Novel strategy for encapsulation and targeted delivery of poorly water-soluble active substances

Carriers for targeted delivery and controlled release of poorly water-soluble active substances (PWSAS) are facing three challenges: (a) the encapsulation issues, (b) limitations of PWSAS water solubility, and (c) burst drug release which can be pharmacologically dangerous and economically inefficient. The present study brings a novel strategy for encapsulation and controlled release of PWSAS—caffeine in concentrations which are higher than its maximal water solubility without the possibility of burst effect. The modification of hydrophilic carrier based on poly(methacylic acid) was done using casein and liposomes. To further increase the maximal caffeine loading inside the carrier nicotinamide was used. The release study of the encapsulated PWSAS was elaborated with respect to morphology of the carriers and interactions that could be established between its structural components. The carriers swelling and the release of caffeine and nicotinamide were also investigated depending on caffeine concentration, the presence of different liposomal formulations and the volume ratio of liposomal formulation, in three media with different pH simulating the path of the carrier through the human gastrointestinal tract. The synthesized carriers are promising candidates for encapsulation of PWSAS in concentrations which are higher than its maximal water solubility and for the targeted delivery of those dosages.     

Self-assembly of amphiphilic liquid crystal block copolymers containing a cholesteryl mesogen: Effects of block ratio and solvent

We report on the self-assembly, in water and in bulk, of amphiphilic liquid crystal block copolymers consisting of a cholesterol-based smectic LC polymer block (PAChol) and poly(ethylene glycol) (PEG) block. Two series of block copolymers, PEG₄₅-b-PAChol and PEG₁₁₄-b-PAChol (45 and 114 are the degree of polymerization of PEG blocks) with different hydrophilic/hydrophobic weight ratios were synthesized and characterized in detail. Depending on the diblock composition, smectic polymer vesicles and/or nanofibers were formed by adding water into a dilute solution of copolymers in dioxane. If THF is used instead of dioxane as solvent, solid spherical aggregates were obtained upon water addition for PEG₄₅-b-PAChol series, while macroscopic precipitation occurred for PEG₁₁₄-b-PAChol series. The mesomorphic and microphase segregation structures of the block copolymers in bulk were studied by X-ray scattering, DSC and POM. The interdigital smectic A (SmA_d) phase with a lamellar period of 4.25 nm was detected in all block copolymers. For PEG₁₁₄-b-PAChol₅ (PEG/PAChol weight ratio = 66/34) and PEG₁₁₄-b-PAChol₁₂ (45/55), lamellar type of microphase segregation was observed.     

Photopolymerization of biomaterials: issues and potentialities in drug delivery,tissue engineering,and cell encapsulation applications

Photopolymerization is a widely explored technology that has recently been recognized to have also great potentialities in the biomedical field. This paper aims to provide a general overview of this technology by briefly describing materials and methods used to produce linear or crosslinked polymer networks for drug delivery, tissue engineering and cell encapsulation. In addition, potentialities and areas of investigation that are not fully explored but that could provide solutions for better control over the technology when applied to the biomedical field will be indicated as well. Copyright © 2006 Society of Chemical Industry     

Self-assembly of POSS-containing block copolymers: Fixing the hierarchical structure in networks

A series of P(MMA-co-GMA)-b-PMAPOSS block copolymers (BCPs) were synthesized by ATRP. The BCPs contain POSS (polyhedral oligomeric silsesquioxane) as a pendant unit on a particular polymer block chain. In selective solvents, the BCPs self-assemble to form ordered micellar-like structures. Spherical, cylindrical or vesicle-like morphologies were produced by tuning the BCP and mixed solvent compositions. Crosslinking of the BCP by the reaction of the glycidyl groups in the P(MMA-co-GMA) block of the micelle shell (GMA = glycidyl methacrylate) with a diamine results in a long-range structure ordering. The hexagonally packed cylindrical arrangement of the BCP networks was revealed by SAXS and TEM. The hierarchical, ordered structure of the POSS-containing hybrids was fixed by crosslinking. In addition, transient physical gels were prepared from triblock copolymers with outer MAPOSS blocks, and their rheological behavior was investigated.     

PEO-PPO-PEO嵌段共聚物在水溶液中的自组装行为及其应用

聚氧乙烯-聚氧丙烯-聚氧乙烯(PEO-PPO-PEO)嵌段共聚物是一类重要的非离子表面活性剂,在选择性溶剂中可以自组装成多种形貌的介观结构。对PEO-PPO-PEO嵌段共聚物在水溶液中自组装行为进行了综述,介绍了其自组装行为的实验研究技术;阐明了嵌段共聚物构型、分子量、温度、浓度、添加剂等因素对PEO-PPO-PEO嵌段共聚物聚集行为的调控和作用机理;介绍了嵌段共聚物自组装特性的热力学模型、分子模拟及计算机预报等研究方法和研究进展;重点介绍了PEO-PPO-PEO嵌段共聚物在介孔材料制备、药物载体、生物大分子分离、嵌段共聚物修饰等方面的应用。     

Self-assembly and sol-to-gel transition of thermosensitive methoxy-polyethylene glycol-polyalanine block copolymer hydrogels

Certain amphiphilic polymers can self-assemble to form various structures, such as micelles and hydrogels in aqueous medium, depending on the concentration or temperature. These different structures have found many applications in biomedical and material processing fields. The assembly processes of the polypeptide-containing diblock copolymer, methoxy poly(ethylene glycol)-block-poly(L-alanine) (mPEG-PA), was studied to elucidate the relationship between different structures with parameters such as chain lengths (volume fraction) of the two blocks, molecular weights, medium polarity, temperature, and concentration. Gelation mechanism was especially focused in the study. Various solution-cast morphologies observed by scanning electron microscopy (SEM) imaging including cylinders and micelles aggregates can be obtained by using solvents with different polarity for casting with simply tuning the chain lengths. The sol-to-gel transition mechanism can be best explained by phase separation between polymer-rich and water-rich phases. It might be spinodal decomposition process to cause the phase separation. Furthermore, the branch and flack structures can be observed due to phase separation mechanism and different chain lengths by SEM images. This result offers new insights into behavior of mPEG-PA system, enabling more controlled manipulation to various applications.     

Electrospun core–shell nanofibers for drug encapsulation and sustained release

Fabrication of core–shell nanofibers by coaxial electrospinning system suited for drug delivery applications was investigated based on tetracycline hydrochloride (TCH) as the core and poly(lactide‐co‐glycolide) as the shell materials. Comparison of drug release from monolithic fibers (blend electrospinning) and core–shell structures was performed to evaluate the efficacy of the core–shell morphology. The nanofibrous webs are potentially interesting for wound healing purposes since they can be maintained for an adequate length of time to gradually disinfect a local area without the need of bandage renewal. Further, our studies showed the potential of core–shell nanostructures for sustained drug release, which also suppressed the burst release effect from 62 to 44% in the first 3 hours by adding only 1 wt% TCH to the polymeric shell. POLYM. ENG. SCI., 2013. © 2013 Society of Plastics Engineers     

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.     

Dual-sensitive and folate-conjugated mixed polymeric micelles for controlled and targeted drug delivery

For this study, we prepared a new type of drug carrier with the characteristics of stimuli-responsive transition and tumor-specific recognition through the co-assembly of two series of amphiphilic block copolymers, poly(ε-caprolactone)-b-poly[triethylene glycol methacrylate-co-N-methacryloyl caproic acid] and poly(ε-caprolactone)-b-poly[triethylene glycol methacrylate-co-N-(2-(methacrylamido)ethyl) folatic amide]. The pH-dependent thermal transition and the content of the targeting ligands of the mixed polymeric micelles are well correlated with the chemical structures and compositions of these two copolymers. Doxorubicin-loaded mixed polymeric micelles are stable at body temperature in the neutral condition for prolonged circulation in blood vessels, and demonstrated rapid drug release at acidic pH levels. The cumulative drug release profiles showed a relatively slow release at pH 7.4, and a quick release of 85% in 3 h at pH 5.3. The cytotoxicity tests against FA-positive (HeLa) and FA-negative (HT-29) tumor cell lines suggest that this mixed polymeric micelle system has potential merits as a controlled and targeted drug delivery system.     

Swelling behavior of temperature- and pH-sensitive block terpolymers for drug delivery

Summary Hydrogels prepared by block terpolymerization of N-isopropylacrylamide (NIPAAm), acrylic acid (AA) and 2-hydroxyethyl methacrylate (HEMA) exhibit significant temperature sensitivity due to the block structure of the NIPAAm moiety, even at concentrations as low as 10 mol%. pH-Sensitivity was also observed due to the ionizable AA component. The swelling ratio dependence on temperature is significantly more prominent for block terpolymers than for the corresponding random terpolymers.     

Carbohydrate – lipid conjugates for targeted drug and gene delivery

The role of macrophages in the uptake and processing of liposomes evident from the increased deposition of liposomal content in cells. It has been reported that macrophages may serve as a secondary drug carrier for the delivery of liposomal drugs. The uptake of liposomal content by macrophages can be promoted by incorporation of ligands capable of interacting with macrophage surface receptors. Therefore, carbohydrate‐based molecules for targeted drug and gene delivery must be developed for rational therapy. In this article, we report the synthesis of glycolipid conjugates for applications in liposomal drug delivery systems and for targeting drugs and genes to receptors.     

Amide pectin: A carrier material for colon‐targeted controlled drug release

In order to deliver bioactive components to the colon, an oral colon‐targeted bioadhesive microparticle delivery system based on pectin was developed. Unmodified pectin exhibited a poor hydrophobicity and weak tablet‐crushing strength. Pectin was modified by an amide reaction, which results in a dramatic decrease in water solubility and viscosity, as well as favorable controlled release properties. Amide pectin (AP) were characterized by Fourier transform infrared spectroscopy (FTIR), Nuclear magnetic resonance (¹H‐NMR), and Differential scanning calorimetry (DSC). Results of FTIR and ¹H‐NMR revealed that amide groups were introduced into the pectin molecules; DSC analysis exhibited that the thermal stability of pectin was decreased. An in vitro release assay demonstrated that matrix tablets prepared by AP could deliver bioactive components to the colon when the pectin content and hydrophobicity were properly controlled. The relationship between the structure and in vitro release properties of amide pectin suggests that an optimal tablet structure and composition can be responsible for a suitable BSA release rate. The optimal tablets making conditions were using methylcellulose (MC) as tablet adhesive, amidation reaction time of 60 min, drug loading of 0.008 g and tableting pressure of 8 kg/mm. The results indicated that matrix tablets made by AP exhibited good colon‐targeted drug release. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43697.     

Self-assembly and morphology transition of amphipathic spiropyran-based random copolymers to control drug release

An amphipathic spiropyran-based random copolymer P(SPMA-co-DMAEMA) was synthesized by atom transfer radical polymerization, and the resulting copolymer was characterized by means of ¹H nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, and gel permeation chromatography. The self-assembly behaviors and morphology transition were systematically investigated under single and combined external environmental stimuli by transmission electron microscopy. With coumarin 102 as the model drug molecule, the self-assembly micelles were used to control drug loading, release, and re-encapsulation to some extent. The characterization results indicated the successful preparation of the spiropyran-based random copolymer P(SPMA-co-DMAEMA). The external stimuli had some influences on the morphology of the self-assembly aggregate, and the ‘schizophrenic’ behavior was interestingly found in this work. The drug release experiments showed the reversible loading and release process up to a point, which might expand the potential application domain of the amphiphilic spiropyran-based random copolymer in drug delivery.     

Drug loading,dispersion stability,and therapeutic efficacy in targeted drug delivery with carbon nanotubes

We have designed a drug delivery system for the anti-cancer drugs doxorubicin and mitoxantrone based on carbon nanotubes, which is stable under biological conditions, allows for sustained release, and promotes selectivity through an active targeting scheme. Carbon nanotubes are particularly promising for this area of application due to their high surface area, allowing for high drug loading, and their unique interaction with cellular membranes. We have taken a systematic approach to PEG conjugation in order to create a formulation of stable and therapeutically effective CNTs. The presented drug delivery system may be a means of improving cancer treatment modalities by reducing drug-related side effects.     

Synthesis, characterization, and drug delivery research of an amphiphilic biodegradable star-shaped block copolymer

An amphiphilic biodegradable three-arm star-shaped diblock copolymer containing poly(ε-caprolactone) (PCL) and poly(N-vinylpyrrolidone) (PVP) (TEA(PCL-b-PVP)₃) has been successfully synthesized by the ring-opening polymerization of ε-caprolactone (ε-CL), RAFT polymerization of N-vinylpyrrolidone and a coupling reaction of PCL with carboxyl-terminated PVP (PVP-COOH). In aqueous media, the star-shaped copolymer self-assembled into spherical micelles with diameters of near 106 nm. The critical micelle concentration of TEA(PCL-b-PVP)₃ copolymer was determined to be 5.96 × 10^?3 mg/mL. Folic acid was then used as a model drug to incorporate into TEA(PCL-b-PVP)₃ micelles, the drug loading content and encapsulation efficiency is 16.36 and 49.08 %, respectively. In vitro release experiments of the drug-loaded micelles exhibited sustained release behavior and it was affected by the pH of release media. These results indicate that the copolymer may serve as a promising “intelligent” drug delivery alternative.     

Synthesis and characterization of P(MMA-AA) copolymers for targeted oral drug delivery

This paper describes the development of pH-sensitive poly(methyl methacrylate-acrylic acid) copolymers for the enteric coating of pharmaceutical products for oral administration. To obtain the dissolution at the desired pH level, different pH-sensitive polymers are available on the market. Usually, for each desired dissolution pH, an ad hoc polymer is designed. Thus, different dissolution pH values could ask for completely different polymers. Instead, the materials proposed in this work are copolymers of the same two monomers, and the different dissolution pH was obtained by changing the volume fraction of the hydrophobic methyl methacrylate monomer to the hydrophilic acrylic acid monomer. Increasing the volumetric percentage of methyl methacrylate causes the polymer to dissolve at increasing pH, until the dissolution does not take place at all, and it is replaced by a slow swelling phenomenon. The copolymers obtained were characterized by differential scanning calorimetry, in order to evaluate their glass transition temperature, and these latter were related to %MMA. The molecular weights of the pure polymers (PAA, PMMA) were measured by intrinsic viscosity, to further validate the glass transition temperatures observed. The dissolution of the copolymers was carefully tested in buffer solutions for a dense set of pH values. A linear relationship between dissolution pH and volumetric percentage of methyl methacrylate was obtained from these measurements. As a result, for any physiological compartment, the copolymer which dissolves at the pH of interest can be easily synthesized.     

Design and characterization of pH stimuli-responsive nanofiber drug delivery system: The promising targeted carriers for tumor therapy

New carrier platforms have been designed for an electrospun pyridinium calixarene nanofiber for controlled drug delivery. First, 5,11,17,23-tetra-tert-butyl-25,27-bis(3-aminomethyl-pyridineamido)-26,28-dihydroxycalix[4]arene (3-AMP) scaffold was produced by electrospinning. AMP scaffold was modified by human serum albumin (HSA), folic acid (FA), and glutathione (GSH). Doxorubicin (DOX) was loaded to surfaces of the AMP, AMP-HSA, AMP-HSA-FA, and AMP-HSA-GSH nanofibers by using DOX solution in different buffers with, 2.2, 4.0, 6.0, and 7.4 pH. The release studies DOX from four different nanofibers was also done in a various amount microenviroments by changing pH values. The loading and release amount of DOX was estimated from the calibration curve drawn at 480 and 560 nm of excitation and emission wavelengths by using a fluorescence spectrophotometer. The loading studies were confirmed by Fourier transforms infrared, atomic force microscopy, transmission electron microscopy, scanning electron microscope, and energy-dispersive X-ray (EDX) analysis.     

Novel polymersomes based on amphiphilic graft polyphosphazenes and their encapsulation of water-soluble anti-cancer drug

A series of amphiphilic graft polyphosphazenes with hydrophilic weight fraction ranging from 0.40 to 0.55 were synthesized. These copolymers could self-assemble into distinct aggregates in aqueous solutions. Spherical micelles were observed for the copolymer sample with higher hydrophilic weight fraction. However, when the hydrophilic weight fractions decreased to less than 0.50, vesicle-like polymersomes were formed. Doxorubicin hydrochloride (DOX·HCl), a water-soluble anti-cancer drug, was successfully loaded into the aqueous core of polymersome, which was clearly observed by transmission electron microscopy. The in vitro release of DOX·HCl from polymersome carries further confirmed its encapsulation. In addition, the cytotoxicity of DOX against HepG2 cells was significantly enhanced via polymersome delivery. These results suggest that amphiphilic graft polyphosphazenes could be used for the delivery of water-soluble drugs as polymersome vehicles.