively bind to FGFR1 through reverse molecular docking and could cooperate with VEGFR3 to achieve targeting of A549 cells. CP7 was modified on the surface of the liposome to construct a targeted and safe nanovehicle for the delivery of a therapeutic gene, Mcl-1 siRNA. Due to the specific binding between CP7 and A549 cells, siRNA-loaded liposome-PEG-CP7 showed increased cellular uptake in vitro, resulting in significant apoptosis of tumor cells through silencing of the Mcl-1 gene, which is associated with apoptosis and angiogenesis. This gene delivery system also showed significantly better antitumor activity in tumor-bearing mice in vivo. All of these suggested that siRNA-loaded liposome-PEG-CP7 could be a promising gene drug delivery system with good bioavailability and minimal side effects for treatment.     

In Vitro Investigation of Self-Assembled Nanoparticles Based on Hyaluronic Acid-Deoxycholic Acid Conjugates for Controlled Release Doxorubicin: Effect of Degree of Substitution of Deoxycholic Acid

Self-assembled nanoparticles based on a hyaluronic acid-deoxycholic acid (HD) chemical conjugate with different degree of substitution (DS) of deoxycholic acid (DOCA) were prepared. The degree of substitution (DS) was determined by titration method. The nanoparticles were loaded with doxorubicin (DOX) as the model drug. The human cervical cancer (HeLa) cell line was utilized for in vitro studies and cell cytotoxicity of DOX incorporated in the HD nanoparticles was accessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, cellular uptake of fluorescently labeled nanoparticles was also investigated. An increase in the degree of deoxycholic acid substitution reduced the size of the nanoparticles and also enhanced their drug encapsulation efficiency (EE), which increased with the increase of DS. A higher degree of deoxycholic acid substitution also lead to a lower release rate and an initial burst release of doxorubicin from the nanoparticles. In summary, the degree of substitution allows the modulation of the particle size, drug encapsulation efficiency, drug release rate, and cell uptake efficiency of the nanoparticles. The herein developed hyaluronic acid-deoxycholic acid conjugates are a good candidate for drug delivery and could potentiate therapeutic formulations for doxorubicin–mediated cancer therapy.     

GSH-responsive polyglutamic acid nanocarriers for dual targeted cancer therapy

In order to reduce the toxic side effects of chemotherapeutic drugs and improve the targeting and efficiency of cancer treatment, the development of drug delivery system has received great attention. In this study, second generation polyglutamic acid dendrimers (G₂) are used as basic materials to produce porous nanoparticles through cross link by crosslinkers containing disulfide bonds. The crosslinked products (G₂)_n have negative electricity and abundant voids, which enable them to adsorb the electronegative anticancer drug DOX. At the same time, in order to transport DOX to the tumor site, we modified FA on DOX and encapsulated it in magnetic mesoporous silica (FA-DOX-MSNs). Therefore, the final nanoparticles (FA-DOX-MSNs/(G₂)_n) not only have dual targeting ability to transport DOX to the tumor site, but also have reductive responsiveness that can release drugs responsively in the tumor cells. In addition, it has good biocompatibility and endocytosis ability.     

One pot preparation of polyurethane-based GSH-responsive core-shell nanogels for controlled drug delivery

In this work, we present a new type of glutathione (GSH)-responsive polyurethane-based core‑shell nanogels (RS-CS-PUNGs) with hydrophilic methoxypolyethylene glycols (mPEG) shell, which was prepared by a one-pot synthetic method. The obtained RS-CS-PUNGs not only show a good size distribution with the hydrodynamic radii around of 20 nm, but also exhibit good stability in the organic solvent. The results demonstrate that GSH (10 mM) trigger the nanogel swelling and accelerate the loaded drug release in PBS (pH = 7.4). Although the RS-CS-PUNGs loaded with DOX show a slower cellular uptake behavior than the free doxorubicin (DOX), which is likely caused by the controlled drug release property of the nanocarrier, the enhanced cellular uptake fluorescence intensity of RS-CS-PUNGs loaded with DOX is still observed compared to the control group. Both MTT and CCK-8 assay indicate that although an obvious lower initial cytotoxicity is observed compared to free DOX at 24 h postincubation, the cytotoxicity of the RS-CS-PUNGs loaded with DOX is obvious enhanced after treated 72 h, which stayed at the similar level with free DOX. Attributing to the easy preparation progress and GSH-responsive property, RS-CS-PUNGs maybe hold the potential for further application in the field of drug delivery. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48473.