Smart Drug Carriers Research Articles

2,2′-Dithiodisuccinic acid-stabilized polyion complex micelles for pH and reduction dual-responsive drug delivery

In this work, a new kind of polyion complex (PIC) micelles with pH and reduction dual responsiveness was developed for effective intracellular drug delivery. The PIC micelles can be readily prepared by mixing a polycationic block polymer, methoxy poly(ethylene glycol)-b-poly(l-lysine) (mPEG-PLL), with a small molecule polyacid, 2, 2′-dithiodisuccinic acid (DTS) in aqueous media. The resultant PIC micelles are of uniform spherical shapes with hydrodynamic radii ranging from 65 to 75 nm based on different feeding ratios of mPEG-PLL and DTS. Interestingly, by using the small molecule polyacid DTS, the obtained PIC micelles show distinct pH-responsive disintegration in acid solution. Meanwhile, the PIC micelles were also assessed to be reduction-responsive due to the presence of disulfide bond in DTS. In view of these stimuli-responsive properties, the potential use of this PIC micelle as smart drug carrier was then investigated. Doxorubicin (DOX), a cationic anticancer drug, was loaded into the PIC micelles with high efficiency. In vitro drug release studies revealed that release of DOX from the PIC micelles was suppressed in neutral solutions due to the stable electrostatic interactions between PIC micelles and DOX, but could be accelerated in acidic solutions or under high GSH condition. Furthermore, flow cytometry and confocal laser scanning microscopy (CLSM) studies indicated that the DOX-loaded PIC micelles could be effectively internalized by MCF-7 human breast cancer cells and release the loaded DOX in intracellular environment. Consequently, the DOX-loaded PIC micelles were capable of inhibiting the proliferation of C26 murine colon cancer and MCF-7 human breast cancer cells in high efficiency, showing similar IC50 values as free DOX. Thus, this biocompatible PIC micelle may be promising for intracellular drug delivery.

Recent Advances in pH-Sensitive Polymeric Nanoparticles for Smart Drug Delivery in Cancer Therapy

Rapid developments in the field of nanoparticles during the last decades have led to its increased application in drug delivery approaches. The advantages of nano-based drug delivery systems include improved therapeutic efficacy of drugs and the reduction of side effects. This review aims to highlight advances in stimuli-triggered drug delivery approaches using polymeric nanoparticles with a focus on pH-sensitive drug- and theranostic delivery systems. Of the various organic/inorganic nanoparticles, polymeric nanoparticles have fulfilled an integral role in the advancement of drug delivery systems by virtue of the ease to incorporate and modify targeting moieties in combination with controlled drug release over prolonged periods. Furthermore, polymeric nanoparticles facilitate theranostic treatment by the incorporation of imaging agents in addition to therapeutics. Recently, stimuli-responsive polymeric nanoparticles emerged as smart drug carriers, in which drug release is affected by physical and/or chemical structural changes induced by a specific stimulus (e.g. pH, temperature, and specific enzymes). The use of these nanocomposites reduces premature drug release and maintains effective drug levels at the pathological target.

PH- and thermo-sensitive MTX-loaded magnetic nanocomposites: synthesis, characterization, and in vitro studies on A549 lung cancer cell and MR imaging

In the current study, we proposed a facile method for fabrication of multifunctional pH- and thermo-sensitive magnetic nanocomposites (MNCs) as a theranostic agent for using in targeted drug delivery and magnetic resonance imaging (MRI). To this end, we decorated Fe3O4 magnetic nanoparticles (MNPs) with N,N-dimethylaminoethyl methacrylate (DMAEMA) and N-isopropylacrylamide (NIPAAm), best known for their pH- and thermo-sensitive properties, respectively. We also conjugated mesoporous silica nanoparticles (MSNs) to polymer matrix acting as drug container to enhance the drug encapsulation efficacy. Methotroxate (MTX) as a model drug was successfully loaded in MNCs (M-MNCs) via surface adsorption onto MSNs and electrostatic interaction between drug and carrier. The pH- and temperature-triggered release of MTX was concluded through the evaluation of in vitro release at both physiological and simulated tumor tissue conditions. Based on in vitro cytotoxicity assay results, M-MNCs significantly revealed higher antitumor activity compared to free MTX. In vitro MR susceptibility experiment showed that M-MNCs relatively possessed high transverse relaxivity (r2) of about 0.15 mM−1·ms−1 and a linear relationship between the transverse relaxation rate (R2) and the Fe concentration in the M-MNCs was also demonstrated. Therefore, the designed MNCs can potentially become smart drug carrier, while they also can be promising MRI negative contrast agent.

Neurotrophin-conjugated nanoparticles prevent retina damage induced by oxidative stress

Glaucoma and other optic neuropathies are characterized by a loss of retinal ganglion cells (RGCs), a cell layer located in the posterior eye segment. Several preclinical studies demonstrate that neurotrophins (NTs) prevent RGC loss. However, NTs are rarely investigated in the clinic due to various issues, such as difficulties in reaching the retina, the very short half-life of NTs, and the need for multiple injections. We demonstrate that NTs can be conjugated to magnetic nanoparticles (MNPs), which act as smart drug carriers. This combines the advantages of the self-localization of the drug in the retina and drug protection from fast degradation. We tested the nerve growth factor and brain-derived neurotrophic factor by comparing the neuroprotection of free versus conjugated proteins in a model of RGC loss induced by oxidative stress. Histological data demonstrated that the conjugated proteins totally prevented RGC loss, in sharp contrast to the equivalent dose of free proteins, which had no effect. The overall data suggest that the nanoscale MNP-protein hybrid is an excellent tool in implementing ocular drug delivery strategies for neuroprotection and therapy.

Application Progress of DNA Nanostructures in Drug Delivery and Smart Drug Carriers

Abstract The nanocarrier systems have been widely used for improving solubility, stability and therapeutic activity of drugs due to their high drug-loading efficiency, good target specificity and long circulation time. To achieve precisely controlled loading and tumor-selective release of drugs, extensive researches have been focused on developing nanocarriers with low toxicity, excellent biocomapatibility and biodegradability. As a type of nano-biomaterials with various functions and applications, self-assembled DNA nanostructures explored new ways to develop drug carriers in smart drug delivery based on their well-defined structures, good biocompatibility and stability, high cell membrane permeability and controlled drug releasing property. In this review, we summarized the developing course and the recent advances of DNA nanostructures for drug delivery, including the application of both static and dynamic DNA nanostructures. The application of dynamic DNA nanostructures for controllable drug release showed great potential in smart drug delivery.

Adaptive Chitosan Hollow Microspheres as Efficient Drug Carrier.

Smart drug carrier with function-oriented adaptations is highly desired due to its unique properties in medical applications. Herein, adaptive chitosan hollow microspheres (CHM) are fabricated by employing interfacial Schiff-base bonding reaction. Hydrophilic macromolecules of glycol chitosan are fixed at the oil/water interface through numerous hydrophobic small molecules of borneol 4-formylbenzoate, forming the CHM with a positively charged surface and lipophilic cavity. These CHM have an average size of 400-1000 nm after passing through the 0.22 μm apertures of filter paper. This phenomenon combined with SEM measurements demonstrates its remarkable shape-adaptive behavior. Furthermore, the CHM present a pH-dependence of structural stability. When pH value reduces from 7.06 to 5.01, the CHM begin to lose their integrity. All those characteristics make the CHM an intelligent drug carrier, especially for water-insoluble anticancer drugs, paclitaxel (PTX) in particular. Both cell uptake and cell cytotoxicity assays suggest that the PTX-loaded CHM are highly efficient on HepG2 and A549 cells. Therefore, rather than most of the traditional materials, these adaptive CHM show great potential as a novel drug carrier.

Photo-controlled aptamers delivery by dual surface gold-magnetic nanoparticles for targeted cancer therapy

Dual surfaced dumbbell-like gold magnetic nanoparticles (Au-Fe3O4) were synthesized for targeted aptamers delivery. Their unique biological properties were characterized as a smart photo-controlled drug carrier. DNA aptamers targeting vascular endothelial growth factor (VEGF) were assembled onto the surface of Au-Fe3O4 by electrostatic absorption. The binding capacity of the nanoparticles with VEGF aptamers was confirmed by gel electrophoresis. The targeted recognization of ovarian cancer cells by the aptamers-functionalized Au-Fe3O4 nanoparticles (Apt-Au-Fe3O4 NPs) was observed by confocal microscopy. Apt-Au-Fe3O4 was found to bind with SKOV-3 ovarian cancer cells specifically, leading to marked intracellular release of aptamers upon plasmon-resonant light (605nm) radiation, and to enhance the in vitro inhibition against tumor cell proliferation. The results show high potential of Apt-Au-Fe3O4as a targeted cancer hyperthermia carrier by remote control with high spatial/temporal resolution.

A porous Zn-based metal-organic framework for pH and temperature dual-responsive controlled drug release

A porous metal-organic framework Zn-TBDA (TBDA = 4′-(1H-tetrazol-5-yl) -[1,1′-biphenyl]-3,5-dicarboxylic acid) with one-dimensional channels has been synthesized from zinc ions and bifunctional ligands. The negligible cytotoxicity of Zn-TBDA is confirmed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) assay and microscopy observation. The anticancer drug methotrexate (MTX) is loaded into Zn-TBDA successfully via in-situ encapsulation and the loading capability reaches about 12.59 wt% in resulting composite MTX-encapsulated Zn-TBDA. Under different physiological microenvironments, MTX-encapsulated Zn-TBDA exhibits sensitive pH and temperature dual-responsive release manners, revealing its practical value as a smart drug carrier with controlled release in certain site and improved therapeutic efficacy without any additional external fields.

Preparation and characterization of DOX loaded keratin nanoparticles for pH/GSH dual responsive release

Smart drug carriers are the current need of the hour in controlled drug delivery applications. In this work, pH and redox dual responsive keratin based drug-loaded nanoparticles (KDNPs) were fabricated through two-step strategies. Keratin nanoparticles were first prepared by desolvation method and chemical crosslinking, followed by electrostatic adsorbing doxorubicin (DOX) to afford drug loaded keratin nanoparticles (KDNPs). The size, size distribution, and morphology of the KDNPs were characterized with dynamic light scattering (DLS) and Scan electronic microscope (SEM). Drug delivery profiles showed that KDNPs exhibited pH and glutathione (GSH) dual-responsive characters. Under tumor tissue/cell microenvironments (more acidic and high GSH level), KDNPs tended to accumulate at the tumor region through a potential enhanced permeability and retention (EPR) effect and perform surface negative-to-positive charge conversion. Hemolysis assay indicated that KDNPs had good blood compatibility. Cellular uptake assay demonstrated that KDNPs could be internalized by A 549 cells through endocytosis. Intriguingly, KDNPs were capable of promoting nitric oxide (NO) release from endogenous donor of S-nitrosoglutathione in the presence of GSH. All of these results demonstrated that keratin based drug carriers had potential for drug/NO delivery and cancer therapy in clinical medicine.

Design of Magnetic Polymeric Particles as a Stimulus-Responsive System for Gastric Antimicrobial Therapy.

The treatment of peptic ulcers induced by H. pylori remains challenging due to the deep mucous layer location of bacteria preventing antimicrobial drug access. The present work aimed to design and evaluate in vitro dual responsive (both pH and magnetic field-sensitive) polymeric magnetic particles loaded with amoxicillin as a smart drug carrier for deep mucous layer penetration and in situ drug release. Magnetite particles were produced by the co-precipitation method and subsequently coated with the Eudragit®S100 and amoxicillin by using the spray-drying technique. The physicochemical characterization of the obtained particles was carried out by optical and scanning electron microscopy, X-ray powder diffraction, Fourier transform infrared spectroscopy, nitrogen adsorption/desorption isotherms, and vibrating sample magnetometry. Additionally, drug release tests and antibacterial activity tests were evaluated in vitro. Microparticles presented 17.2 ± 0.4μm in size and their final composition was 4.3 ± 1.5% of amoxicillin, 87.0 ± 2.3% of Eudragit, and 9.0 ± 0.3% ofmagnetite. They were both pH and magnetic field responsive while presenting antimicrobial activity. On one side, magnetic field responsiveness of particles is expected to prompt them to reach bacterium niche in deep mucous layer by means of magnetic forces. On the other side, pH responsiveness is expected to enable drug release in the neutral pH of the deep mucous layer, preventing undesired delivery in the acidic gastric lumen. Smart microparticles were designed presenting both pH and magnetic field responsiveness as well as antimicrobial activity. These may be promising assets for peptic ulcer treatment.

Intracellular redox induced drug release in cancerous and mesenchymal stem cells

In this report, we investigated intracellular redox induced drug release in cancerous cells and human mesenchymal stem cells (MSCs) as an example of healthy cells using redox-responsive microcapsules with covalently bonded anti-cancer drug (doxorubicin) via the amine-reactive cross-linker, 3,3′-dithiobis(sulfosuccinimidyl propionate) containing disulfide bond. Such rationally designed capsules with incorporated redox-sensitive cross-linker are capable of controllable Dox release in the presence of glutathione (GSH) due to a thiol-cleavable disulfide bonds. The treatment of human MSCs and human cervical cancer cell line (HeLa) with Dox-conjugated capsules showed that the Dox release was observed only when capsules incubated with HeLa cells which can be induced by high GSH level in cancerous (HeLa) cells. Moreover, the results of cell viability indicated that Dox-conjugated capsules are more effective when inducing cell death of HeLa than free Dox improving the anti-tumor efficacy of chemotherapeutic drug and simultaneously they possess lower cytotoxicity against MSCs compared to cancerous cells. Such properties are important in design of smart drug carriers for efficient cancer therapy.

Synthesis and characterization of a multi-conjugated ELP-liposome complex with thermo-sensitivity as a smart drug carrier

Synthesis and characterization of a multi-conjugated ELP-liposome complex with thermo-sensitivity as a smart drug carrier

Synthesis and Characterization of Cleavable Core-Cross-Linked Micelles Based on Amphiphilic Block Copolypeptoids as Smart Drug Carriers.

Amphiphilic block copolypeptoids consisting of a hydrophilic poly(N-ethyl glycine) segment and a hydrophobic poly[(N-propargyl glycine)-r-(N-decyl glycine)] random copolymer segment [PNEG-b-P(NPgG-r-NDG), EPgD] have been synthesized by sequential primary amine-initiated ring-opening polymerization (ROP) of the corresponding N-alkyl N-carboxyanhydride monomers. The block copolypeptoids form micelles in water and the micellar core can be cross-linked with a disulfide-containing diazide cross-linker by copper-mediated alkyne-azide cycloaddition (CuAAC) in aqueous solution. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis revealed the formation of spherical micelles with uniform size for both the core-cross-linked micelles (CCLMs) and non-cross-linked micelles (NCLMs) precursors for selective block copolypeptoid polymers. The CCLMs exhibited increased dimensional stability relative to the NCLMs in DMF, a nonselective solvent for the core and corona segments. Micellar dissociation of CCLMs can be induced upon addition of a reducing agent (e.g., dithiothreitol) in dilute aqueous solutions, as verified by a combination of fluorescence spectroscopy, size exclusion chromatography (SEC), and (1)H NMR spectroscopic measurement. Doxorubicin (DOX), an anticancer drug, can be loaded into the hydrophobic core of CCLMs with a maximal 23% drug loading capacity (DLC) and 37% drug loading efficiency (DLE). In vitro DOX release from the CCLMs can be triggered by DTT (10 mM), in contrast to significantly reduced DOX release in the absence of DTT, attesting to the reductively responsive characteristic of the CCLMs. While the CCLMs exhibited minimal cytotoxicity toward HepG2 cancer cells, DOX-loaded CCLMs inhibited the proliferation of the HepG2 cancer cells in a concentration and time dependent manner, suggesting the controlled release of DOX from the DOX-loaded CCLMS in the cellular environment.

A three-dimensional Nd(iii)-based metal–organic framework as a smart drug carrier

A 3D lanthanide MOF with formula [Nd2(abtc)1.5(H2O)3(DMA)]·H2O·DMA has been synthesized. It shows efficient encapsulation and controllable release of an anticancer drug (5-Fu).

A thermo- and pH-responsive poly(N-isopropylacrylamide)–Mn–ZnS nanocomposite for controlled release and real-time photoluminescence tracking of doxorubicin

A novel multifunctional poly(N-isopropylacrylamide)–Mn–ZnS (PMZS) nanocomposite was developed as a smart drug carrier for thermo- and pH-controlled release of doxorubicin (Dox) and real-time photoluminescence tracking of the released Dox.

Recent advances in mesoporous silica nanoparticles for antitumor therapy: our contribution.

Since 2001, when our research group proposed for the first time MCM-41 as a drug release system, the scientific community has demonstrated a growing interest in mesoporous silica nanoparticles (MSNs) for their revolutionary potential in nanomedicine. Among the diverse pathologies that can be treated with MSNs, cancer has received increasing attention. MSNs can be loaded with large amounts of therapeutic cargoes and once intravenously administrated preferentially accumulate in solid tumours via the enhanced permeation and retention (EPR) effect. Herein we report the recent developments achieved by our research group as a pioneer in this field, highlighting: the design of sophisticated MSNs as stimuli-responsive drug delivery systems to release the entrapped cargo upon exposure to a given stimulus while preventing the premature release of highly cytotoxic drugs before reaching the target; transporting non-toxic prodrugs and the enzyme responsible for its conversion into cytotoxic agents into the same MSNs; improving the selectivity and cellular uptake by cancer cells by active targeting of MSNs; increasing the penetration of MSNs within the tumour mass, which is one of the major challenges in the use of NPs to treat solid tumours.

The synthesis and application of heparin-based smart drug carrier

Heparin based polymer drug which could self-assemble into sphere micelle in water was firstly prepared by grafting paclitaxel (PTX) into the hydroxyl of heparin via aconitic bond as pH sensitive spacer. Positive charged drug DOX·HCl and cationic folic acid (CFA) can be further loaded into the polymer drug via electrostatic interaction in aqueous solution so as to prepare smart drug carrier. The drug carrier was able to release more PTX and DOX at pH 4.8 than that at pH 7.4, exhibiting pH sensitivity for two drugs. Furthermore, tumor cell cytotoxicity test proved it possessed significant cytotoxicity against tumor cells MDA-MB-231 as well as its active tumor targeting ability resulting from the loading of CFA. Cellular uptake and intracellular distribution were further revealed by confocal laser scanning microscopy (CLSM). In conclusion, this paper not only provided a simple strategy but also indicated heparin is a versatile platform for the design of smart drug carrier. The as-prepared drug carrier also showed promising potential in chemotherapy.

Thermo‐Induced Double Phase Transition Behavior of Physically Cross‐Linked Hydrogels Based on Oligo(ethylene glycol) methacrylates

Double thermosensitive clay/P(MEO2MA‐co‐POEGMA) nanocomposite (NC) hydrogels are prepared by in situ free radical polymerization of 2‐(2‐methoxyethoxy) ethyl methacrylate (MEO2MA) and oligo(ethylene glycol) methacrylate (OEGMA) in the presence of physical cross‐linker clay. The temperature‐induced phase transition behavior of NC hydrogels is investigated by turbidity, temperature dependent nuclear magnetic resonance, and variable temperature Fourier transform infrared spectroscopy. 2D infrared analysis is employed to study the sequential order of changes of all groups in NC hydrogels during the heating and cooling process. The obtained novel clay/P(MEO2MA‐co‐POEGMA) NC hydrogels exhibit an unusual thermally induced multistep aggregation process and successively undergo three consecutive microstructural changes: “loose clay/polymer microaggregation ↔ homogeneous network structure ↔ dense clay/polymer macroaggregation.” Dynamic light scattering and transmission electron microscopy measurements show similar results of the NC nanogel at the same temperature regions, confirming the three consecutive microstructural changes. This new generation of thermosensitive hydrogel offers promising potential for applications as smart devices, biomedical materials, and drug carriers. image

Hollow PUA/PSS/Au microcapsules with interdependent near‐infrared/pH/temperature multiresponsiveness

ABSTRACTIn this work, smart hollow microcapsules made of thermal‐/pH‐dual sensitive aliphatic poly(urethane‐amine) (PUA), sodium poly(styrenesulfonate) (PSS), and Au nanoparticles (AuNPs) for interdependent multi‐responsive drug delivery have been constructed by layer‐by‐layer (LbL) technique. The electrostatic interactions among PUA, PSS, and AuNPs contribute to the successful self‐assembly of hollow multilayer microcapsules. Thanks to the shrinkage of PUA above its lower critical solution temperature (LCST) and the interaction variation between PUA and PSS at different pH conditions, hollow microcapsules exhibit distinct pH‐ and thermal‐sensitive properties. Moreover, AuNPs aggregates can effectively convert light to heat upon irradiation with near‐infrared (NIR) laser and endow the hollow microcapsules with distinct NIR‐responsiveness. More importantly, the NIR‐responsive study also demonstrates that the microcapsule morphology and the corresponding NIR‐responsive drug release are strongly dependent on the pH value and temperature of the media. The results indicate that the prepared hollow PUA/PSS/Au microcapsules have the great potential to be used as a novel smart drug carrier for the remotely controllable drug delivery. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 43008.

Mesoporous-Silica-Functionalized Nanoparticles for Drug Delivery.

The ever-growing interest for finding efficient and reliable methods for treatment of diseases has set a precedent for the design and synthesis of new functional hybrid materials, namely porous nanoparticles, for controlled drug delivery. Mesoporous silica nanoparticles (MSNPs) represent one of the most promising nanocarriers for drug delivery as they possess interesting chemical and physical properties, thermal and mechanical stabilities, and are biocompatibile. In particular, their easily functionalizable surface allows a large number of property modifications further improving their efficiency in this field. This Concept article deals with the advances on the novel methods of functionalizing MSNPs, inside or outside the pores, as well as within the walls, to produce efficient and smart drug carriers for therapy.