Co-delivery of Doxorubicin and Afatinib with pH-responsive Polymeric Nanovesicle for Enhanced Lung Cancer Therapy

Drug-resistance and drastic side effects are two major issues of traditional chemotherapy which may result in trail failure even death. Nanoparticle-mediated multidrug combination treatment has been proven to be a feasible strategy to overcome these challenges. In the present study, amphipathic block polymer of methoxyl poly(ethylene glycol)-poly(aspartyl(dibutylethylenediamine)-co-phenylalanine)(m PEG-P(Asp(DBA)-co-Phe)) was synthesized and self-assembled into p H-responsive polymeric vesicle. The vesicle was utilized to co-deliver cancer-associated epidermal growth factor(EGFR) inhibitor of afatinib and DNA-damaging chemotherapeutic doxorubicin hydrochloride(DOX) for enhanced non-small-cell lung cancer(NSCLC) therapy. As evaluated in vitro, the p H-responsive design of nanovesicle resulted in a rapid release of encapsulated drugs into tumor cells and caused enhanced cell apoptosis. In addition, in vivo therapeutic studies were conducted and the results evidenced that the co-delevery of DOX and afatinib using p H-sensitive nanovector was a promising strategy for NSCLC treatment.     

Comb‐Like Amphiphilic Polycarbonates with Different Lengths of Cationic Branches for Enhanced siRNA Delivery

Owing to the biodegradability and good biocompatibility polycarbonates show the versatile class of applications in biomedical fields. While their poor functional ability seriously limited the development of functional polycarbonates. Herein, a new Br‐containing cyclic carbonate (MTC‐Br) and a polycarbonate atom transfer radical polymerization (ATRP) macro‐initiator (PEG‐PMTC‐Br) is synthesized. Then, by initiating the side‐chain ATRP of 2‐(dimethyl amino)ethyl methacrylate (DMAEMA) on PEG‐PMTC‐Br, a series of comb‐like amphiphilic cationic polycarbonates, PEG‐b‐(PMTC‐g‐PDMAEMA) (GMDMs), with different lengths of cationic branches are successfully prepared. All these poly(ethylene glycol)‐b‐(poly((5‐methyl‐2‐oxo‐1,3‐dioxane‐5‐yl) methyl 2‐bromo‐2‐methylpropanoate/1,3‐dioxane‐2‐one)‐g‐poly(2‐dimethyl aminoethyl methacrylate) (GMDMs) self‐assembled nanoparticles (NPs) (≈180 nm, +40 mV) can well bind siRNA to form GMDM/siRNA NPs. The gene silence efficiency of GMDM/siRNA high to 80%, which is even higher than the commercial transfection reagent lipo2000 (76%). But GMDM/siRNA shows lower cell uptake than lipo2000. So, the high gene silence ability of GMDM/siRNA NPs can be attributed to the strong intracellular siRNA trafficking capacity. Therefore, GMDM NPs are potential siRNA vectors and the successful preparation of comb‐like polycarbonates also provides a facile way for diverse side‐chain functional polycarbonates, expanding the application of polycarbonates.     

Facile and One-step Direct Synthesis of Poly(valine) as a Robust Drug Nanocarrier for Enhanced Breast Cancer Therapy

Synthetic poly(amino acid)s with good biodegradable and biocompatible properties have attracted increased attention as carriers in biomedical applications in recent years, their synthesis and purification procedures are usually complicated and some by-products would occur yet. Given this, polypeptide with good biodegradable and biocompatible properties is prepared and optimized by one-step and direct synthesis strategy and poly(valine)(PVal) is selected here as a model polypeptide in this study....     

Co-delivery of doxorubicin and paclitaxel with linear-dendritic block copolymer for enhanced anti-cancer efficacy

A series of well-defined amphiphilic linear-dendritic block copolymers (telodendrimers, MPEG-b-PAMAM-cholesterol) with 1,2,4 or 8 cholesteryl groups (named as P1, P2, P4, P8, respectively) were synthesized. Their chemical structures were characterized with ¹H NMR and mass spectrum (MALDI-TOF MS). The telodendrimers could self-assemble into micelles in aqueous solution, and encapsulate chemotherapeutic drug doxorubicin (DOX) and paclitaxel (PTX) for combination therapy. All the telodendrimers could encapsulate DOX with similar capability. However, their drug-loading capability of PTX is increased with the increasing number of cholesteryl groups. P8 exhibited much higher PTX loading efficiency than its counterparts. Thus, P8 was selected for further application of drug delivery in the paper. The drug-loading micellar nanoparticles (NPs) of P8 were spherical in shape and their diameters were less than 150 nm which were determined by dynamic light scattering measurements (DLS) and transmission electron microscope (TEM). In vitro drug release experiment demonstrated that P8 exhibited a controlled release manner for both DOX and PTX, and the two drugs were released simultaneously. In vitro cytotoxicity experiment further demonstrated that the co-delivery of DOX and PTX in P8 exhibited better anti-cancer efficiency than the delivery systems encapsulated with single drug (DOX or PTX). This indicates a synergistic effect. The co-delivery system showed potential in future anti-cancer treatment.     

Polydopamine‐Coated Porous Microspheres Conjugated with Immune Stimulators for Enhanced Cytokine Induction in Macrophages

Polydopamine‐coated porous microsphere (PPM) is investigated as a simple and versatile immobilization strategy for immune‐stimulating biomolecules to enhance delivery efficiency and immune‐stimulating effects such as cytokine induction in macrophages. The PPMs, with diameters of about 2 μm, exhibit simultaneous and efficient incorporation of biomolecules (nucleotides and proteins), which is comparable to that achieved using microspheres carrying biomolecules internally by virtue of their porous structure. Ovalbumin‐conjugated PPMs are internalized into macrophages efficiently and selectively via the phagocytic pathway, without any noticeable toxicity. Internalized CpG oligodeoxynucleotide (ODN)‐conjugated PPMs (PPM‐CpG) greatly enhance the induction of selected cytokines (TNF‐α and IL‐6) in RAW 264.7 cells compared to that by the soluble CpG ODN and ionic complexes. Therefore, PPMs generated in this study may serve as effective carriers of immune‐stimulating biomolecules such as diverse toll‐like receptor agonists.

     

双刺激响应型纳米载药系统的构建及性能

采用聚乙二醇单甲醚(mPEG)为亲水段,聚赖氨酸(PzLL)为疏水段,通过二硫键和碳氮双键串联桥连合成了两嵌段共聚物(mPEG-CN-SS-PzLL),其中的二硫键具有还原敏感性,碳氮双键具有pH酸敏感性。通过红外光谱和核磁共振谱等手段测试分析了产物的化学结构。将聚合物通过透析法自组装制备得到双刺激响应型纳米载药粒子。结果表明:该纳米载药粒子的药物包封率较高,达到52%。该载药系统在还原环境或酸性环境下具有良好的体外释药性能。     

Simultaneous Determination of Andrographolide and Dehydroandrographolide in Chicken Plasma for Application to Pharmacokinetic Studies

A simple, suitable reverse phase liquid chromatographic method was developed for simultaneous determination of andrographolide (1) and dehydroandrographolide (2) in chicken plasma after orally administrating the ultra-fine powder of Andrographis paniculata. Plasma samples were extracted with ethyl acetate. Analysis of the extract was performed on a reversed-phase C18 column with gradient eluent composed of acetonitrile and 0.5% acetic acid. The flow rate was kept at 1 mL min⁻¹ and the detection wavelength was set at 225 and 255 nm for 1 and 2, respectively. All calibration curves showed good linear regression (R ≥ 0.9991). The good precision and recoveries with intra-day and inter-day were 3.2–8.7% and 91.1–98.4%, respectively. The limit of detection was 0.016 µg mL⁻¹ and the limit of quantitation was 0.040 µg mL⁻¹ for the target analytes. This validated method has been successfully applied in the pharmacokinetics study of 1 and 2 after orally administrating the Andrographis paniculata ultra-fine powder to chicken.

     

Co-delivery of enzymes and photosensitizers via metal-phenolic network capsules for enhanced photodynamic therapy

The intrinsic hypoxic tumor microenvironment and limited accumulation of photosensitizers（PSs） result in unsatisfied efficiency of photodynamic therapy（PDT）.To enhance the PDT efficiency against solid tumors,a functional oxygen self-supplying and PS-delivering nanosystem is fabricated via the combination of catalase（CAT）,chlorin e6（Ce6） and metal-phenolic network（MPN） capsule.It is demonstrated that the CAT encapsulated in the capsules（named CCM capsules） could catalyze the degradation of hydrog...     

Co-delivery of anticancer drugs and cell penetrating peptides for improved cancer therapy

Delivery systems based on nanoparticles (NPs) have shown great potential to reduce side effects and improve the therapeutic efficacy. Herein, we report the one-pot synthesis of poly(ethylene glycol)-mediated zeolitic imidazolate framework-8 (ZIF-8) NPs for the co-delivery of an anticancer drug (i.e., doxorubicin) and a cell penetrating peptide containing histidine and arginine (i.e., H4R4) to improve the efficacy of therapeutic delivery. The cargo-encapsulated ZIF-8 NPs are pH-responsive, which are stable at neutral pH and degradable at acidic pH to release the encapsulated cargos. The released H4R4 can help for endosome/lysosome escape to enhance the cytotoxicity of the encapsulated drugs. In vivo studies demonstrate that the co-delivery of doxorubicin and H4R4 peptides can efficiently inhibit tumor growth without significant side effects. The reported strategy provides a new perspective on the design of drug delivery systems and brings more opportunities for biomedical applications.     

Lysinated Multiwalled Carbon Nanotubes with Carbohydrate Ligands as an Effective Nanocarrier for Targeted Doxorubicin Delivery to Breast Cancer Cells

Multiwalled carbon nanotubes (MWCNTs) are elongated, hollow cylindrical nanotubes made of sp2 carbon. MWCNTs have attracted significant attention in the area of drug delivery due to their high drug-loading capacity and large surface area. Furthermore, they can be linked to bioactive ligands molecules via covalent and noncovalent bonds that allow for the targeted delivery of anticancer drugs such as doxorubicin. The majority of methodologies reported for the functionalization of MWCNTs for drug delivery are quite complex and use expensive linkers and ligands. In the present study, we report a simple, cost-effective approach for functionalizing MWCNTs with the carbohydrate ligands, galactose (GA), mannose (MA) and lactose (LA), using lysine as a linker. The doxorubicin (Dox)-loaded functionalized MWCNTs were characterized using FT-IR, NMR, Raman, XRD and FE-SEM. The drug–loaded MWCNTs were evaluated for drug loading, drug release and cell toxicity in vitro, in breast cancer cells. The results indicated that the carbohydrate-modified lysinated MWCNTs had greater Dox loading capacity, compared to carboxylated MWCNTs (COOHMWCNTs) and lysinated MWCNTs (LyMWCNTs). In vitro drug release experiments indicated that the carbohydrate functionalized LyMWCNTs had higher Dox release at pH 5.0, compared to the physiological pH of 7.4, over 120 h, indicating that they are suitable candidates for targeting the tumor microenvironment as a result of their sustained release profile of Dox. Doxorubicin-loaded galactosylated MWCNTs (Dox-GAMWCNTs) and doxorubicin loaded mannosylated MWCNTs (Dox-MAMWCNTs) had greater anticancer efficacy and cellular uptake, compared to doxorubicin–loaded lactosylated MWCNTs (Dox-LAMWCNTs) and pure Dox, in MDA-MB231 and MCF7 breast cancer cells. However, neither the ligand conjugated multiwall blank carbon nanotubes (GAMWCNTs, MAMWCNTs and LAMWCNTs) nor the lysinated multiwalled blank carbon nanotubes produced significant toxicity in the normal cells. Our results suggest that sugar-tethered multiwalled carbon nanotubes, especially the galactosylated (Dox-GAMWCNTs) and mannosylated (Dox-MAMWCNTs) formulations, may be used to improve the targeted delivery of anticancer drugs to breast cancer cells.     

Polymer-based photocoupling agent for the efficient immobilization of nanomaterials and small molecules

A highly efficient photocoupling agent, based on perfluorophenylazide (PFPA)-conjugated polyallylamine (PAAm), was developed for the efficient immobilization of polymers, nanoparticles, graphene, and small molecules. The conjugate, PAAm-PFPA, was synthesized, and the percentage of the photoactive moiety, PFPA, can be controlled by the ratio of the two components in the synthesis. By treating epoxy-functionalized wafers with PAAm-PFPA, photoactive surfaces were generated. Compared with the PFPA surface, these polymer-based photocoupling matrix resulted in significantly enhanced immobilization efficiencies, especially for nanomaterials and small molecules. Thus, polystyrene nanoparticles (PS NPs) and alkyl-functionalized silica nanoparticles (SNPs) were successfully immobilized on the PAAm-PFPA surface, resulting in a high material density. Graphene flakes patterned on the PAAm-PFPA surface showed improved feature resolution in addition to a higher material density compared to that of flakes immobilized on the PFPA surface. Furthermore, 2-O-α-D-mannopyranosyl-D-mannopyranose (Man2) immobilized on the PAAm-PFPA surface exhibited significantly enhanced signals when treated with lectin concanavalin A (Con A).     

Co-delivery of docetaxel and doxorubicin using biodegradable PEG-PLA micelles for treatment of breast cancer with synergistic anti-tumour effects

Poly(ethylene glycol)-poly(lactic acid) copolymer, prepared by ring opening polymerization, was used as a single platform to co-deliver both hydrophilic doxorubicin and hydrophobic docetaxel (DTX) in a simulated physiological environment. The average size of the negatively charged drug loaded polymeric micelles were found to be 293 nm. The drug loading (%) and encapsulation efficiency (%) were calculated to be 1.21 and 59.0, respectively. The in vitro cytotoxicity test using MCF7 breast cancer cells was conducted using 1 × 10⁴ cells in 10% FBS and 1% antibiotic, and the absorbance of formazan was evaluated at 570 nm. Cell growth inhibition by MTT assay showed viability of 33% of the MCF7 cells after treatment with drug-loaded micelles for 48 h. Controlled release of drugs from the polymeric micelles indicated a burst release effect initially; whereas, 98% of drug could be released at pH 7.4 within a time period of 96 h. Time period for drug release shorten to 48 h only in simulated mild acidic pH (5.4) condition. The in vitro drug release study from micelles indicated synergistic cytotoxicity effect in human metastatic breast cancer MCF7 cell.     

Preparation and SPECT imaging of the novel Anxa 1-targeted probe 99mTc-p-SCN-Bn-DTPA-GGGRDN-IF7

Annexin 1 (Anxa1) is a highly specific surface marker of tumor vasculature in several solid tumors. The IF7 peptide was modified with a hydrophic linkers,GGGRDN, and introduced into a new bifunctional chelating agent p-SCN-Bn-DTPA. The resulting peptides (p-SCN-Bn-DTPA-GGGRDN-IF7) was successfuly labeled with ^99mTc. The targeting characteristics to Anxa1 of the radiolabeled peptide were evaluated by in vitro and in vivo study is on U87 tumor models. SPECT imaging revealed that the U87 tumors were clearly visualized (3.64 ± 0.44%ID/g at 2 h p.i.). ^99mTc-p-SCN-Bn-DTPA-GGGRDN-IF7 (Tc-RIF7) might be a potential target probe for detecting Anxa1 levels in cancers due to the favorable characterizations such as convenient synthesis, specific Anxa1 targeting and moderate tumor uptakes.

     

叶酸功能化介孔碳纳米球负载阿霉素的细胞靶向传递及可控释放

以粒径90 nm的介孔碳纳米球作为靶向传药载体, 采用酸化处理改进了材料表面的亲疏水性及在溶液中的分散性, 通过壳寡糖功能化, 并利用EDC-NHS将叶酸修饰到介孔碳纳米球表面. 通过共聚焦激光扫描显微镜及流式细胞仪对实验体系的系统研究, 结果表明基于叶酸功能化的介孔碳纳米球能够有效提高负载药物对于HeLa细胞的跨膜转运效率, 叶酸阳性表达的HeLa细胞对于叶酸修饰的介孔碳纳米小球的吞噬效率明显高于叶酸阴性表达的MCF-7细胞. 对HeLa细胞毒性的定量分析表明叶酸的靶向作用在提高介孔碳纳米球内吞效率的同时, 进一步提高了阿霉素对于HeLa细胞的毒性.     

Co-delivery of antigen and a lipophilic anti-inflammatory drug to cells via a tailorable nanocarrier emulsion

Nanotechnology promises new drug carriers that can be tailored to specific applications. Here we report a new approach to drug delivery based on tailorable nanocarrier emulsions (TNEs), motivated by a need to co-deliver a protein antigen and a lipophilic drug for specific inhibition of nuclear factor kappa B (NF-κB) in antigen presenting cells (APCs). Co-delivery for NF-κB inhibition holds promise as a strategy for the treatment of rheumatoid arthritis. We used a highly surface-active peptide (SAP) to prepare a nanosized emulsion having defined surface properties predictable from the SAP sequence. Incorporating the lipophilic drug into the oil phase at the time of emulsion formation enabled its facile packaging. The SAP is depleted from bulk during emulsification, allowing simple subsequent addition of the drug-loaded oil-in-water emulsion to a solution of protein antigen. Decoration of emulsion surface with antigen was achieved via electrostatic deposition. In vitro data showed that the TNE prepared this way was internalized and well-tolerated by model APCs, and that good suppression of NF-κB expression was achieved. This work reports a new type of nanotechnology-based carrier, a TNE, which can potentially be tailored for co-delivery of multiple therapeutic components, and can be made using simple methods using only biocompatible materials.     

Co-delivery of doxorubicin and curcumin via cRGD-peptide modified PEG-PLA self-assembly nanomicelles for lung cancer therapy

Lung cancer is the most common malignancy in the world, with a high mortality rate. Nevertheless,therapies to act effectively against lung cancer remain elusive. So far, chemotherapy is still the frontline treatment of lung cancer. Doxorubicin(DOX) is a broad-spectrum anti-tumor drug. However, DOX often has serious side effects and causes multi-drug resistance, which greatly limits its clinical application.In this work, biodegradable methoxy poly(ethylene glycol)-poly(lactic acid)(MPEG-PLA) and ...     

Co-delivery of doxorubicin and curcumin via cRGD-peptide modified PEG-PLA self-assembly nanomicelles for lung cancer therapy

Lung cancer is the most common malignancy in the world, with a high mortality rate. Nevertheless,therapies to act effectively against lung cancer remain elusive. So far, chemotherapy is still the frontline treatment of lung cancer. Doxorubicin(DOX) is a broad-spectrum anti-tumor drug. However, DOX often has serious side effects and causes multi-drug resistance, which greatly limits its clinical application.In this work, biodegradable methoxy poly(ethylene glycol)-poly(lactic acid)(MPEG-PLA) and ...