Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging

Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs and in vivo imaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles (NP) are first reviewed. Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from entering the brain. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Potential treatments for common neurological disorders, such as stroke, tumours and Alzheimer's, are therefore a much sought-after application of nanomedicine. Likewise any other drug delivery system, a number of parameters need to be registered once functionalized NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion. Finally, direct in vivo imaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable for in vivo imaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical and hybrid contrast, such as fluorescent protein tomography and multispectral optoacoustic tomography. Overall, great potential is foreseen for nanocarriers in medical diagnostics, therapeutics and molecular targeting. A proposed roadmap for ongoing and future research directions is therefore discussed in detail with emphasis on the development of novel approaches for functionalization, targeting and imaging of nano-based drug delivery systems, a cutting-edge technology poised to change the ways medicine is administered.     

Preparation and evaluation of novel mixed micelles as nanocarriers for intravenous delivery of propofol

Novel mixed polymeric micelles formed from biocompatible polymers, poly(ethylene glycol)-poly(lactide) (mPEG-PLA) and polyoxyethylene-660-12-hydroxy stearate (Solutol HS15), were fabricated and used as a nanocarrier for solubilizing poorly soluble anesthetic drug propofol. The solubilization of propofol by the mixed micelles was more efficient than those made of mPEG-PLA alone. Micelles with the optimized composition of mPEG-PLA/Solutol HS15/propofol = 10/1/5 by weight had particle size of about 101 nm with narrow distribution (polydispersity index of about 0.12). Stability analysis of the mixed micelles in bovine serum albumin (BSA) solution indicated that the diblock copolymer mPEG efficiently protected the BSA adsorption on the mixed micelles because the hydrophobic groups of the copolymer were efficiently screened by mPEG, and propofol-loaded mixed micelles were stable upon storage for at least 6 months. The content of free propofol in the aqueous phase for mixed micelles was lower by 74% than that for the commercial lipid emulsion. No significant differences in times to unconsciousness and recovery of righting reflex were observed between mixed micelles and commercial lipid formulation. The pharmacological effect may serve as pharmaceutical nanocarriers with improved solubilization capacity for poorly soluble drugs.     

Preparation and evaluation of novel amphiphilic glycopeptide block copolymers as carriers for controlled drug release

In the present study we describe a synthesis and self-assembly and an in vitro evaluation of a kind of novel amphiphilic glycopeptide block copolymers as carriers for controlled drug release. Initially, an amphiphilic ABA triblock copolymer comprising polytetrahydrofuran (PTHF) as a central hydrophobic block flanked by poly(l-lysine)s (PLLs) as outer hydrophilic blocks was synthesized through the ring-opening polymerization of ?-benzyloxycarbonyl-l-lysine N-carboxyanhydride with a distal amine-terminated PTHF as a macroinitiator, followed by removal of the protecting group. Afterwards the resulting triblock copolymer was allowed to react with d-gluconolactone and lactobionolactone in the varying feeding ratios in the presence of diisopropylethylamine leading to the target glycopeptide block copolymers with high yields. They were found to easily self-assemble into nano-sized aggregates in water. The critical aggregation concentrations (CACs) were assessed by fluorescence measurement with N-phenyl-1-naphthylamine employed as a molecular probe. The particle sizes of the aggregates before and after doxorubicin loading were determined by dynamic light scattering (DLS) and the aggregate morphologies were evidenced by transmission electron microscopy (TEM) measurements. Finally, the in vitro doxorubicin loading capacity and release behavior were investigated with these glycopeptide copolymers as carriers for controlled release.     

Starch–acrylics graft copolymers and blends: Synthesis,characterization, and applications as matrix for drug delivery

A series of acrylic monomers–starch graft copolymers were prepared by ceric ion initiation method by varying the amount of monomers. These graft copolymers were characterized by IR and ¹³C‐NMR spectroscopy. It was seen that as the concentration of monomer [acrylic acid (AA), methacrylic acid (MA), and methyl methacrylate (MMA)] increased the percent add‐on increased in all the graft copolymers, whereas grafting efficiency increased initially but showed a slight decrease with further increase in the monomer concentration (except for MMA). The release rate of paracetamol as a model drug from graft copolymers as well as their blends was studied at two different pH, 1.2 and 7.4, spectrophotometrically. The release of paracetamol in phosphate buffer solution at pH 1.2 was insignificant in the first 3 h for St‐g‐PAA‐ and St‐g‐PMA‐graft copolymers, which was attributed to the matrix compaction and stabilization through hydrogen bonding at lower pH. At pH 7.4, the release rate was seen to decrease with increase in add‐on. The tablet containing poly(methyl methacrylate) (PMMA) did not disintegrate at the end of 30–32 h, which may be attributed to the hydrophobic nature of PMMA. These results indicate that the graft copolymers may be useful to overcome the harsh environment of the stomach and can be used as excipients in colon‐targeting matrices. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Design and characterization of PNVCL-based nanofibers and evaluation of their potential applications as scaffolds for surface drug delivery of hydrophobic drugs

In this work, nanofiber scaffolds for surface drug delivery applications were obtained by electrospinning poly(N-vinylcaprolactam) (PNVCL) and its blends with poly(ε-caprolactone) and poly(N-vinylcaprolactam)-b-poly(ε-caprolactone). The process parameters to obtain smooth and beadless PNVCL fibers were optimized. The average fibers diameter was less than 1 μm, and it was determined by scanning electron microscopy analyses. Their affinity toward water was evaluated by measuring the contact angle with water. The ketoprofen release behavior from the fibers was analyzed using independent and model-dependent approaches. The low values of the release exponent (n < 0.5) obtained for 20 and 42 °C, indicating a Fickian diffusion mechanism for all formulations. Dissolution efficiencies (DEs) revealed the effect of polymer composition, methodology used in the electrospinning process, and temperature on the release rate of ketoprofen. PNVCL/poly(N-vinylcaprolactam)-b-poly(ε-caprolactone)-based nanofibers showed greater ability to control the in vitro release of ketoprofen, in view of reduced kinetic constant and DE, making this material promising system for controlling release of hydrophobic drugs. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48472.     

Design and study of the potential of crosslinked cationic polymers as drug delivery systems for dermal application

Crosslinked carriers based on cationic monomer [2‐(acryloyloxy)ethyl]trimethylammonium chloride or 2‐(dimethylamino)ethyl methacrylate were developed and investigated as new platform for ibuprofen transdermal delivery. Series of networks of varied composition and structure were synthesized and characterized by FTIR spectroscopy and following swelling kinetics in different solvents. Dermal safety tests to examine the skin irritation and sensitization potential of the network films were performed in vivo. Chosen network compositions were loaded with ibuprofen by swelling in its ethanol solution. The structures of the drug carriers were investigated by scanning electron microscopy. Ibuprofen release from the developed drug delivery systems was followed in phosphate buffer solution at 37 °C. The investigation proved the feasibility of the developed cationic copolymer networks as effective platforms with modified ibuprofen release for potential dermal application. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46420.     

Development of self-microemulsifying drug delivery system of mebendazole by spray drying technology: Characterization,in vitro and in vivo evaluation

In this study, a novel liquid self-microemulsifying drug delivery system (SMEDDS) containing mebendazole was formulated and further developed into a solid form by a spray drying method using Aerosil 200 as the solid carrier. The optimum liquid SMEDDS consisted of Labrafil 2125 CS, Tween 20, and Maisine 35-1 as the oil phase, the surfactant, and the cosurfactant, respectively. The formulated SMEDDS was completely emulsified or dispersed within a minute. All formulations were dissolved within 1 h using 0.1 N HCl as dissolution medium, whereas pure drug was less significantly dissolved in this time period. The droplet size was found to be within 250 nm for solid forms of SMEDDS. Solid state characterization was performed by scanning electron micrograph, differential scanning calorimetry, and X-ray powder diffraction. After oral administration to Wistar rats, mebendazole in the solid SMEDDS resulted in the significant improvement in bioavailability compared with that of pure drug analyzed by RP-HPLC. The optimized formulation showed 24.87 folds increase in bioavailability as compared to pure drug and 8.39 folds increase in bioavailability in comparison to marketed tablet of mebendazole. The optimized batch has found to be 3.1726 years of shelf life. In conclusion, the solid SMEDDS is a promising solid dosage form for poorly water-soluble and low bioavailability drugs.     

Functionalization of microspheres with malonates using Michael Addition as a pathway to create a drug delivery system for platinum drugs for the treatment of liver cancer

Microspheres have been modified post-polymerization via Michael Addition to suit the requirement of these beads as a drug delivery carrier for platinum drugs. Ethyleneglycol dimethacrylate (EGDMA) was polymerized in a suspension system leading to microspheres with an excess of vinyl functionalities. Solid state NMR was employed to determine the amount of repeating groups with unreacted vinyl groups and a molar ratio of 28% was obtained. The percentage of vinyl groups was approximately confirmed using FT-Raman (34%). Subsequent Michael Addition of these vinyl functionalities with diethyl malonate leads to modification of almost half of the vinyl groups. Ester hydrolysis and reaction with cisplatin (cis-diammineplatinum(II) dichloride) lead to microspheres with a loading of around 9 wt% of platinum. The platinum drug was slowly released at a rate of 20% in 10 days making these microspheres suitable for the treatment of liver cancer via transarterial chemoembolization. Indeed, the drug-loaded carrier was found to be highly toxic to liver cancer cells (ATCC, HepG2) while the empty carrier is non-toxic.     

Development of natural and synthetic polymer-based semi-interpenetrating polymer network for controlled drug delivery: optimization and in vitro evaluation studies

This research paper describes the development, optimization and in vitro characterization of chemically cross-linked pectin–polyvinyl alcohol-co-poly(2-Acrylamido-2-methylpropane sulfonic acid) semi-interpenetrating polymer network hydrogel [pectin–PVA-co-poly(AMPS) semi-IPN hydrogel] for controlled delivery of model drug tramadol HCl. Response surface methodology based on 3² factorial design was used for optimization and investigating the effect of independent factors: polymer-blend ratio (pectin:PVA = X ₁) and monomer (AMPS = X ₂) concentration on the dependent variables, swelling ratio (q _18th), percent drug release (R _18th, %), time required for 80 % drug release (t _{80 %}, h), drug encapsulation efficiency (DEE, %) and drug loaded contents (DLC, mg/g) in pectin-PVA-co-poly(AMPS) gels prepared by free radical polymerization. The optimized semi-IPN gel (FPP-10) showed controlled in vitro drug release (R _18th) of 56.34 % in 18 h, t _{80 %} of 30 h, and DEE of 23.40 %. These semi-IPN hydrogels were also characterized through SEM, FTIR, sol–gel analysis, swelling studies and drug release characteristics. Therefore, this newly synthesized polymeric network could be a potential polymeric system for controlled drug delivery of tramadol HCl for prolonged drug release.     

Biocompatible hydrogels for the controlled delivery of anti-hypertensive agent: development,characterization and in vitro evaluation

The aim of the present exploration was to develop novel pH-sensitive cross-linked Gelatin/Polyvinyl pyrrolidone hydrogels using different ratios of both the polymers and to investigate the effect of polymers and degree of crosslinking on dynamic, equilibrium swelling and invitro release pattern of the model drug (captopril). Grafting polymerization technique was used for the preparation of these hydrogels using glutaraldehyde as crosslinking agent. These polymeric materials were then used as model systems to envisage various important characterizations like FTIR (Fourier transform infrared spectroscopy), XRD (X-ray diffraction) and scanning electron microscopy (SEM). Phosphate buffers of pH 1.2, 6.5 and 7.5 were used for swelling and invitro drug release profile investigation. Different parameters like swelling analysis, porosity, sol-gel analysis, average molecular weight between crosslinks (Mc), solvent interaction parameter (χ), volume fraction of polymer (V_2,s) and diffusion coefficient that affects the drug release behavior were also determined. Higher swelling and release was observed at lower pH values. FTIR spectra showed interaction between gelatin and polyvinyl pyrrolidone and successful formation of cross-linked structure. Pulsatile drug release study showed the controlled delivery of model drug. The release of drug occurred through non-fickian diffusion or anomalous mechanism. Aforementioned characterizations reveal successful formation of copolymer. pH sensitive swelling ability and drug release behavior suggest that the rate of polymer chain relaxation and the rate of drug diffusion from these hydrogels are comparable which also predicts their possible use for site specific captopril delivery.     

M/MnAl类混合氧化物的合成及其FCC硫转移性能的研究

采用酸胶溶法制备不同金属氧化物硫转移剂,用模拟FCC反应装置的微型固定床反应器,重点考察了不同硫转移剂的氧化吸附性能及其含量对脱硫性能的影响。结果表明,5种硫转移剂均具有不同程度的氧化吸硫性能,不同金属氧化物硫转移剂的吸附性能为:Co-MnAlOZn-MnAlOCu-MnAlOSr-MnAlOBa-MnAlO。     

Quaternary and pentanary mesoporous bioactive glass nanoparticles as novel nanocarriers for gallic acid: Characterisation,drug release and antibacterial activity

Mesoporous bioactive glass nanoparticles (MBGNs) have gained considerable attention as multifunctional platforms for simultaneously releasing ions and phytotherapeutic compounds. Thus, in the first part of this study, MBGNs based on the 53SiO₂–4P₂O₅–20CaO–23Na₂O (wt %) (S53P4) composition were synthesized by a microemulsion assisted sol-gel method. More precisely, P₂O₅ was substituted with B₂O₃ and Na₂O with MgO and/or ZnO. For B containing MBGNs all ions were successfully incorporated into the borosilicate structure without inducing crystallisation. In contrast, for S53P4 a poorly crystalline hydroxyapatite phase was identified. All MBGNs had a typical spherical shape with an internal radial network of mesopores. Additionally, for S53P4 a second fraction of particles with a smaller size and compact core was observed. Secondly, the feasibility of MBGNs as nanocarriers for gallic acid (GA) was evaluated. All drug-loaded samples showed a similar in vitro release profile which can be divided into three main phases: burst release, slow release and sustained release. Among the different compositions, S53P4 exhibited the highest cumulative release, whereas B and Mg containing particles exhibited the opposite. The presence of Zn in the MBGN compositions improved their antibacterial effect against both E. coli and S. aureus. Moreover, it was shown that depending on the MBGNs’ composition, the antibacterial activity of GA loaded MBGNs can be enhanced. Thus, the results proved that MBGNs can be used as controlled drug delivery system and, by tailoring the composition, a synergistic antibacterial effect can be achieved, considering that GA and biologically active ions are simultaneously released.     

Beyond platinum: synthesis,characterization, and in vitro toxicity of Cu(II)-releasing polymer nanoparticles for potential use as a drug delivery vector

The field of drug delivery focuses primarily on delivering small organic molecules or DNA/RNA as therapeutics and has largely ignored the potential for delivering catalytically active transition metal ions and complexes. The delivery of a variety of transition metals has potential for inducing apoptosis in targeted cells. The chief aims of this work were the development of a suitable delivery vector for a prototypical transition metal, Cu²⁺, and demonstration of the ability to impact cancer cell viability via exposure to such a Cu-loaded vector. Carboxylate-functionalized nanoparticles were synthesized by free radical polymerization and were subsequently loaded with Cu²⁺ via binding to particle-bound carboxylate functional groups. Cu loading and release were characterized via ICP MS, EDX, XPS, and elemental analysis. Results demonstrated that Cu could be loaded in high weight percent (up to 16 wt.%) and that Cu was released from the particles in a pH-dependent manner. Metal release was a function of both pH and the presence of competing ligands. The toxicity of the particles was measured in HeLa cells where reductions in cell viability greater than 95% were observed at high Cu loading. The combined pH sensitivity and significant toxicity make this copper delivery vector an excellent candidate for the targeted killing of disease cells when combined with an effective cellular targeting strategy.     

Evaluation of alginate–chitosan bioadhesive beads as a drug delivery system for the controlled release of theophylline

This study describes the preparation of mucoadhesive alginate–chitosan beads containing theophylline intended for colon‐specific delivery. The calcium alginate beads were coated with chitosan by the ionotropic hydrogelation method with a polyelectrolyte complex reaction between two oppositely charged polyions. The release profiles of theophylline from the beads were determined by ultraviolet–visible absorption measurement at 272 nm. Scanning electron microscopy was used for morphology observation. The in vitro mucoadhesive tests for particles were carried out with the freshly excised jejunum of Sprague‐Dawley rats. The bead particles, which ranged in size from 200 to 400 μm, exhibited excellent mucoadhesive properties. The results showed that the formulated coated beads succeeded in controlling the release of theophylline over a 24‐h period. In conclusion, the release of theophylline was found to be dependent on the composition of the beads, the component polymer and its possible interactions, and the bioadhesiveness. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

TiO2 hollow spheres as a novel antibiotic carrier for the direct delivery of gentamicin

The TiO₂ hollow spheres were synthesized using a green, cheap, and easy process, in which carbonaceous spheres were chosen as the removable template. The prepared materials were characterized by X-ray diffraction (XRD), Field emission scanning electron microscopy (FESEM), Energy-dispersive X-ray spectroscopy (EDX), Atomic force microscopy (AFM), Fourier Transform Infrared Spectroscopy (FTIR), and Brunauer–Emmett–Teller (BET) analysis. According to the results, the obtained mesoporous TiO₂ hollow spheres demonstrated an external diameters less than 200?nm with shell thickness around 40?nm. The antibacterial activities of the TiO₂ hollow spheres were evaluated against gram-positive (Bacillus subtilis and Staphylococcus aureus) and gram-negative (Escherichia coli and Pseudomonas aeruginosa). No antibacterial activity was found for TiO₂ hollow spheres in the used concentrations. TiO₂ hollow spheres were loaded with gentamycin as a selected antibiotic to magnify their benefits in biomedical applications. TiO₂ hollow spheres exhibited good antibiotic carrier activity for the direct delivery of gentamicin, which was attributed to interaction between gentamicin and surface due to their larger specific surface area, more abundant porous structure, and their spherical morphology. The application of TiO₂ hollow spheres as gentamicin carrier undoubtedly opens an avenue to use hollow sphere materials in other drug delivery applications.     

A novel condensation-addition-type phenolic resin (MPN): Synthesis, characterization and evaluation as matrix of composites

This paper reports a novel methylol and propargyl-containing dual-cure-mechanism novolac-based phenolic resin (MPN). MPN resins with varying contents of reactive groups were synthesized by a two-step one-pot method facilly and characterized by Flourier transfer infrared spectra (FT-IR), hydrogen magnetic resonance spectra (¹H NMR), gel permeation chromatography (GPC), dynamic scanning calorimetry (DSC) and dynamic mechanical analysis (DMA) techniques. The resins could be thermally cured by two gradual but fused stages: Condensation of methylol groups and addition polymerization of propargyl groups. This novel resin has advantages over conventional condensation-cure and addition-cure phenolic resins in processing capability. The results of DMA and thermogravimetry analysis (TGA) showed the cured resins possessed high thermal properties. Evaluation of MPN as matrices for advanced composites indicated the enhanced crosslink network derived from dense reactive groups in one single molecule was beneficial to the admirable thermal stability, but was detrimental to the mechanical properties of the resultant composites. MPN resin was amongst ideal candidates for matrices of high temperature materials.     

Degradation of azo-containing polyurethane by the action of intestinal flora: its mechanism and application as a drug delivery system

Several segmented polyurethanes comprising azo aromatic and hydrophilic groups were synthesized by reaction of m-xylylene diisocyanate with a mixture of m,m′-dihydroxyazobenzene, poly(ethylene glycol) (PEG, M_a = 2000) and 1,2-propanediol (propylene glycol, PG). Their polymer films were made by solution casting, and pellets of a hydrophilic drug (FOY-305) were coated with these polymers. Both the films and the coated pellets were incubated anaerobically in a culture of human intestinal flora. It was found that the azo groups in the polymer were reduced to hydrazo groups during incubation, which induced degradation of the films and the coatings without decreasing the molecular weight of the polymer. The rate of drug release from the pellets depended on both the azo and PEG compositions. Based on these findings, a new degradation mechanism of the polyurethane films and coatings is proposed.     

Synthesis and characterization of the environmental‐sensitive hyperbranched polymers as novel carriers for controlled drug release

Novel hyperbranched polymers, which contain a hydrophobic branched poly(p‐(chloromethy)styrene) (PCMS) core and poly(N,N‐dimethylaminoethyl methacrylate) (PDMA) shell that exhibited environmental sensitivity, have been synthesized by atom transfer radical polymerization (ATRP). At first, a hyperbranched polymer (PCMS) core is obtained via ATRP of p‐(chloromethy)styrene (CMS), which may act as an “inimer”‐monomer and initiator. Then the modified hyperbranched polymers having different average arm length consisting of PCMS and PDMA are synthesized by ATRP using anterior PCMS as macroinitiators. Their macromolecular structures are characterized by FTIR and ¹H NMR. Using chlorambucil as a model drug, the behaviors of the controlled drug release from the environmental‐sensitive hyperbranched polymers with different average chain length of PDMA and degree of branching are studied. The data demonstrate that the rate of the drug release can be effectively controlled by pH value, and these environmental‐sensitive hyperbranched polymers have the potential to be used as novel carriers in some controlled drug release systems in the future. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 101: 311–316, 2006