Controlled release of 5-fluorouracil or mitomycin-c from polymer matrix: Preparation by radiation polymerization and in vivo evaluation of the anticancer drug/polymer composites

Polymer tablets containing anticancer drugs such as 5-fluorouracil (5-FU) and mitomycin-C (MMC) have been prepared to evaluate the drug-release characteristics in vitro and the effect on local control of mouse solid tumors in vivo. Radiation-induced polymerization of hydrophilic monomers (2-hydroxyethyl methacrylate and related monomers) at low temperature (-80°C) was performed to immobilize 5-FU or MMC in the polymer matrix. The drug was dispersed as microcrystallines within the polymer matrix. The rate of drug release in vitro in buffer solution (pH7.0, 37°C) increased with increase in hydrophilicity of polymer matrix. Appropriate amount of crosslinks within the polymer matrix, as formed by ethylene glycol dimethacrylate (2G) added in the polymerization system, was effective to control the rate of drug release. The drug release became faster upon the addition of increasing amount of water in the radiation-induced polymerization. The tablet consisting of drug/polymer was buried surgically near solid tumors of striate muscle sarcoma (S180) transplanted to Kunming mice and the therapeutic effect of slow releasing drugs was evaluated in vivo by reference to intraperitoneal (i.p.) injection of the corresponding drugs. The slow releasing drugs led to high chemotherapeutic gain for local control of solid tumors with remarkable reduction of toxic side effect of the drugs.     

pH-Responsive supramolecular micelle based on host-guest interaction of poly(β-amino ester) derivatives and adamantyl-terminated poly(ethylene glycol) for cancer inhibition

A pH-responsive supramolecular micelle consisting of β-cyclodextrin-contained poly(β-amino ester) and adamantyl-terminated poly(ethylene glycol) was prepared through host-guest interaction. The micelle can encapsulate curcumin to achieve significant inhibition effect against sarcoma 180 in vivo.     

Synthesis and micellization of amphiphilic poly(sebacic anhydride)–poly(ethylene glycol)–poly(sebacic anhydride) block copolymers

Amphiphilic biodegradable block copolymers [poly(sebacic anhydride)–poly(ethylene glycol)–poly(sebacic anhydride)] were synthesized by the melt polycondensation of poly(ethylene glycol) and sebacic anhydride prepolymers. The chemical structure, crystalline nature, and phase behavior of the resulting copolymers were characterized with ¹H NMR, Fourier transform infrared, gel permeation chromatography, and differential scanning calorimetry. Microphase separation of the copolymers occurred, and the crystallinity of the poly(sebacic anhydride) (PSA) blocks diminished when the sebacic anhydride unit content in the copolymer was only 21.6%. ¹H NMR spectra carried out in CDCl₃ and D₂O were used to demonstrate the existence of hydrophobic PSA domains as the core of the micelle. In aqueous media, the copolymers formed micelles after precipitation from water‐miscible solvents. The effects on the micelle sizes due to the micelle preparation conditions, such as the organic phase, dropping rate of the polymer organic solution into the aqueous phase, and copolymer concentrations in the organic phase, were studied. There was an increase in the micelle size as the molecular weight of the PSA block was increased. The diameters of the copolymer micelles were also found to increase as the concentration of the copolymer dissolved in the organic phase was increased, and the dependence of the micelle diameters on the concentration of the copolymer varied with the copolymer composition. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 1271–1278, 2006     

Hydrophilic silicone hydrogels with interpenetrating network structure for extended delivery of ophthalmic drugs

In the current work, hydrophilic silicone hydrogels were prepared for extended drug delivery applications. The preparation method was based on sequential interpenetrating network synthesis. A hydrophilic network was prepared by radical copolymerization of hydrophilic monomers 2‐hydroxyethyl methacrylate and poly(ethylene glycol) diacrylate. A hydrophobic silicone network was obtained by crosslinking polymerization of bifunctional methacrylated polydimethylsiloxanes macromonomer. The morphology of the silicone hydrogels was characterized by transmission electron microscopy. The result showed that the silicone hydrogels exhibited heterogeneous morphology. The properties of the silicone hydrogels such as equilibrium swelling ratio (ESR), mechanical property, oxygen permeability, contact angle, and protein repelling ability were investigated. Finally, the silicone hydrogels were loaded with timolol by pre‐soaking in drug solution to evaluate drug‐loading capacity and in vitro release behavior. The results showed that mechanical strength and oxygen permeability increased, and the ESR decreased with the increase of silicone component in the silicone hydrogels. The result of the contact angle measurement indicated that the silicone hydrogels possessed hydrophilic surfaces. The drug loading and in vitro releases were dependent on the composition of hydrophilic/hydrophobic phase of silicone hydrogels. Copyright © 2011 John Wiley & Sons, Ltd.     

Doubly hydrophilic multiarm hyperbranched polymers with acylhydrazone linkages as acid-sensitive drug carriers

A novel type of drug carrier capable of controlled drug release is proposed. It consists of an acid-sensitive doubly hydrophilic multiarm hyperbranched copolymer with a hyperbranched polyamidoamine core and many linear poly(ethylene glycol) arms. Using pH-sensitive acylhydrazone linkages, the polymer forms unimolecular micelles that can encapsulate hydrophobic drugs. Due to their amphiphilicity, the drug-loaded unimolecular micelles can self-assemble into multimolecular micelles that show acid-triggered intracellular delivery of the hydrophobic drugs.     

In vitro drug release from silicone rubber–polyacrylamide composite

Composite materials containing drugs were prepared from silicone rubber and hydrogel. Cross linked polyacrylamide (PAAm) hydrogel particles were incorporated into a silicone rubber to enhance the hydrophilicity and drug release capacity of silicone rubber as a matrix. Progesterone and Thymol Blue were used as a hydrophobic and hydrophilic drug model, respectively. Different amounts of polyacrylamide (PAAm) were mixed with the drugs and uncured silicone rubber at room temperature. The composite matrices were formed using a compression molding press and cured by thermal and γ-irradiation curing methods. In vitro drug release behavior of composites and their physical and mechanical properties were investigated. The results indicated that the hydrophilic character of silicone rubber was more pronounced with increasing the amount of PAAm. Also, a significant effect on the drug release profiles was observed. The γ-irradiation curing method improved mechanical properties of composites and affected the drug release profiles. It was found that the amounts of released progesterone from γ-irradiated samples increased in comparison with the thermally cross linked composite since released Thymol Blue was reduced.     

Bioreducible unimolecular micelles based on amphiphilic multiarm hyperbranched copolymers for triggered drug release

A novel type of bioreducible amphiphilic multiarm hyperbranched copolymer (H40-star-PLA-SS-PEG) based on Boltorn® H40 core, poly(l-lactide) (PLA) inner-shell, and poly(ethylene glycol) (PEG) outer-shell with disulfide-linkages between the hydrophobic and hydrophilic moieties was developed as unimolecular micelles for controlled drug release triggered by reduction. The obtained H40-star-PLA-SS-PEG was characterized in detail by nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR), gel permeation chromatography (GPC), differential scanning calorimeter (DSC), and thermal gravimetric analysis (TGA). Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analyses suggested that H40-star-PLA-SS-PEG formed stable unimolecular micelles in aqueous solution with an average diameter of 19 nm. Interestingly, these micelles aggregated into large particles rapidly in response to 10 mM dithiothreitol (DTT), most likely due to shedding of the hydrophilic PEG outer-shell through reductive cleavage of the disulfide bonds. As a hydrophobic anticancer model drug, doxorubicin (DOX) was encapsulated into these reductive unimolecular micelles. In vitro release studies revealed that under the reduction-stimulus, the detachment of PEG outer-shell in DOX-loaded micelles resulted in a rapid drug release. Flow cytometry and confocal laser scanning microscopy (CLSM) measurements indicated that these DOX-loaded micelles were easily internalized by living cells. Methyl tetrazolium (MTT) assay demonstrated a markedly enhanced drug efficacy of DOX-loaded H40-star-PLA-SS-PEG micelles as compared to free DOX. All of these results show that these bioreducible unimolecular micelles are promising carriers for the triggered intracellular delivery of hydrophobic anticancer drugs.     

Distribution coefficients in the water-dodecane system and heats of adsorption of ethylene glycol monoalkyl ethers on hydrophilic and hydrophobic carriers

The distribution coefficients in the water-dodecane system and the heats of adsorption of ethylene glycol monoalkyl ethers on hydrophilic (Silochrom S-80) and hydrophobic (Apiezon L on Chromaton) carriers were determined by gas chromatography. At low concentrations and 25°C, ethers with C₁-C₄ alkyl radials predominantly occurred in the aqueous phase, whereas the amyl ether of ethylene glycol was better soluble in the organic phase. Ethers adsorbed formed monomolecular and polymolecular coatings on the hydrophobic and hydrophilic adsorbents, respectively. The heats of adsorption of ethers on the hydrophilic adsorbent were higher than the heats of adsorption on the hydrophobic adsorbent by factors of from 1.93 to 2.20.     

Synthesis of well‐defined star‐shaped poly(ε‐caprolactone)/poly(ethylbene glycol) amphiphilic conetworks by combination of ring opening polymerization and “click” chemistry

Well‐defined star‐shaped hydrophobic poly(ε‐caprolactone) (PCL) and hydrophilic poly(ethylene glycol) (PEG) amphiphilic conetworks (APCNs) have been synthesized via the combination of ring opening polymerization (ROP) and click chemistry. Alkyne‐terminated six arm star‐shaped PCL (6‐s‐PCLx‐C?CH) and azido‐terminated PEG (N₃‐PEG‐N₃) are characterized by ¹H NMR and FT‐IR. The swelling degree of the APCNs is determined both in water and organic solvent. This unique property of the conetworks is dependent on the nanophase separation of hydrophilic and hydrophobic phases. The morphology and thermal behaviors of the APCNs are investigated by SEM and DSC respectively. The biocompatibility is determined by water soluble tetrazolium salt reagents (WST‐1) assay, which shows the new polymer networks had good biocompatibility. Through in vitro release of paclitaxel (PTX) and doxorubicin (DOX), the APCNs is confirmed to be promising drug depot materials for sustained hydrophobic and hydrophilic drugs. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 407–417     

Thermoresponsive terpolymers based on methacrylate monomers: Effect of architecture and composition

A series of amphiphilic thermoresponsive copolymers was synthesized by group transfer polymerization. Seven copolymers were prepared based on the nonionic hydrophobic n‐butyl methacrylate (BuMA), the ionizable hydrophilic and thermoresponsive 2‐(dimethylamino)ethyl methacrylate (DMAEMA) and the nonionic hydrophilic poly(ethylene glycol)methyl methacrylate (PEGMA). In particular, one diblock copolymer and six tricomponent copolymers of different architectures and compositions, one random and five triblock copolymers, were synthesized. The polymers and their precursors were characterized in terms of their molecular weight and composition using gel permeation chromatography and proton nuclear magnetic resonance spectroscopy, respectively. Aqueous solutions of the polymers were studied by turbidimetry, hydrogen ion titration, and light scattering to determine their cloud points, pK_as, and hydrodynamic diameters and investigate the effect of the polymers' composition and architecture. The thermoresponsive behavior of the copolymers was also studied. By increasing the temperature, all polymer solutions became more viscous, but only one polymer, the one with the highest content of the hydrophobic BuMA, formed a stable physical gel. Interestingly, the thermoresponsive behavior of these triblock copolymers was affected not only by the terpolymers' composition but also by the terpolymers' architecture. These findings can facilitate the design and engineering of injectable copolymers for tissue engineering that could enable the in situ formation of physical gels at body temperature. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 775–783, 2010     

Synthesis and characterization of a biodegradable amphiphilic copolymer based on branched poly(ϵ‐caprolactone) and poly(ethylene glycol)

A novel biodegradable amphiphilic copolymer with hydrophobic poly(ε‐caprolactone) branches containing cholic acid moiety and a hydrophilic poly(ethylene glycol) chain was synthesized. The copolymer was characterized by FTIR, ¹H NMR, gel permeation chromatography (GPC), differential scanning calorimetry (DSC), polarizing light microscopy (PLM), and wide‐angle X‐ray diffraction (WAXD) analysis. The amphiphilic copolymer could self‐assemble into micelles in an aqueous solution. The critical micelle concentration of the amphiphilic copolymer was determined by fluorescence spectroscopy. A nanoparticle drug delivery system with a regularly spherical shape was prepared with high encapsulation efficiency. The in vitro drug release from the drug‐loaded polymeric nanoparticles was investigated. Because of the branched structure of the hydrophobic part of the copolymer and the relatively fast degradation rate of the copolymer, an improved release behavior was observed. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 5256–5265, 2007     

Reduction and pH dual‐responsive block copolymers containing pendent p‐nitrobenzyl carbamate functionalities: Synthesis and self‐assembly behavior

We report on the preparation of reduction‐responsive amphiphilic block copolymers containing pendent p‐nitrobenzyl carbamate (pNBC)‐caged primary amine moieties by reversible addition–fragmentation chain transfer (RAFT) radical polymerization using a poly(ethylene glycol)‐based macro‐RAFT agent. The block copolymers self‐assembled to form micelles or vesicles in water, depending on the length of hydrophobic block. Triggered by a chemical reductant, sodium dithionite, the pNBC moieties decomposed through a cascade 1,6‐elimination and decarboxylation reactions to liberate primary amine groups of the linkages, resulting in the disruption of the assemblies. The reduction sensitivity of assemblies was affected by the length of hydrophobic block and the structure of amino acid‐derived linkers. Using hydrophobic dye Nile red (NR) as a model drug, the polymeric assemblies were used as nanocarriers to evaluate the potential for drug delivery. The NR‐loaded nanoparticles demonstrated a reduction‐triggered release profile. Moreover, the liberation of amine groups converted the reduction‐responsive polymer into a pH‐sensitive polymer with which an accelerated release of NR was observed by simultaneous application of reduction and pH triggers. It is expected that these reduction‐responsive block copolymers can offer a new platform for intracellular drug delivery. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1333–1343     

Synthesis and characterization of amphiphilic diblock copolymers of methyl tri(ethylene glycol) vinyl ether and isobutyl vinyl ether

Water-soluble diblock copolymers of methyl tri(ethylene glycol) vinyl ether (hydrophilic block) and isobutyl vinyl ether (hydrophobic block) of different molecular weights and composition were synthesized by living cationic polymerization. The molecular weight and comonomer composition of these copolymers were determined by GPC and ¹H NMR spectroscopy, respectively. Aqueous solutions of the copolymers were characterized in terms of their micellar behavior using dynamic light scattering, aqueous GPC, and dye solubilization. All the copolymers formed aggregates with the exception of a diblock copolymer with only two hydrophobic monomer units. The micellar hydrodynamic size scaled with the 0.61 power of the number of hydrophobic units, in good agreement with a theoretical exponent of 0.73. An increase in the length of the hydrophobic block at constant hydrophilic block length or an increase in the overall polymer size at constant block length ratio both resulted in lower critical micelle concentrations (cmcs). The cloud points of 1% w/w aqueous solutions of the polymers were determined by turbidimetry. An increase in the length of the hydrophobic block at constant hydrophilic block length caused a decrease in the cloud points of the copolymers. However, an increase in the overall polymer size at constant block length ratio led to an increase in the cloud point. © 1996 John Wiley & Sons, Inc.     

Unusual in vitro degradation behavior of physically cross-linked liposome gel network

In this study, the in vitro degradation behavior of self-assembled liposome gel was investigated, especially in comparison with rheological studies. The liposome gel, physically cross-linked by hydrophobic interactions, was obtained by mixing liposome solution with cholesterol-end capped polyethylene glycol. The liposome gel was found to have rheological behavior similar to that of Maxwell model. The plateau modulus of the liposome gel, an important value to reflect the effective cross-linking density among the network, was dependent on both the liposome concentration and the polymer concentration. When the liposome gels were exposed to an aqueous solution, they first showed a period of swelling phase due to adsorption of water and then a dissolution phase began, leading to the full degradation of the network. The liposome gel with higher plateau modulus (i.e. higher effective cross-linking density) was found to degrade more slowly, indicating that the degradation behavior of the gel was closely related with the rheological properties. In order to study the gel degradation mechanism more directly, dextran blue-loaded liposome gel was prepared. In the initial period of the liposome gel exposure to the aqueous solution, the dextran blue release was of Fickian diffusion transport behavior. After that period, the release mechanism was found to be of Super Case II transport, which was gel matrix relaxation controlled.     

NIPAAm系互穿网络凝胶的合成及载药释药性能研究

合成了三种亲疏水性不同的温度及pH敏感的PAAc／P（NIPAAm-co-BMA）、PAAc／PNIPAAm和PAAc／P（NIPAAm-co-AAm）互穿网络（IPN）水凝胶,以水杨酸钠和水杨酸为模型药物,研究了温度、pH值及药物和凝胶的亲疏水性相互作用对模型药物释药性能的影响。研究结果表明,随着凝胶亲水性的增强,水杨酸钠的载药率提高,释药率也越大;相反疏水性增强也有利于提高水杨酸的载药率;IPN凝胶在水中的释药过程属于溶胀支配型释放,药物释放率随凝胶的亲水性增强而增强,同时,载药凝胶在45℃水中的释药率大于25℃时的释药率。在25℃时,水杨酸在pH=2．2的缓冲溶液中几乎不释放,而在pH=7．4的缓冲溶液中能以较快的速率释放。     

Synthesis and erosion properties of PEG-containing polyanhydrides

To tailor the erosion rate of polyanhydrides while retaining their surface erosion characteristics, new three-component polyanhydrides of sebacic acid, 1,3-bis(p-carboxyphenoxy)propane and poly(ethylene glycol) were synthesized. The hydrophilicity of the polymer increased and its mechanical strength decreased with increasing PEG content. Correspondingly, the erosion rate increases with increasing PEG content, whereas it decreases with increasing specimen thickness. This indicates that the incorporation of poly(ethylene glycol) into traditional two-component polyanhydrides retains their surface erosion properties while making the erosion rate tunable. The new polyanhydrides hold potential for drug delivery applications.     

Potential application of poly(N-isopropylacrylamide) gel containing polymeric micelles to drug delivery systems

We have investigated rapidly thermo-responsive NIPA gel containing polymer surfactant PMDP (NIPA-PMDP gel) as a potential drug carrier using (+)-l-ascorbic acid as a model drug. In the NIPA-PMDP gel system micelles of polymer surfactant PMDP are trapped by the entanglement of polymer chains inside the gel networks. Therefore, in principle the gel system tightly stores targeted drug in the micelles and rapidly releases controlled amount of the drug by switching on-off of external stimuli such as temperature or infrared laser beam. In our investigation on release profile, the NIPA-PMDP gel system showed completely different releasing behavior from that of the conventional NIPA gel. The NIPA-PMDP gel released rapidly all loaded (+)-l-ascorbic acid above the phase transition temperature (ca. 34 degrees C), while slowly released the corresponding amount of the drug below the temperature. In contrast, the conventional NIPA gel released more slowly limited amount of the drug above the phase transition temperature while similarly did to the NIPA-PMDP gel below the temperature. The release profile of the NIPA-PMDP gel seems to be governed by only kinetics of volume phase transition of the gel network but not by the hydrophobic domains of the micelles probably because of too hydrophilic nature of (+)-l-ascorbic acid.     

Preparation and properties of silicon- and titanium-containing hybrid nanocomposite films based on ethyl cellulose

Nanocomposite hybrid films containing silicon and titanium compounds in the polymer matrix are prepared through the sol-gel method via the hydrolytic polycondensation of Si and Ti alkoxides (tetraethoxysilane and titanium tetrabutoxide) in the THF solution of a hydrophobic polymer, ethyl cellulose. Their structure and properties are studied with the use of a complex of physicochemical methods. During the hydrolysis of tetraethoxysilane and the subsequent polycondensation of the reaction products, silicon atoms are incorporated into the polymer and form -O-Si-O-bonds involving hydroxyl groups of ethyl cellulose. In the sol-gel method, titanium alkoxide yields nanosized particles of titanium dioxide that play the role of fillers in the polymer matrix. Titanium-containing films show solubility in THF and, after prolonged contact with the solvent, precipitate titanium dioxide from the solution. Hybrid films containing silicon are insoluble owing to the formation of a chemical network between polymer molecules and Si-OH groups of the products of hydrolysis of silicon alkoxide, as confirmed by the IR data. It is shown that the amounts and types of alkoxides and the diameters of the structures formed in the polymer matrix via the sol-gel procedure affect the hydrophilicity levels of ethyl cellulose hybrid films and their abilities to swell in water and aqueous solutions of organic dyes (brilliant blue and methylene blue). Ethyl cellulose hybrid films are hydrophilic, and they facilitate the removal of dye molecules from aqueous solutions. The best properties are featured by the films containing nanosized particles of titanium dioxide in the polymer matrix.     

Interactions between an anticancer drug and polymeric micelles based on biodegradable polyesters

Interactions between the anticancer drug quercetin and biodegradable polyesters within micelles were investigated by DSC, WAXD, and UV analyses. For micelles based on poly(ethylene glycol) methyl ether-block-poly(epsilon-caprolactone) (MPEG-PCL), DSC analysis indicated that the interactions were between the hydrophobic core and the drug within the micelle. For micelles based on poly(ethylene glycol) methyl ether-block-poly(L-lactide) (MPEG-PLLA), the interactions were between the hydrophobic core and the drug and between hydrophilic segments and the drug. WAXD results indicated that no crystalline phase of the drug was found in either of the micelle types. Based on the DSC and WAXD results, two probable micelle structures were proposed. The UV spectra revealed the presence of hydrogen bonding as the main interaction between the drug and the polyesters. In vitro studies demonstrated that quercetin release from micelles was sustained and was affected by the polymer-drug interaction.     

Stabilization of O/W emulsion with hydrophilic/hydrophobic clay particles

In this study, a stabilizing behavior of clay in a 40/60 w/w oil-in-water (O/W) emulsion is investigated by macro- and microscopic morphological observations, rheology, and X-ray diffraction measurements. Hydrophilic and hydrophobic clays (Montmorillonites) are tested for stabilization of emulsion. When hydrophilic clay showing interfacial localization is added to the emulsion, emulsion is not stable to phase separation (creaming). With hydrophobic clay, the emulsion shows phase inversion to water-in-oil (W/O) emulsion due to the increase in oil viscosity which results in phase separation of sedimentation. On the other hand, with the mixture of hydrophilic and hydrophobic clays, the emulsion shows a synergistic macroscopic and microscopic stabilization due to the formation of composite structure at the interface by hydrophilic and hydrophobic clays.