Self‐immolative (SI) spacers are sophisticated chemical constructs designed for molecular delivery or material degradation. We describe herein a (S)‐2‐(aminomethyl)pyrrolidine SI spacer that is able to release different types of anticancer drugs (possessing either a phenolic or secondary and tertiary hydroxyl groups) through a fast cyclization mechanism involving carbamate cleavage. The high efficiency of drug release obtained with this spacer was found to be beneficial for the in vitro cytotoxic activity of protease‐sensitive prodrugs, compared with a commonly used spacer of the same class. These findings expand the repertoire of degradation machineries and are instrumental for the future development of highly efficient delivery platforms. 相似文献
Phosphorus-based self-immolative (SI) linkers offer a wide range of applications, such as smart materials and drug-delivery systems. Phosphorus SI linkers are ideal candidates for double-cargo delivery platforms because they have a higher valency than carbon. A series of substituted phosphate linkers was designed for releasing two phenolic cargos through SI followed by chemical hydrolysis. Suitable modifications of the lactate spacer increased the cargo release rate significantly, from 1 day to 2 hours or 5 minutes, as shown for linkers containing p-fluoro phenol. In turn, double cargo linkers bearing p-methyl phenol released their cargo more slowly (4 days, 4 hours, and 15 minutes) than their p-fluoro analogues. The α-hydroxyisobutyrate linker released both cargos in 25 minutes. Our study expands the current portfolio of SI constructs by providing a double cargo delivery option, which is crucial to develop universal SI platforms. 相似文献
Oral delivery of proteins and peptides is one of the main challenges in pharmaceutical drug development. Microdevices have the possibility to protect the therapeutics until release is desired, avoiding losses by degradation. One type of microdevice is polymeric microcontainers. In this study, lysozyme is chosen as model protein and loaded into microcontainers with the permeation enhancer sodium decanoate (C10). The loaded microcontainers are sealed and functionalized by applying polymeric lids onto the cavity of the devices. The first lid is poly(lactic‐co‐glycolic) acid (PLGA) and on top of this either polyethylene glycol (PEG) or chitosan is applied (PLGA+PEG or PLGA+chitosan, respectively). The functionalization is evaluated in vitro for morphology, drug release, and mucoadhesive properties. These are coupled with in vitro and ex vivo studies using Caco‐2 cells, Caco‐2/HT29‐MTX‐E12 co‐cultures, and porcine intestinal tissue. PLGA+chitosan shows slower release compared to PLGA+PEG or only PLGA in buffer and the transport of lysozyme across cell cultures is not enhanced compared to the bulk powder. Microcontainers coated with chitosan or PEG demonstrate a three times stronger adhesion during ex vivo mucoadhesion studies compared to samples without coatings. Altogether, functionalized microcontainers with mucoadhesive properties and tunable release for oral protein delivery are developed and characterized. 相似文献
Nanosized near infrared (NIR) responsive nanohybrids are synthesized by surface‐initiated atom transfer radical polymerization (SI‐ATRP) of N‐isopropylacrylamide (NIPAAm) on gold nanorods (Au NRs). Transmission electron microscopy images demonstrate that the nanohybrids have a clear core/shell structure. Temperature‐variable 1H NMR spectroscopy, quasi‐elastic light scattering (QELS), UV‐vis spectroscopy, and laser irradiation prove that the nanohybrids are both temperature and NIR responsive. Norvancomycin (NVan) loading and release experiments show that the drug release rate can be modulated by NIR irradiation. Such an intelligent drug‐delivery system might find applications in non‐invasive controlled drug release in future.
AbstractArtemisia vulgaris hydrogel (AVH) was acetylated (AAVH) and characterized by FTIR, CP/MAS 13C-NMR spectroscopic techniques and thermogravimetric analysis. Flynn–Waal–Ozawa model was used to investigate thermal degradation kinetics. Energy of activation (Ea) values of first and major thermal degradation steps were found to be 128.14 and 116.85 kJmol?1 for AVH and AAVH, respectively. Thermodynamic triplet, order of degradation reaction, integral procedural decomposition temperature (IPDT) and comprehensive index of intrinsic thermal stability (ITS) were also taken into account. In vitro caffeine release from AVH-based matrix tablets indicates potential of AVH for the development of oral delivery systems for sustained drug release. 相似文献
In this study, implantable and degradable molecularly imprinted cryogel was prepared for pH-responsive delivery of doxorubicin. Cryogel discs were synthesized using amino acid-based functional monomer with HEMA and gelatin. The molecularly imprinted discs were characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, degradation and swelling tests. In vitro delivery experiments were carried out in order to examine the effects of medium pH and drug content. The degree of degradation of composite cryogels was found to be 83.45±1.86% after 56 days. The release profiles of DOX from molecularly imprinted cryogel discs exhibit a biphasic delivery. It was observed that an initial burst release step from 0 to 12 h was followed by a slower and sustained release. Release rate of DOX from cryogel discs increased in more acidic conditions. Kinetic studies showed that a combination of diffusion and erosion control is mainly responsible from the general release behaviors of molecularly imprinted cryogel discs. 相似文献
The pre-polymer poly(but-2-ene-1,4-diyl malonate) (PBM) and a series of PBM-based materials are shown to be degradable under physiological conditions in vitro and they are therefore presented as potential materials for biomedical applications. Four different PBM-based materials are synthesized: a PBM homopolymer, crosslinked PBM with and without spacer, and a triblock copolymer of PBM and PLLA with the PBM as an amorphous middle block. The polymers are subjected to hydrolytic degradation in phosphate-buffered saline at pH = 7.4 and 37 °C. The results show that all the PBM-based materials degrade without a rapid release of acidic degradation products or any substantial lowering of the pH that might jeopardize their biocompatibility. 相似文献
Polyphosphazene derivatives having amino acid ester side groups were prepared by reaction of poly(dichlorophosphazene) with ethyl esters of amino acids. The in vitro degradation studies demonstrated that the rate of degradation depends on the nature of the amino acids. Introducing small amounts of hydrolytically sensitive groups such as depsipeptide ester or hydrolysis-catalysing moieties, such as histidine ethyl ester co-substituents, resulted in an increase of the degradation. The rate of hydrolytic degradation of the polyphosphazene material could be controlled by the content of the hydrolytically sensitive side groups or by blending hydrolysis-sensitive polymers with more stable derivatives. The results obtained from the in vivo implantation of biodegradable polyphosphazenes in mice indicate that the materials are very well tolerated by the animal body. Biodegradable polyphosphazenes have been used as matrix for the design of drug delivery systems. The rate of the in vitro release of mitomycin C from biodegradable polyphosphazenes can be controlled by changing the chemical composition of the polymer or by blending polymers of different chemical compositions. 相似文献
The development of electro-stimulated drug release devices is an innovative approach to attain the drug delivery in accurate doses at target sites in a programmed manner. In this work, novel electroactive nanocomposite hydrogels were prepared by encapsulating green-synthesized polypyrrole (PPy) colloids within chondroitin sulfate (CS) networks during the self-crosslinking of CS via N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide chemistry. The structural and morphological properties of CS/PPy hydrogels were studied by Fourier-transformed infrared spectroscopy, scanning electron microscopy, and swelling kinetic measurements. The chemotherapeutic agent 5-fluorouracil (5-FU) was loaded into CS/PPy samples by hydrogel swelling method, or alternatively, by pre-incubating the drug in polymer mixture before crosslinking. Different electrical stimulations can be used to switch ON and accurately tune the 5-FU delivery from GG/PPy hydrogels. A single pulse potential of 5 V switched on the drug delivery up to 90% from nanocomposite hydrogel, in contrast to the low 5-FU amount released in a passive form (< 20%). PPy electroactive behavior played a determining role as the main driving force in 5-FU release activation. Cytotoxicity of hydrogels with and without 5-FU was examined in normal and cancer cells. Considering the high cytotoxicity of 5-FU, the ON/OFF 5-FU release patterns evidenced the potential of CS/PPy hydrogels for electrically controlled drug delivery in implantable or transdermal drug release devices. 相似文献
Analytical models - based on kinetic and mechanistic considerations- have been developed, for describing the enzymic degradation of polymers. The models were applied to delineate the degradation patterns expected when endo- or exo- acting enzymes are used, and when the kinetic constant KM varies with the size (i) of the macromolecular substrate. Utilization of these models, in conjunction with experimentally available data, provides the possibility to define the mechanism of enzymic action, and to determine the kinetic constants of the process. Thus, for example, for the degradation of poly-N-(2-hydroxyethyl)-L-glutamine (PHEG) by papain, the correlation between KM and i was established. The above models can also be used to provide data that cannot be obtained experimentally (e.g. exact chain length distribution of degradation products), and to determine, with minimum effort, the experimental set up required for obtaining a desired array of products. They are, therefore, most useful tools for the design of enzyme–actuated drug delivery devices. 相似文献
The aim of this study was the synthesis, physico‐chemical characterization and preliminary evaluation of biological activity of novel polymer drugs based on conjugates of anti‐cancer drug doxorubicin (Dox) with water‐soluble polymer drug carriers based on N‐(2‐hydroxypropyl)methacrylamide (HPMA) copolymers. In the conjugates, Dox is attached to the polymer via a pH‐sensitive linkage susceptible to hydrolysis at pH ≈ 5–6, thus enabling intracellular Dox release. Seven Dox‐containing polymer conjugates differing in the length and structure of the single‐amino‐acid or oligopeptide spacer were synthesized (Gly, β‐Ala, 6‐aminohexanoyl, 4‐aminobenzoyl, GlyGly, GlyLeuGly, Gly‐DL ‐PheLeuGly) and the relationship between the spacer structure and the rate of in vitro Dox release was studied at various pH. The rate of Dox release at pH 5 (close to lysosomal pH) ranged from 70 to 96% of total Dox/48 h, depending on the spacer structure and being the highest for the conjugate containing the 6‐aminohexanoyl spacer. The rate of Dox release from most conjugates incubated at pH 7.4 (blood pH) was more than 10 times slower, ca. 4–10% of total Dox/48 h. Molecular weight of the polymer (25 000–115 000 g/mol) did not significantly influence the rate. The presence of lysosomal enzyme cathepsin B in incubation media increased the rate of Dox release from the conjugates with oligopeptide GlyLeuGly and Gly‐DL ‐PheLeuGly spacers by 15–30%, whereas the release from conjugates with other spacers remained unchanged. Cytotoxicity of all hydrazone conjugates for mouse EL‐4 T cell lymphoma cells was much higher and close to that of free Dox (IC50 ≈ 0.1–0.34 μg Dox/mL), in contrast to cytotoxicity of similar classic conjugates bearing Dox attached via an amide bond (IC50 ≈ 19 μg Dox/mL). 相似文献
In this study, thermoresponsive copolymers that are fully injectable, biocompatible, and biodegradable and are synthesized via graft copolymerization of poly(N‐isopropylacrylamide) onto alginate using a free‐radical reaction are presented. This new synthesis method does not involve multisteps or associated toxicity issues, and has the potential to reduce scale‐up difficulties. Chemical and physical analyses verify the resultant graft copolymer structure. The lower critical solution temperature, which is a characteristic of sol–gel transition, is observed at 32 °C. The degradation properties indicate suitable degradation kinetics for drug delivery and bone tissue engineering applications. The synthesized P(Alg‐g‐NIPAAm) hydrogel is noncytotoxic with both human osteosarcoma (MG63) cells and porcine bone marrow derived mesenchymal stem cells (pBMSCs). pBMSCs encapsulated in the P(Alg‐g‐NIPAAm) hydrogel remain viable, show uniform distribution within the injected hydrogel, and undergo osteogenic and chondrogenic differentiation under appropriate culture conditions. Furthermore, for the first time, this work will explore the influence of alginate viscosity on the viscoelastic properties of the resulting copolymer hydrogels, which influences the rate of medical device formation and subsequent drug release. Together the results of this study indicate that the newly synthesized P(Alg‐g‐NIPAAm) hydrogel has potential to serve as a versatile and improved injectable platform for drug delivery and bone tissue engineering applications. 相似文献
Novel polymeric delivery systems for the photosensitizer mesochlorin e6 (Mce6) were synthesized to overcome problems of systemic toxicity. A disulfide bond was included to allow for quick release of Mce6 from the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer backbone once internalized in tumor tissue. The synthesized conjugates demonstrated a time-dependent reductive cleavage with an accompanying increase in the quantum yield of singlet oxygen generation on exposure to DTT. Quicker release kinetics and a higher cytotoxicity in SKOV-3 human ovarian carcinoma cells were obtained as compared to polymer conjugate with a proteolytically cleavable GFLG spacer. These novel conjugates hold promise as clinically relevant drug delivery systems for photodynamic therapy of cancer. 相似文献