Anticancer drug delivery systems based on inorganic nanocarriers with fluorescent tracers

In recent years, anticancer nanomedicines have mainly been developed for chemotherapy and combination therapy in which the main contributing anticancer drugs are delivered by deliberately designed nano drug delivery systems (nano‐DDSs). Inorganic nanocarriers equipped with fluorescent tracers have become attractive tools to monitor the whole drug delivery and release processes. The fluorescence signal of tracers could be observed concomitantly with drug release, and thus, this strategy is of great benefit to evaluate the therapeutic effects of the nano‐DDSs. This review provides a brief overview about three inorganic nanocarriers for drug delivery, including mesoporous silica, Fe₃O₄, and hydroxyapatite. We mainly discussed about their preparation processes, drug loading capacities, and the development of different fluorescent materials (fluorescent dyes, quantum dots, fluorescent macromolecules, and rare earth metals) hybridized to nanocarriers for real‐time monitoring of drug release both in vitro and in vivo. This review also provides some recommendations for more in‐depth research in future. © 2017 American Institute of Chemical Engineers AIChE J, 64: 835–859, 2018     

Surface decoration of magnetic nanoparticles with folate-conjugated poly(N-isopropylacrylamide-co-itaconic acid): A facial synthesis of dual-responsive nanocarrier for targeted delivery of doxorubicin

The aim of study was to develop a novel drug nanocarrier via facile coating of a folate-conjugated dual-responsive copolymer with carboxylic functional groups on the surface of magnetic nanoparticles for the efficient loading and cell-specific targeting of a positively charged anticancer agent. The nanocarrier exhibited many favorable capabilities such as narrow distributed nano-ranged size (～30 nm), high drug loading capacity (～65%), and stimuli-responsive drug release. The results of various cell cytotoxicity studies such as MTT assay, DAPI staining, and flow cytometry concluded that the developed smart nanocarrier paves a way for efficient cancer therapy by the multiple targeting strategies.     

Dual stimuli-responsive polymeric hollow nanocapsules as “smart” drug delivery system against cancer

ABSTRACT

Novel thermal- and pH-responsive hollow nanocapsules (HNCaps) were fabricated through the grafting of a thiol-end capped PNIPAAm-b-PAA by thiol-ene “click” reaction onto PMMA HNCaps. The lowest critical solution temperature (LCST) of the fabricated HNCaps was obtained as 38–40°C. The fabricated nanosystem was loaded with doxorubicin hydrochloride (Dox), and its drug loading and encapsulation efficiencies were obtained as 62 and 53%, respectively. The in vitro stimuli-responsive drug release behavior of the fabricated nanomedicine was investigated extensively. The anticancer activity of the drug-loaded HNCaps was evaluated using MTT assay against MCF7 cells. The results exhibited excellent potential of nanosystem as a drug delivery system (DDS) for cancer chemotherapy.     

Preparation of N-Isopropylacrylamide/Itaconic Acid Magnetic Nanohydrogels by Modified Starch as a Crosslinker for Anticancer Drug Carriers

A novel approach is presented for the synthesis of thermoresponsive and pH-sensitive magnetic nanohydrogels by using the biodegradable starch-maleate as a crosslinker and magnetic nanoparticles stabilizer. Chemically modified starch-maleate produces highly stable Fe₃O₄ magnetic nanopaticles (MNPs) aqueous dispersion. Then, N-isopropylacrylamide (NIPAAm) and itaconic acid (IA) are successfully polymerized from the vinyl double bonds of the starch-maleate-MNPs to prepare the thermo- and pH-responsive magnetic nanohydrogels. The obtained PNIPAAm-g-(starch-MNPs) and (PNIPAAm-co-IA)-g-(starch-MNPs) nanohydrogels are characterized by transmission electron microscopy, dynamic light scattering, Fourier transform infrared spectrometer, X-ray diffraction, differential scanning calorimetry, thermal gravimetric analysis, and vibrating sample magnetometer. Also, pH- and temperature-responsive behaviors of the synthesized magnetic nanohydrogels are investigated and, finally, the cytotoxicity and drug loading are examined with mitoxantrone (MTX) as an anticancer drug model. The results confirm the low toxicity and enhanced anticancer effect of MTX-loaded magnetic nanohydrogels.     

A Biomimetic Hybrid Hydrogel Based on the Interactions between Amino Hydroxyapatite and Gelatin/Gellan Gum

In this work, a gelatin (Gel)‐oxidized gellan gum (OG)/amino hydroxyapatite (mHap) hybrid hydrogel with Schiff base linkages is reported. The mHap is obtained by modifying hydroxyapatite with tetraethyl orthosilicate and 3‐aminopropyl‐triethoxysilane. The effects of different mHap contents on the structure, morphology, and properties of hydrogels are particularly investigated. Scanning electron microscopy coupled with energy dispersion spectroscopy reveals that mHap of around 100 nm is uniformly distributed inside the hydrogel with interconnected porous structures. Notably, the hydrogel with 1 wt% mHap possesses the highest compressive stress (2.01 ± 0.10 MPa) at 90% strain, as well as the lowest equilibrium swelling ratio (97% ± 5%) and degradation rate than other hydrogels. Besides, an ultra‐high compressive stress equivalent to 91% of the initial stress can be obtained by this hydrogel after 50 loading‐unloading cycles (85% strain). Meanwhile, after being swollen, this improved hydrogel also exhibits better structural stability than Gel‐OG hydrogel. The in vitro 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay further shows that all hydrogels are nontoxic against mouse fibroblasts. This work provides a biomimetic strategy to construct the organic/inorganic hydrogels with excellent interactions, elasticity, reversibility, and biocompatibility, which is of great importance for the practical applications in cartilage tissue engineering.     

PEGylated hollow pH‐responsive polymeric nanocapsules for controlled drug delivery

Novel pH‐responsive PEGylated hollow nanocapsules (HNCaps) were fabricated through a combination of distillation–precipitation copolymerization and surface thiol–ene ‘click’ grafting reaction. For this purpose, SiO₂ nanoparticles were synthesized using the Stöber approach, and then modified using 3‐(trimethoxysilyl)propyl methacrylate (MPS). Afterward, a mixture of triethyleneglycol dimethacrylate (as crosslinker), acrylic acid (AA; as pH‐responsive monomer) and MPS‐modified SiO₂ nanoparticles (as sacrificial template) was copolymerized using the distillation–precipitation approach to afford SiO₂@PAA core–shell nanoparticles. The SiO₂ core was etched from SiO₂@PAA using HF solution, and the obtained PAA HNCaps were grafted with a thiol‐end‐capped poly(ethylene glycol) (PEG) through a thiol–ene ‘click’ reaction to produce PAA‐g‐PEG HNCaps. The fabricated HNCaps were loaded with doxorubicin hydrochloride (DOX) as a model anticancer drug, and their drug loading and encapsulation efficiencies as well as pH‐dependent drug release behavior were investigated. The anticancer activity of the drug‐loaded HNCaps was extensively evaluated using MTT assay against human breast cancer cells (MCF7). The cytotoxicity assay results as well as superior physicochemical and biological features of the fabricated HNCaps mean that the developed DOX‐loaded HNCaps have excellent potential for cancer chemotherapy. © 2020 Society of Chemical Industry     

Magnetic liposomes for colorectal cancer cells therapy by high-frequency magnetic field treatment

In this study, we developed the cancer treatment through the combination of chemotherapy and thermotherapy using doxorubicin-loaded magnetic liposomes. The citric acid-coated magnetic nanoparticles (CAMNP, ca. 10 nm) and doxorubicin were encapsulated into the liposome (HSPC/DSPE/cholesterol = 12.5:1:8.25) by rotary evaporation and ultrasonication process. The resultant magnetic liposomes (ca. 90 to 130 nm) were subject to characterization including transmission electron microscopy (TEM), dynamic light scattering (DLS), X-ray diffraction (XRD), zeta potential, Fourier transform infrared (FTIR) spectrophotometer, and fluorescence microscope. In vitro cytotoxicity of the drug carrier platform was investigated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using L-929 cells, as the mammalian cell model. In vitro cytotoxicity and hyperthermia (inductive heating) studies were evaluated against colorectal cancer (CT-26 cells) with high-frequency magnetic field (HFMF) exposure. MTT assay revealed that these drug carriers exhibited no cytotoxicity against L-929 cells, suggesting excellent biocompatibility. When the magnetic liposomes with 1 μM doxorubicin was used to treat CT-26 cells in combination with HFMF exposure, approximately 56% cells were killed and found to be more effective than either hyperthermia or chemotherapy treatment individually. Therefore, these results show that the synergistic effects between chemotherapy (drug-controlled release) and hyperthermia increase the capability to kill cancer cells.     

Development of multifunctional cobalt ferrite/hydroxyapatite nanocomposites by microwave assisted wet precipitation method: A promising platform for synergistic chemo-hyperthermia therapy

Functional nanocomposites capable of multimodal therapy hold great potential to improve the efficiency of cancer therapy. Herein, we report a magnetic nanocomposite of cobalt ferrite/hydroxyapatite followed by loading a chemotherapeutic drug (5-fluorouracil, FU) to construct the intelligent drug delivery system and/or hyperthermia carrier. To do that, cobalt ferrite/hydroxyapatite nanocomposite was successfully synthesized by microwave assisted wet precipitation method, subsequently, FU loaded onto the formed composites through adsorption method. This nanocomposite exhibits ferromagnetic behaviour with a magnetic saturation value of approximately 2.5–8.2 emu/g. Upon alternating magnetic field, it could generate hyperthermia temperature within a short time (43°C in 4.5 min) and facilitate the release of encapsulated FU from the composite with enhanced release rate. These multifunctional carriers also demonstrate a noticeable proliferative activity against healthy fibroblast cells (L929) and suppressed growth against osteosarcoma cells (MG63). Therefore, this studied nanoplatform might be a promising candidate for synergistic chemo-hyperthermia therapy.     

An In Vitro Experimental Approach to Study Magnetically Targeted Release of Methotrexate From Superparamagnetic Starch Nanocarriers

In the field of drug delivery, magnetic nanoparticles have great potential to modernize anticancer therapy. In the present study iron oxides containing superparamagnetic starch nanoparticles were prepared by emulsion crosslinking method. The anticancer drug methotrexate was used for loading onto the magnetic starch nanoparticles and released drug was spectrophotometrically monitored at physiological pH (7.4) under application of a modulating magnetic field. The spectroscopic techniques such as FTIR, TEM, X-ray diffraction, and vibrating sample magnetometer (VSEM) studies were used to characterize the magnetic starch nanocarriers. The influence of various experimental parameters such as pH and temperature of the release media, percent drug loading, chemical compositions of nanocarriers, and applied magnetic field were investigated on the drug release profiles of synthesized magnetic starch nanoparticles. The nanoparticles were also evaluated for cytotoxicity and in vitro blood compatibility.     

Preparation and characterization of PVA films with magnetic nanoparticles: The effect of particle loading on drug release behavior

This article deals with the drug release behavior of theophylline (Th) from poly(vinyl alcohol) (PVA) hydrogels, prepared with magnetic nanoparticles at different particle loadings. These biocompatible matrices were obtained by incorporating different amounts of an aqueous ferrofluid into PVA hydrogels, loaded with Th as a marker for drug‐delivery studies. PVA films with magnetic particles proved to be magnetic field‐responsive materials as the drug release decreased through the application of a relative low and uniform magnetic field for particle concentrations of 0.9% w/w or higher. Moreover, the percentage of restriction of drug release is found to be correlated with particle loading. The in vitro release profiles were analyzed by applying a semiempirical power law to obtain the kinetic parameters. The value of the release exponent was found to be in the range 0.54–0.56 in all experiments, which thus indicates a predominant diffusional mechanism for drug release from these smart magnetic hydrogels. This effect suggests the possibility of modulating the release behavior by controlling the particle content in the preparation of the composites. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Design and fabrication of a triple-responsive chitosan-based hydrogel with excellent mechanical properties for controlled drug delivery

A pH-, temperature- and salinity responsive hydrogel with enhanced mechanical performance was developed based on semi interpenetrating network that was formed as a result of concurrent free radical polymerization of acrylic acid (AA), oligo(ethylene glycol) methacrylate (OEGMA) and 2-(2-methoxyethoxy) ethyl methacrylate (MEO₂MA) along with chitosan (CS) for controlled drug delivery. The mechanical behaviors and swelling properties of these hydrogels were systematically investigated, and the results indicated that they were strongly affected by the content of AA and MEO₂MA and exhibited strong pH-, temperature and salinity sensitivity. Bovine serum albumin (BSA) and 5-Fluorouracil (5-Fu) were used as the model drugs to evaluate the sustained release of the hydrogel. The result indicated that the amount of both drugs released was relatively low in acidic condition (pH 1.2) but high in neutral environment (pH 7.4), and the release rate of the drugs was slower at 37 °C than that at 25 °C. Cytotoxicity results suggested that the blank hydrogels had negligible toxicity to normal cells, whereas the 5-Fu-loaded hydrogels remained high in cytotoxicity for LO2 and HepG2 cancer cells. These results suggest that the synthesized hydrogels have the potential to be used as an effective pH/temperature sustainable site-specific oral drug delivery in intestine and colon.     

Antimicrobial Activity of Curcumin in Nanoformulations: A Comprehensive Review

Curcumin (CUR) is a natural substance extracted from turmeric that has antimicrobial properties. Due to its ability to absorb light in the blue spectrum, CUR is also used as a photosensitizer (PS) in antimicrobial Photodynamic Therapy (aPDT). However, CUR is hydrophobic, unstable in solutions, and has low bioavailability, which hinders its clinical use. To circumvent these drawbacks, drug delivery systems (DDSs) have been used. In this review, we summarize the DDSs used to carry CUR and their antimicrobial effect against viruses, bacteria, and fungi, including drug-resistant strains and emergent pathogens such as SARS-CoV-2. The reviewed DDSs include colloidal (micelles, liposomes, nanoemulsions, cyclodextrins, chitosan, and other polymeric nanoparticles), metallic, and mesoporous particles, as well as graphene, quantum dots, and hybrid nanosystems such as films and hydrogels. Free (non-encapsulated) CUR and CUR loaded in DDSs have a broad-spectrum antimicrobial action when used alone or as a PS in aPDT. They also show low cytotoxicity, in vivo biocompatibility, and improved wound healing. Although there are several in vitro and some in vivo investigations describing the nanotechnological aspects and the potential antimicrobial application of CUR-loaded DDSs, clinical trials are not reported and further studies should translate this evidence to the clinical scenarios of infections.     

Nanotechnology-based combinational drug delivery systems for breast cancer treatment

Modern chemotherapeutic anticancer treatments have come a long way in the fight against breast cancer, thus bringing science closer to a cure. However, the nature of these drugs is to attack both cancerous and non-cancerous cells at the same time. In our studies, we synthesized Magnetic Cyclodextrin-polyurethane based nano-composite (Fe₃O₄-ECA-PU-CD) which is a drug delivery system using a biocompatible magnetic polymer that directs chemotherapeutic drugs to cancerous regions in the body with an external magnet. This nano-composite was able to facilitate the loading and simultaneous release of the hydrophilic antitumor drug Doxorubicin (DOX) along with the hydrophobic antitumor drug docetaxel. The composite was made using a simple co-precipitation method with magnetic nano-particles (MNPs) followed by a silica coating process and an in situ polymerization process. Verification of synthesis for the drug carrier was carried out using techniques such as scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), Thermogravimetric Analysis (TGA), and a vibrating sample magnetometer (VSM) to measure magnetic properties. Drug loading and release efficiencies were monitored using an HPLC-UV detector. Finally, an MTT assay was performed in order to evaluate the biocompatibility and toxicity of the synthetic nano-composite on MCF7 cell lines. Our findings present a new biocompatible drug delivery system with a high capacity for loading and directing two different chemotherapeutic drugs simultaneously to cancer sites with little to no toxicity to the surrounding non-cancerous cells. These studies present a viable tool for cancer treatment and research where the cancer is efficiently removed while the patient remains healthy.     

Cisplatin-loaded carbon-encapsulated iron nanoparticles and their in vitro effects in magnetic fluid hyperthermia

Iron nanoparticles encapsulated by carbon are protected from reactions with their environment avoiding oxidation in ambient conditions and thus, preserving their magnetic properties. Such particles are good candidates for magnetic fluid hyperthermia. When graphite shells are present, acidic treatments allow the formation of carboxylic groups on the nanoparticle surface. Those carboxylic groups can be used for further complexation with the drug cisplatin. We show the possibility of loading cisplatin on such nanoparticles and that the loading is dependent on the degree of surface functionalization. The drug release is dependent on time and temperature, making it ideal for applications involving hyperthermia. We show the possibility of applying hyperthermia in vitro using these nanoparticles. When loaded with cisplatin a stronger cytotoxic effect is observed. Such particles could be potentially used as multimodal anti-cancer agents for therapies based on the synergistic effect of chemotherapy and hyperthermia.     

Preparation and characterization of sodium alginate/poly(<Emphasis Type="Italic">N</Emphasis>-isopropylacrylamide)/clay semi-IPN magnetic hydrogels

pH- and temperature-responsive semi-interpenetrating magnetic nanocomposite hydrogels (NC hydrogels) were prepared by using linear sodium alginate (SA), poly(N-isopropylacrylamide) (PNIPAM) and Fe₃O₄ nanoparticles with inorganic clay as an effective multifunctional cross-linker. The effects of cross-linker and SA contents on various physical properties were investigated. The NC hydrogels exhibited a volume phase transition temperature (VPTT) around 32 °C with no significant deviation from the conventional chemically cross-linked PNIPAM hydrogels (OR hydrogels). The swelling ratios of NC hydrogels were much larger than those of OR hydrogels. Moreover, the swelling ratios of NC hydrogels gradually decreased with increasing the contents of clay and increased with increasing the contents of SA. The pH sensitivity of NC hydrogels was evident below their VPTT. The NC hydrogels had a much better mechanical property than the OR hydrogels. The results showed that the incorporation of clay did not affect the saturation magnetization of the hydrogels.     

Dual stimuli-responsive poly(succinyloxyethylmethacrylate-b-N-isopropylacrylamide) block copolymers as nanocarriers and respective application in doxorubicin delivery

Stimuli-responsive nanostructures were developed as anticancer drug delivery carriers. To this end, poly(2-hydroxyethylmethacrylate)-b-(N-isopropylacrylamide) (poly(HEMA-b-NIPAAm)) diblock copolymers were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization with two ratios remarked with (1) and (2). Based on gel permeation chromatography, the molecular weights of synthesized diblock copolymers were 17802 (1) and 13090 (2) g?mol^?1. The pH- and thermoresponsive poly(succinyloxyethylmethacrylate-b-N-isopropylacrylamide) (poly)SEMA-b-NIPAAm)) diblock copolymers were obtained by reacting poly(HEMA-b-NIPAAm) with excess succinic anhydride in pyridine under mild conditions. Developed micelles with poly(SEMA-b-NIPAAm) (1) and poly(SEMA-b-NIPAAm) (2) diblock copolymers around pH of 3–4 at 25°C demonstrated the critical micelles concentrations (CMCs) of 0.026 and 0.019?g?L^?1, respectively. The average sizes of poly)SEMA-b-NIPAAm) micelles using dynamic light scattering (DLS) measurements at pH 3.0, 6.0, and 9.0 were 240, 190, and 150?nm, respectively. The core-shell poly(SEMA-b-NIPAAm) micelles at pH 3 and 9 were 100–200?nm. The lower critical solution temperature (LCST) of poly)SEMA-b-NIPAAm) sample was determined to be 40°C by ultraviolet-visible (UV-vis) spectroscopy. The micelles of diblock copolymers were formed to enhance the drug solubility in aqueous solutions. Doxorubicin hydrochloride (DOX)-loading capacity was 99.1%. The release of DOX acted better at 42°C compared to 40°C. The results confirmed that pH- and temperature-dependent release of this drug carrier was particularly useful and important for the anticancer drug delivery at the tumor-like environment. Therefore, the biocompatibility of diblock copolymer was confirmed by assessing survival rate of breast cancer cell line (MCF7) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The synthesized nanoparticles would have an excellent potential as anticancer drug delivery.     

Versatile Types of Polysaccharide-Based Drug Delivery Systems: From Strategic Design to Cancer Therapy

Chemotherapy is still the most direct and effective means of cancer therapy nowadays. The proposal of drug delivery systems (DDSs) has effectively improved many shortcomings of traditional chemotherapy drugs. The technical support of DDSs lies in their excellent material properties. Polysaccharides include a series of natural polymers, such as chitosan, hyaluronic acid, and alginic acid. These polysaccharides have good biocompatibility and degradability, and they are easily chemical modified. Therefore, polysaccharides are ideal candidate materials to construct DDSs, and their clinical application prospects have been favored by researchers. On the basis of versatile types of polysaccharides, this review elaborates their applications from strategic design to cancer therapy. The construction and modification methods of polysaccharide-based DDSs are specifically explained, and the latest research progress of polysaccharide-based DDSs in cancer therapy are also summarized. The purpose of this review is to provide a reference for the design and preparation of polysaccharide-based DDSs with excellent performance.     

In situ gelling aqueous solutions of pH- and temperature-sensitive poly(ester amino urethane)s

A series of novel pH- and temperature-sensitive multiblock poly(ester amino urethane)s were synthesized. The copolymers were characterized by ¹H NMR, FT-IR and GPC. In the multiblock copolymers, the tertiary amino groups of the poly(amino urethane) segments act as pH-responsive moieties, while the PCL-PEG-PCL blocks act as biodegradable and temperature-sensitive segments. At a relatively high pH (7.0 or above), the multiblock copolymer aqueous solution showed a sol-to-gel-to-aggregation transition with increasing temperature. In contrast, at a lower pH (below 7.0), the polymer solution always existed as a sol state within the experimental temperature range. The gel window covers the physiological conditions. After subcutaneous injection of the 20 wt% multiblock copolymer solutions into mice, polymeric hydrogels were formed in situ in a short time. The in vitro release of an anticancer drug, paclitaxel, persisted over 1 month under physiological conditions.     

Enhancing mechanical strength of hydrogels via IPN structure

In this investigation, polyacrylamide (PAAm) as the flexible network is introduced to enhance the mechanical strength of hyaluronic acid–gelatin (HA–Gel) hydrogels by interpenetrating polymer network (IPN). The structure, mechanical property, and rheology property of the IPN hydrogels are investigated. It is found that the compressive strength of the HA–Gel/PAAm IPN hydrogels has increased five times higher than that of HA–Gel hydrogels. Rheological test demonstrates that elastic moduli (G′) and viscous moduli (G″) of HA–Gel/PAAm IPN hydrogels increase 100 times higher than those of HA–Gel hydrogels. Moreover, the HA–Gel hydrogels are fractured under the low compressive stress, whereas HA–Gel/PAAm IPN hydrogels are not broken under the high compressive stress. It is envisioned that the IPN hydrogels will be an effective approach to enhance the mechanical strength and broaden the range of hydrogels' applications. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 44503.     

A computational and experimental approach to develop minocycline-imprinted hydrogels and determination of their drug delivery performances

In this study, minocycline-imprinted hydrogels are developed for controlled drug delivery in ocular disease treatments. An integrated computational and experimental study are conducted for investigating the relationship between design parameters and the drug loading/release performance of hydrogels. First, suitable functional monomers are determined for successful drug-imprinting by studying pre-polymerization conditions with full-atom molecular dynamics (MD) simulations. MD simulations suggest that acrylic acid and itaconic acid are suitable monomers for imprinting minocycline. Then, minocycline-imprinted hydrogels are synthesized with acrylic acid, commonly used in hydrogels, and three different amounts of cross-linker ethylene glycol dimethacrylate, 1, 2 and 3 mol%. All hydrogels are characterized and their drug loading and release performances are determined. Our computational and experimental calculations indicate an optimum cross-linker amount of 2 mol% for controlled minocycline release from imprinted hydrogels with an imprinting factor of almost 3. Finally, the drug release kinetics are determined by Korsmeyer-Peppas model.