自组装肽基纳米材料运载药物和基因的研究进展

肽基分子自组装以其丰富的自组装驱动力、新颖的自组装体纳米结构、自组装体的特殊功能及良好的生物相容性等,在纳米生物材料、护肤和化妆产品、药物传输释放、组织工程支架材料等方面有着广泛的应用前景。由天然氨基酸组成的自组装短肽具有良好的低细胞毒性,可控的降解性能,高的运载效率及细胞摄取率,同时还具有降低药物的毒副作用等优点。因此,它在作为药物和基因的纳米载药材料方面有着巨大的发展前景。使用自组装肽基材料形成的纳米载体对疏水性抗癌药物、蛋白质药物及基因等进行传递释放已成为生物医药学领域的研究重点,因此,对近年来自组装肽基纳米材料作为药物和基因载体在生物医药学上的研究进展做了综述。     

Characterization and Application of Intercalated Montmorillonite with Verapamil and its Polymethyl Methacrylate Nanocomposite in Drug Delivery

This work examined two drug delivery systems: the first system studied the adsorption of Verapamil hydrochloride drug into montmorillonite clay (MMT) by intercalation process to prepare MMT-Verapamil hybrid at different intercalating time, temperatures, pH values and initial drug concentrations. The second system includes the preparation of MMT-Verapamil hybrid combined with polymethyl methacrylate via an emulsion polymerization process to produce a novel nanocomposite material to be used in drug delivery. The polymerization process was carried out using an ultrasonic technique to achieve a biologically safe drug delivery system. Best conditions for the intercalation of verapamil hydrochloride drug into the interlayer of MMT clay were found to be at 50°C and 1 hr using pH ranges of 4–6. The prepared MMT-Verapamil hybrid and the produced MMT-verapamil-MMA nanocomposite material were characterized by X-ray diffraction (XRD), scanning electron microscope (SEM) and thermal gravimetric analysis (TGA). The in-vitro release profile of Verapamil in the case of a drug hybrid is faster than the release in the case of a drug nanocomposite in both gastric and intestinal fluids where, in the case of gastric fluid (pH 1.2), about 40% of the loaded drug was released from the drug hybrid in the first 4 h against only 37% in 5 h in the case of drug nanocomposite. Also in the intestinal fluid (pH 7.4), the verapamil release from drug hybrid reached 68% in 5 h against only 57% was released from drug nanocomposites in 7 h.     

Liraglutide-Loaded Milk Exosomes Lower Blood Glucose When Given by Sublingual Route

Bovine milk is rich in extracellular vesicles (mEVs) which have been suggested as a possible drug delivery vehicle with oral bioavailability. As the digestive fluids contain many lipid- and protein-degrading enzymes, we explored whether mEVs given sublingually could be taken up systemically. mEVs were isolated using three different protocols, which were 120 nm in diameter and carried bovine CD81. Fluorescently stained mEVs given by sublingual route were detected in the circulation, whereas mEVs given by gavage were detected at 2-Log lower concentrations. As proof of the concept, we loaded mEVs with the antidiabetic drug Liraglutide (LRT-EV), which reduced blood glucose levels when given by the sublingual route but showed no efficacy via gavage. This study suggests that mEV may be an efficient delivery vehicle for drugs that are not orally bioavailable, and LRT-loaded EVs have the potential as the next-generation drug delivery platform for the treatment of chronic diseases, including diabetes.     

F3-functionalized nanoscale metal–organic frameworks for tumor-targeting combined chemotherapy and chemodynamic therapy

Nanoscale metal–organic frameworks (nMOFs) have attracted much attention as emerging porous materials as drug delivery carriers. Appropriate surface modification of them can greatly improve stability and introduce biocompatibility and cancer targeting functionality into drug delivery systems. Herein, we prepared nano-sized MIL-101(Fe)-N₃ and loaded anticancer drug doxorubicin (DOX) into it. The synthetic polymer layer Alkyne-PLA-PEG was then attached to the F3 peptide (labeled as Alkyne-PLA-PEG-F3), and the surface of DOX/MIL-101(Fe)-N₃ was covalently modified with it to obtain DOX/MIL-101-PLA-PEG-F3. Nano-sized MIL-101(Fe)-N₃ has high drug loading capacity and the modification of MIL-101(Fe)-N₃ by polymer Alkyne-PLA-PEG not only improved the dispersion, but also avoided the sudden release of the drugs and increased the biocompatibility of nanocarriers. The F3 peptide introduced into the nanocarriers also enabled it to specifically target tumor tissues and achieved active targeted drug delivery. As a nucleolin-mediated endocytosis drug delivery system, DOX/MIL-101-PLA-PEG-F3 can not only deliver anticancer drugs to tumors accurately, but also participate in Fenton-like reaction to generate hydroxyl radicals (•OH) for chemodynamic therapy (CDT), thus enabling combination therapy. It holds great promise as drug candidates to reduce systemic toxicity and improve the efficacy of cancer treatment.     

Gastroretentive floating sterculia–alginate beads for use in antiulcer drug delivery

To improve the bioavailability and therapeutic efficacy of the drugs used for the diseases associated with the stomach, the retention of drug delivery systems in the stomach for longer time is requred. Therefore, in the present study, an attempt has been made to synthesize gastro-retentive floating drug delivery system by simultaneously ionotropic gelation of alginate and sterculia gum by using CaCl₂ as crosslinker. The beads thus formed have been characterized by scanning electron micrographs (SEMs), electron dispersion X-ray analysis (EDAX), Fourier transform infrared spectroscopy (FTIR) analysis. The swelling of beads has been carried out as a function of various reaction parameters and pH of the swelling media. In addition, in vitro release dynamics of anti-ulcer model drug pantoprazole from drug loaded beads in different release media has been carried out for the evaluation of the drug release mechanism and diffusion coefficients. Release of drug from beads occurred through Fickian type diffusion mechanism.     

CRPC Membrane-Camouflaged,Biomimetic Nanosystem for Overcoming Castration-Resistant Prostate Cancer by Cellular Vehicle-Aided Tumor Targeting

Castration-resistant prostate cancer (CRPC) is the most common malignant tumor of the male urinary system. Nanodrug delivery systems (NDDS) have been widely applied in drug delivery for tumor therapy; however, nanotherapeutics encounter various biological barriers that prevent successful accumulation of drugs, specifically at diseased sites. Therefore, there is an urgent need to develop a CRPC-targeting nanocomposite with fine biocompatibility for penetrating various biological barriers, delivering sufficient drugs to the targeting site and improving therapeutic efficiency. In this work, CRPC cell membranes were firstly adapted as biomimetic vectors for the encapsulating PEG−PLGA polymer containing the chemotherapy drug docetaxel (DTX). The CRPC membrane-camouflaged nanoparticles can easily escape early recognition by the immune system, penetrate the extracellular barrier, and evade clearance by the circulatory system. In addition to the characteristics of traditional nanoparticles, the CRPC cell membrane contains an arsenal of highly specific homotypic moieties that can be used to recognize the same cancer cell types and increase the targeted drug delivery of DTX. In vivo fluorescence and radionuclide dual-model imaging were fulfilled by decorating the biomimetic nanosystem with near-infrared dye and isotope, which validated the homotypic targeting property offered by the CRPC cell membrane coating. Importantly, remarkably improved therapeutic efficacy was achieved in a mice model bearing CRPC tumors. This homologous cell membrane enabled an efficient drug delivery strategy and enlightened a new pathway for the clinical application of tumor chemotherapy drugs in the future.     

A Comparison of Electric‐Field‐Driven and Pressure‐Driven Fiber Generation Methods for Drug Delivery

Polymeric fibers are prepared by using electric field driven fiber production technology—electrospinning and pressure driven fiber production technology—pressurized gyration. Fibers of four different polymers: polyvinylidene fluoride (PVDF), poly(methyl methacrylate (PMMA), poly(N‐isopropylacrylamide), and polyvinylpyridine (PVP), are spun by both techniques and differences are analyzed for their suitability as drug carriers. The diameters of electrospun fibers are larger in some cases (PVDF and PMMA), producing fibers with lower surface area. Pressurized gyration allows for a higher rate of fiber production. Additionally, drug‐loaded PVP fibers are prepared by using two poorly water‐soluble drugs (Amphotericin B and Itraconazole). In vitro dissolution studies show differences in release rate between the two types of fibers. Drug‐loaded gyrospun fibers release the drugs faster within 15 min compared to the drug‐loaded electrospun fibers. The findings suggest pressurized gyration is a promising and scalable approach to rapid fiber production for drug delivery when compared to electrospinning.     

γ‐Irradiation preparation of poly(acrylic acid)–chitosan hydrogels for in vitro drug release

Biocompatible and biodegradable pH‐responsive hydrogels based on poly(acrylic acid) and chitosan were prepared for controlled drug delivery. These interpolymeric hydrogels were synthesized by a γ‐irradiation polymerization technique. The degree of gelation was over 96% and increased as the chitosan or acrylic acid (AAc) content increased. The equilibrium swelling studies of hydrogels prepared under various conditions were carried out in an aqueous solution, and the pH sensitivity in a range of pH 1–12 was investigated. The AAc/chitosan hydrogels showed the highest water content when 30 vol % AAc and 0.1 wt % chitosan were irradiated with a 30 kGy dose of radiation. In addition, an increase of the degree of swelling with an increase in the pH was noticed and it had the highest value at pH 12. The drug 5‐fluorouracil was loaded into these hydrogels and the release studies were carried out in simulated gastric and intestinal fluids. The in vitro release profiles of the drugs showed that more than 90% of the loaded drugs were released in the first 1 h at intestinal pH and the rest of the drug was released slowly. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 3270–3277, 2003     

Hollow Mesoporous Silica@Metal–Organic Framework and Applications for pH‐Responsive Drug Delivery

Metal?‐organic frameworks (MOFs), a new type of porous crystalline material, hold great potential in biomedical applications, such as drug delivery. However, the efficacy of drug delivery is limited by low drug loading. In this work, we synthesized hollow mesoporous silica (HMS)@MOF capsules that can be used as a pH‐responsive drug delivery system for the anticancer drug doxorubicin (DOX). DOX is loaded into the inner cavity of HMS. Zeolitic imidazolate framework‐8 (ZIF‐8) nanoparticles are then coated on the outer surface of the DOX‐loaded HMS. The obtained material is a capsule (denoted as DOX/HMS@ZIF), in which DOX is encapsulated. The DOX/HMS@ZIF can be used as an efficient pH‐responsive drug delivery system. DOX is not released under physiological conditions (pH 7.4), but is released at low pH (4–6) from DOX/HMS@ZIF. The DOX/HMS@ZIF capsule shows much higher cytotoxicity than free DOX and alters the delivery pathway for DOX in cancer cells, while the drug‐free HMS@ZIF shows excellent biocompatibility. This opens new opportunities to construct a safe and efficient delivery system for targeted molecules using pH‐responsive release for a wide range of applications.     

Thiolated Hydroxypropyl-β-cyclodextrin: A Potential Multifunctional Excipient for Ocular Drug Delivery

The goal of this study was the design and evaluation of a thiolated cyclodextrin providing high drug solubilizing and mucoadhesive properties for ocular drug delivery. Hydroxypropyl-β-cyclodextrin (HP-β-CD) was thiolated via a microwave-assisted method, resulting in a degree of thiolation of 33%. Mucoadhesive properties of thiolated HP-β-CD (HP-β-CD-SH) were determined via rheological measurements and ex vivo studies on isolated porcine cornea. Due to thiolation of HP-β-CD, a 2-fold increase of mucus viscosity and a 1.4-fold increase in residence time on isolated corneal tissue were achieved. After instillation, the mean precorneal residence time and AUC of dexamethasone (DMS) eye drops were 4-fold and 11.7-fold enhanced by HP-β-CD-SH, respectively. Furthermore, in the presence of HP-β-CD-SH, a constant high level of DMS in aqueous humour between 30 and 150 min after administration was observed. These results suggest that HP-β-CD-SH is an excellent excipient for ocular formulations of poorly soluble drugs in order to prolong their ocular residence time and bioavailability.     

Potential for Layered Double Hydroxides-Based,Innovative Drug Delivery Systems

Layered Double Hydroxides (LDHs)-based drug delivery systems have, for many years, shown great promises for the delivery of chemical therapeutics and bioactive molecules to mammalian cells in vitro and in vivo. This system offers high efficiency and drug loading density, as well as excellent protection of loaded molecules from undesired degradation. Toxicological studies have also found LDHs to be biocompatible compared with other widely used nanoparticles, such as iron oxide, silica, and single-walled carbon nanotubes. A plethora of bio-molecules have been reported to either attach to the surface of or intercalate into LDH materials through co-precipitation or anion-exchange reaction, including amino acid and peptides, ATPs, vitamins, and even polysaccharides. Recently, LDHs have been used for gene delivery of small molecular nucleic acids, such as antisense, oligonucleotides, PCR fragments, siRNA molecules or sheared genomic DNA. These nano-medicines have been applied to target cells or organs in gene therapeutic approaches. This review summarizes current progress of the development of LDHs nanoparticle drug carriers for nucleotides, anti-inflammatory, anti-cancer drugs and recent LDH application in medical research. Ground breaking studies will be highlighted and an outlook of the possible future progress proposed. It is hoped that the layered inorganic material will open up new frontier of research, leading to new nano-drugs in clinical applications.     

Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes

Peptide therapeutics offer numerous advantages in the treatment of diseases and disorders of the central nervous system (CNS). However, they are not without limitations, especially in terms of their pharmacokinetics where their metabolic lability and low blood–brain barrier penetration hinder their application. Targeted nanoparticle delivery systems are being tapped for their ability to improve the delivery of therapeutics into the brain non-invasively. We have developed a family of mannosylated glycoliposome delivery systems for targeted drug delivery applications. Herein, we demonstrate via in vivo distribution studies the potential of these glycoliposomes to improve the utility of CNS active therapeutics using dynantin, a potent and selective dynorphin peptide analogue antagonist of the kappa opioid receptor (KOR). Glycoliposomal entrapment protected dynantin against known rapid metabolic degradation and ultimately improved brain levels of the peptide by approximately 3–3.5-fold. Moreover, we linked this improved brain delivery with improved KOR antagonist activity by way of an approximately 30–40% positive modulation of striatal dopamine levels 20 min after intranasal administration. Overall, the results clearly highlight the potential of our glycoliposomes as a targeted delivery system for therapeutic agents of the CNS.     

Preparation of poly(acrylic acid)–chitosan hydrogels by gamma irradiation and in vitro drug release

Biocompatible and biodegradable pH‐responsive hydrogels based on poly(acrylic acid) (AAc) and chitosan were prepared for controlled drug delivery. These interpolymeric hydrogels were synthesized by a gamma irradiation polymerization technique. The degree of gelation was over 96% and increased as the chitosan or acrylic acid content increased. The equilibrium swelling studies of hydrogels prepared in various conditions were carried out in an aqueous solution, and the pH sensitivity in the range of pH 1–12 was investigated. The AAc/chitosan hydrogels showed the highest water content when the 30 vol % AAc and 0.1 wt % chitosan were irradiated with a 30‐kGy radiation dose. Also, an increase of swelling degree with an increase in the pH was noticed and showed the highest value at pH 12. The drug, 5‐fluorouracil, was loaded into these hydrogels and the release studies were carried out in simulated gastric and intestinal fluids. The in vitro release profiles of the drugs showed that more than 90% of the loaded drugs were released in the first 1 h at the intestinal pH and the rest of the drug had been released slowly. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 3660–3667, 2003     

Preparation of pH-Sensitive Polymers/Layered Double Hydroxide Hybrid Beads for Controlled Release of Insulin

The present work introduces new hybrid material based on the combination of layered double hydroxides (LDH) and a pH-sensitive polymer (PSP), alginate, a polysaccharide widely applied for encapsulating drugs to produce a LDH–polymer nanocomposite, able to act as an effective drug delivery system (DDS) in comparison to the Zn–Al LDH or the polymer alone. Insulin has been chosen as a model drug, being loaded in a Zn–Al LDH matrix. In vitro release profiles were established separately in both the presence and absence of glucose phosphate in pH 7. Drug release studies showed that the in the presence of glucose phosphate release rate increases.     

Red Emissive Carbon Dots Prepared from Polymers as an Efficient Nanocarrier for Coptisine Delivery in vivo and in vitro

Negatively charged fluorescent carbon dots (CDs, E_m=608 nm) were hydrothermally prepared from thiophene phenylpropionic acid polymers and then successfully loaded with the positively charged anticancer cargo coptisine, which suffers from poor bioavailability. The formed CD-coptisine complexes were thoroughly characterized by particle size, morphology, drug loading efficiency, drug release, cellular uptake and cellular toxicity in vitro and antitumor activities in vivo. In this nano-carrier system, red emissive CDs possess multiple advantages as follows: 1) high drug loading efficiency (>96 %); 2) sustained drug release; 3) enhanced drug efficacy towards cancer cells; 4) EPR effect; 5) drug release tracing with near-infrared imaging. These properties indicated that red emissive CDs prepared from polymers could be used as a novel drug delivery system with integrated therapeutic and imaging functions in cancer therapy, which are expected to have great potential in future clinical applications.     

Composite polymeric microsponge-based long-acting gel formulation for topical delivery of mupirocin

Topical delivery of medicaments in a controlled manner is still a promising area of research. Drug-containing dammar gum-ethyl cellulose composite microsponge loaded gel formulation (D-MSPG) was developed for controlled topical delivery of mupirocin. The drug-loaded microsponges (D-MSPs) were formulated by the quasi-emulsion solvent diffusion method and were evaluated for morphology, particle size distribution, entrapment efficiency, thermal properties, and crystallinity. The optimized D-MSPs (entrapment efficiency 91.5 ± 4.0% and particle size of 55.15 ± 2.9 μm) were dispersed in carbopol 934 gel (D-MSPG). The final product was characterized for pH, viscosity, texture, spreadability, consistency, syneresis, in vitro drug release, and ex vivo skin penetration study. A comparative study with marketed formulation was performed. For optimized gel formulation (G4), drug content was 104.19 ± 1.68%, and drug release was 84.19% after 24 h. The pH of the optimized gel was observed to be 6.05 ± 0.04. Viscosity of the optimized gel formulation was found to be 1212.15 ± 434.85 mPa-s at 50 s⁻¹. The steady-state flux (J) in ex vivo skin permeation was observed to be 53.96 μg cm⁻² h⁻¹ and the permeability coefficient was 2.69 cm/h for the optimized gel formulation. According to the findings, the D-MSPG-based formulation strategy can act well to prolong the topical delivery of mupirocin or similar drug molecules.     

Electroactive Silk Fibroin Films for Electrochemically Enhanced Delivery of Drugs

Biomaterials capable of controlling the delivery of drugs have the potential to treat a variety of conditions. Herein, the preparation of electrically conductive silk fibroin film‐based drug delivery devices is described. Casting aqueous solutions of Bombyx mori silk fibroin, followed by drying and annealing to impart β‐sheets to the silk fibroin, assure that the materials are stable for further processing in water; and the silk fibroin films are rendered conductive by generating an interpenetrating network of a copolymer of pyrrole and 3‐amino‐4‐hydroxybenzenesulfonic acid in the silk fibroin matrix (characterized by a variety of techniques including circular dichroism, Fourier‐transform infrared spectroscopy, nuclear magnetic resonance, Raman spectroscopy, resistance measurements, scanning electron microscopy‐energy dispersive X‐ray spectroscopy, thermogravimetric analysis, X‐ray diffraction, and X‐ray photoelectron spectroscopy). Fibroblasts adhere on the surface of the biomaterials (viability assessed using an (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay and visualized using a confocal microscope), and a fluorescently labeled drug (Texas‐Red Gentamicin) can be loaded electrochemically and released (µg cm^?2 quantities) in response to the application of an electrical stimulus.     

One-pot synthesis of sustained-released doxorubicin silica nanoparticles for aptamer targeted delivery to tumor cells

Site-specific delivery of drugs can significantly reduce drug toxicity and increase the therapeutic effect. Here, we report a one-pot synthesis of doxorubicin-doped silica nanoparticles (Dox/SiNPs) by using sodium fluoride (NaF) catalyzed hydrolysis of tetraethyl orthosilicate in a water-in-oil microemulsion. Through further surface chemical modification, carboxyl-terminated Dox/SiNPs (COOH-Dox/SiNPs) exhibiting high drug entrapment efficiency, strong fluorescence and long sustained release are obtained. Cell toxicity tests demonstrate that the COOH-Dox/SiNPs kill tumor cells effectively, while pure COOH-SiNPs are nontoxic. An aptamer is further conjugated to the nanoparticles for delivering loaded Dox to target cells. It is demonstrated that Dox/SiNPs modified with the aptamer sgc8c (sgc8c-Dox/SiNPs) could deliver loaded doxorubicin to CCRF-CEM cells with high specificity and excellent efficiency. Furthermore, ex vivo imaging studies show that the COOH-Dox/SiNPs are able to accumulate highly in the tumor areas, thanks to the enhanced permeability and retention (EPR) effects. Our data suggest that the sgc8c-Dox/SiNPs may be a useful new tumor therapy system.     

Engineering a drug eluting ocular patch for delivery and sustained release of anti-inflammatory therapeutics

Ocular inflammation is commonly associated with eye disease or injury. Effective and sustained ocular delivery of therapeutics remains a challenge due to the eye physiology and structural barriers. Herein, we engineered a photocrosslinkable adhesive patch (GelPatch) incorporated with micelles (MCs) loaded with loteprednol etabonate (LE) for delivery and sustained release of drug. The engineered drug loaded adhesive hydrogel, with controlled physical properties, provided a matrix with high adhesion to the ocular surfaces. The incorporation of MCs within the GelPatch enabled solubilization of LE and its sustained release within 15 days. In vitro studies showed that MC loaded GelPatch supported cell viability and growth. In addition, subcutaneous implantation of the MC loaded GelPatch in rats confirmed its in vivo biocompatibility and stability within 28 days. This non-invasive, adhesive, and biocompatible drug eluting patch can be used as a matrix for the delivery and sustained release of hydrophobic drugs.     

Targeted Co-Delivery of Gefitinib and Rapamycin by Aptamer-Modified Nanoparticles Overcomes EGFR-TKI Resistance in NSCLC via Promoting Autophagy

Acquired drug resistance decreases the efficacy of gefitinib after approximately 1 year of treatment in non-small-cell lung cancer (NSCLC). Autophagy is a process that could lead to cell death when it is prolonged. Thus, we investigated a drug combination therapy of gefitinib with rapamycin—a cell autophagy activator—in gefitinib-resistant NSCLC cell line H1975 to improve the therapeutic efficacy of gefitinib in advanced NSCLC cells through acute cell autophagy induction. Cell viability and tumor formation assays indicated that rapamycin is strongly synergistic with gefitinib inhibition, both in vitro and in vivo. Mechanistic studies demonstrated that EGFR expression and cell autophagy decreased under gefitinib treatment and were restored after the drug combination therapy, indicating a potential cell autophagy–EGFR positive feedback regulation. To further optimize the delivery efficiency of the combinational agents, we constructed an anti-EGFR aptamer-functionalized nanoparticle (NP-Apt) carrier system. The microscopic observation and cell proliferation assays suggested that NP-Apt achieved remarkably targeted delivery and cytotoxicity in the cancer cells. Taken together, our results suggest that combining rapamycin and gefitinib can be an efficacious therapy to overcome gefitinib resistance in NSCLC, and targeted delivery of the drugs using the aptamer-nanoparticle carrier system further enhances the therapeutic efficacy of gefitinib.