Article

Biodegradable pH-sensitive prospidine-loaded dextran phosphate based hydrogels for local tumor therapy

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Abstract

The paper focuses on the development of drug delivery systems based on hydrogels of dextran phosphate (DP) for local cancer therapy. The hydrogels were characterized by physicochemical properties including functional group content, morphology, gel fraction, pH-responsive swelling. The desirable pH-sensitive drug release behavior of these hydrogels was demonstrated by a drug release test with Prospidine-loaded hydrogels (DP-Pr hydrogels) at different pH values. In vitro degradation of the DP-Pr hydrogels was determined under simulated physiological conditions. The cytotoxicity of the blank DP hydrogels and DP-Pr hydrogels with different Pr concentrations was evaluated with HeLa and HЕр-2 cells. Investigations of antitumor efficiency in vivo showed that administration of DP-Pr hydrogels in comparison with an aqueous solution of Pr results in the increase of antitumor activity, prolongation of therapeutic action and growth of a number of animals cured. Therefore, such pH-responsive DP hydrogels could be promising candidates as drug delivery carriers.

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... The creation of new dosage forms of anticancer drugs is one of the most important areas of pharmaceutical research due to the high prevalence of malignant diseases, unsatisfactory results of generally accepted standard methods for treatment, high toxicity, and rapid elimination from the blood with intravenous administration of most anticancer agents [1,2]. Possible ways to solve this problem is to design new systems for the delivery of drugs with sustained release, such as polymer hydrogels, micelles, microcapsules, and nanoparticles [3]. Selenium nanoparticles, which have excellent bioavailability, high biological activity, and low toxicity, occupy a special place among the nanoparticles developed for the treatment of cancer [4]. ...
... Previously, we have developed long-acting prospidine delivery systems based on dextran phosphate hydrogels for local cancer therapy in the treatment of disseminated abdominal lesions [3]. It was shown that the sorption of prospidine by modifi ed dextran occurs both by the distribution mechanism with the formation of hydrogen bonds, and due to donor-acceptor interactions and ion exchange [17]. ...
... It is caused by the diff usion of an antitumor substance that interacts with Na-CMC through hydrogen bonds and donor-acceptor interactions. Thus, the release of prospidine from systems containing stabilized Na-CMC selenium nanoparticles has a prolonged pattern and is characterized by the absence of an initial signifi cant release of the sorbed substance, which often occurs when using polyelectrolyte-based active substance delivery systems [3,22]. ...
Article
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Stable selenium nanoparticles were synthesized in a sodium carboxymethylcellulose (Na-CMC) solution with a degree of substitution of 0.85 and an average molar weight of 250 000. The shape and size of selenium nanoparticles were determined by dynamic light scattering and UV spectroscopy. It was found that the nanoparticles coated with Na-CMC are stable upon storage for 28 days. A significant prolongation of the release of the prospidine antitumor agent from stabilized nanoparticles has been shown. Broad spectrum drugs, in particular, anticancer drugs and drugs that compensate for selenium deficiency in the body can be produced based on the selenium nanoparticles coated with Na-CMC.
... The creation of new dosage forms of anticancer drugs is one of the most important areas of pharmaceutical research due to the high prevalence of malignant diseases, unsatisfactory results of generally accepted standard methods for treatment, high toxicity, and rapid elimination from the blood with intravenous administration of most anticancer agents [1,2]. Possible ways to solve this problem is to design new systems for the delivery of drugs with sustained release, such as polymer hydrogels, micelles, microcapsules, and nanoparticles [3]. Selenium nanoparticles, which have excellent bioavailability, high biological activity, and low toxicity, occupy a special place among the nanoparticles developed for the treatment of cancer [4]. ...
... Previously, we have developed long-acting prospidine delivery systems based on dextran phosphate hydrogels for local cancer therapy in the treatment of disseminated abdominal lesions [3]. It was shown that the sorption of prospidine by modifi ed dextran occurs both by the distribution mechanism with the formation of hydrogen bonds, and due to donor-acceptor interactions and ion exchange [17]. ...
... It is caused by the diff usion of an antitumor substance that interacts with Na-CMC through hydrogen bonds and donor-acceptor interactions. Thus, the release of prospidine from systems containing stabilized Na-CMC selenium nanoparticles has a prolonged pattern and is characterized by the absence of an initial signifi cant release of the sorbed substance, which often occurs when using polyelectrolyte-based active substance delivery systems [3,22]. ...
Article
Синтезированы стабильные наночастицы селена в растворе натрий-карбоксиметилцеллюлозы (Na-КМЦ) со степенью замещения 0.85 и среднемассовой молярной массой 250 000. Методами динамического рассеяния света и УФ-спектроскопии определены форма и размер наночастиц селена. Установлено, что покрытые Na-КМЦ наночастицы стабильны при хранении в течение 28 сут. Показано значительное пролонгирование высвобождения противоопухолевого вещества проспидина из стабилизированных наночастиц. Наночастицы селена, покрытые Na-КМЦ, могут быть использованы для создания на их основе лекарственных препаратов широкого спектра действия, в частности противоопухолевых препаратов и препаратов, компенсирующих дефицит селена в организме.
... Solomevich et al. successfully prepared a pH-sensitive and biodegradable DP hydrogel. After encapsulating prospidine (Pr), it could be used in controllable DDSs (Figure 8) [101]. ...
... 2020, 21, x FOR PEER REVIEW 11 of Schematic illustration of the synthesis of dextran phosphate (DP)-prospidine (Pr) hydrogels. Taken from[101]. ...
... Schematic illustration of the synthesis of dextran phosphate (DP)-prospidine (Pr) hydrogels. Taken from[101]. ...
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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.
... Similarly, preclinical studies of hydrogel drug delivery systems are a milestone in the evaluation of the translatability of a system. Nevertheless, most in vivo studies focus on drug efficacy measured by indirect methods, such as the tumor volume monitoring or immunohistochemistry staining of the tissues after sacrifice [15,43,44]. In vivo drug release is not routinely monitored, representing a failure in providing a complete assessment of actual pharmacokinetics. ...
... In vivo study of hydrogel drug delivery systems generally evaluate drug release indirectly by assessing drug efficacy [15,43,44]. The main outputs for tumor inhibition models are the tumor volume and size, the weight of mice over time, and the survival rate of the animals. ...
... Hematoxylin and eosin (H&E) staining of the tumor post sacrifice confirmed higher levels of necrotic tissue for paclitaxel-loaded hydrogel, which indicated the superior efficacy of the hydrogel delivery system over free paclitaxel and taxol injections ( Figure 9E) [43]. Similar in vivo studies were performed to assess the anti-tumor activity of paclitaxel released from gelatin hydrogels [224] and prospidine delivered by dextran phosphate-based hydrogels for local cancer therapy [44] using the animal survival rate and histology staining as common criteria. ...
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Owing to their tunable properties, controllable degradation, and ability to protect labile drugs, hydrogels are increasingly investigated as local drug delivery systems. However, a lack of standardized methodologies used to characterize and evaluate drug release poses significant difficulties when comparing findings from different investigations, preventing an accurate assessment of systems. Here, we review the commonly used analytical techniques for drug detection and quantification from hydrogel delivery systems. The experimental conditions of drug release in saline solutions and their impact are discussed, along with the main mathematical and statistical approaches to characterize drug release profiles. We also review methods to determine drug diffusion coefficients and in vitro and in vivo models used to assess drug release and efficacy with the goal to provide guidelines and harmonized practices when investigating novel hydrogel drug delivery systems.
... Therefore, drug immobilization in a polymer matrix should be considered in the context of controlled release at target sites. Various in vivo and in vitro drug application techniques have been developed with various therapeutic properties [12,[22][23][24], including antifungal [25][26][27], antibacterial [28][29][30][31][32], antitumor [33][34][35][36], ...
... Weak synthetic polybases, such as aromatics 4-vinylpyridine, 2-vinylpyridine, poly(vinyl imidazole), poly(N,N-dimethyl aminoethyl methacrylate), and poly(N,N-diethyl aminoethyl methacrylate), accept protons at low pH [50,110,111]. There is also a large group of natural polymers used in pH-responsive HGs that has advantages over synthetic polymers due to their degradability within the human body, making them excellent biocompatible components in drug delivery [9,33,88,112]. ...
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This review is an extensive evaluation and essential analysis of the design and formation of hydrogels (HGs) for drug delivery. We review the fundamental principles of HGs (their chemical structures, physicochemical properties, synthesis routes, different types, etc.) that influence their biological properties and medical and pharmaceutical applications. Strategies for fabricating HGs with different diameters (macro, micro, and nano) are also presented. The size of biocompatible HG materials determines their potential uses in medicine as drug carriers. Additionally, novel drug delivery methods for enhancing treatment are discussed. A critical review is performed based on the latest literature reports.
... Wichterle and Lim introduced the first synthetic hydrogel structure consisting of poly(2-hydroxyethymethacrylate). After their first report on clinical application as soft contact lenses (Wichterle and Lím 1960), there has been an exponential increase in the scientific reports on hydrogels mostly covering applications in adsorption (Kılıç et al. 2005;Pekel et al. 2001;Şahiner et al. 2000;Shafiq et al. 2019), catalysis (Şahiner 2013; Şahiner et al. 2011; Şahiner and Özay 2011), tissue engineering (García et al. 2019;Hou et al. 2019;Liang et al. 2019;Liu et al. 2020;Tibbitt and Anseth 2009), molecular recognition (Chen et al. 2014;Tomatsu et al. 2006;Yao et al. 2019), and controlled release Yuan et al. 2019;Yue et al. 2019) and drug delivery applications (Ekici et al. 2011;Shi et al. 2019;Sılan et al. 2012;Solomevich et al. 2019;Wu et al. 2019) due to their swelling ability and biocompatibility with living tissue. Nanogels (nanohydrogels) can be defined as nanoscale dispersions of polymer chains (hydrogels) crosslinked in a physical or a chemical way, possessing diameters up to 100 nm (IUPAC). ...
... Wichterle and Lim introduced the first synthetic hydrogel structure consisting of poly(2-hydroxyethymethacrylate). After their first report on clinical application as soft contact lenses (Wichterle and Lím 1960), there has been an exponential increase in the scientific reports on hydrogels mostly covering applications in adsorption (Kılıç et al. 2005;Pekel et al. 2001;Şahiner et al. 2000;Shafiq et al. 2019), catalysis (Şahiner 2013; Şahiner et al. 2011; Şahiner and Özay 2011), tissue engineering (García et al. 2019;Hou et al. 2019;Liang et al. 2019;Liu et al. 2020;Tibbitt and Anseth 2009), molecular recognition (Chen et al. 2014;Tomatsu et al. 2006;Yao et al. 2019), and controlled release Yuan et al. 2019;Yue et al. 2019) and drug delivery applications (Ekici et al. 2011;Shi et al. 2019;Sılan et al. 2012;Solomevich et al. 2019;Wu et al. 2019) due to their swelling ability and biocompatibility with living tissue. Nanogels (nanohydrogels) can be defined as nanoscale dispersions of polymer chains (hydrogels) crosslinked in a physical or a chemical way, possessing diameters up to 100 nm (IUPAC). ...
Chapter
Nanogels/microgels are intramolecularly crosslinked particles with submicron diameters that can swell in a suitable solvent due to their three-dimensional network structure. Nanogels provide beneficial features such as flexibility, biocompatibility, high stability and swelling, fixed shape, large surface/volume ratio, fast stimuli-responsive behavior, etc. Therefore, there is growing interest to further elaborate nanogel formulations in preclinical applications as therapeutics, diagnostics, or nanosensors. However, conventional nanogel synthesis methods may end up with nanogels containing toxic residuals, e.g., initiator, crosslinking agent, and fragments which possess a major disadvantage in biomedical applications requiring tedious purification steps. This chapter reviews the synthesis of nanogels by irradiation of dilute aqueous polymer solutions to induce intramolecular crosslinking by gamma rays or accelerated electrons. This simple, ecofriendly, and cost-effective manufacturing method eliminates the purification step and provides the possibility to produce clean nanogels with desired sizes at room temperature. In the formation of nanogels, the degree of crosslinking can be controlled by polymer solution properties as well as operational parameters such as dose rate of radiation source and total absorbed dose. The method can be applied to many water-soluble polymers, copolymers, or interpolymer complexes for the development of nanogels with desired sizes and properties.
... In addition, hydrogels can be used as pH stimuli-responsive drug delivery systems due to their porosity, high water absorption, and sustained drug release. Incorporation of pH-sensitive cleavable bonds in the hydrogel network [49], pH-dependent difference between swelling and deswelling states of the hydrogel [50], and pH-dependent hydrogen bonding interactions between the drug and hydrogel network [51] account for the cargo release, which are described below. ...
... Solomevich et al. reported another example of biodegradable pHsensitive prospidine-loaded dextran phosphate-based hydrogels for local therapy of hepatoma [50]. The cumulative drug release was highest at pH value of 1.2. ...
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Despite noteworthy developments in tumor therapy, cancer is still one of the main reasons for death worldwide. While present cures supply hopeful marks, they trigger harsh cytotoxicity, with limited success in preventing and recurrence of the disease. To overcome the mentioned issues, implantable biomaterials have been developed as promising systems for the local delivery of therapeutic agents to cancerous tissues. Due to the unique characteristics of biocompatible polymers, they have been used in different approaches of localized drug delivery to ensure accurate control over the release of chemotherapy drugs, genes, proteins, and peptides. In this review article, the recent progress in stimuli-responsive implantable drug delivery systems for preventing tumor recurrence and suppressing tumors are reported. In particular, we reviewed redox-, enzyme-, and pH-responsive systems in programmable drug delivery and the near-infrared-, ultrasound-, electric-, and magnetic-regulated release in on-demand local drug delivery systems. The preparation process, physicochemical characteristics of implantable materials, and kinetic models of the drug release from these platforms were also discussed in detail.
... pH-sensitive nano-drug carriers are thus designed to release the drug under the conditions of the tumor's slightly acidic environment, achieving passively targeting to the tumors (Bai et al., 2018;Wang et al., 2018;Ata et al., 2019;Xie et al., 2018). Injectable hydrogels with tissue adhesion and pH sensitivity are also highly needed for local drug delivery (Wu et al., 2018;Rakhshaei et al., 2019;Solomevich et al., 2019). Chen and Liu (2016) synthesized a mesoporous silica nanocomposite (MSN) of hyaluronic acid (HA) and fluorescein isothiocyanate (FITC), which can selfassemble into hydrogels in situ around tumor tissue by pHresponsive interactions (hydrogen bonds) between HA. ...
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Standard chemotherapy for newly diagnosed ovarian cancer is a platinum-taxane combination. The Gynecologic Oncology Group conducted a randomized, phase 3 trial that compared intravenous paclitaxel plus cisplatin with intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel in patients with stage III ovarian cancer. We randomly assigned patients with stage III ovarian carcinoma or primary peritoneal carcinoma with no residual mass greater than 1.0 cm to receive 135 mg of intravenous paclitaxel per square meter of body-surface area over a 24-hour period followed by either 75 mg of intravenous cisplatin per square meter on day 2 (intravenous-therapy group) or 100 mg of intraperitoneal cisplatin per square meter on day 2 and 60 mg of intraperitoneal paclitaxel per square meter on day 8 (intraperitoneal-therapy group). Treatment was given every three weeks for six cycles. Quality of life was assessed. Of 429 patients who underwent randomization, 415 were eligible. Grade 3 and 4 pain, fatigue, and hematologic, gastrointestinal, metabolic, and neurologic toxic effects were more common in the intraperitoneal-therapy group than in the intravenous-therapy group (P< or =0.001). Only 42 percent of the patients in the intraperitoneal-therapy group completed six cycles of the assigned therapy, but the median duration of progression-free survival in the intravenous-therapy and intraperitoneal-therapy groups was 18.3 and 23.8 months, respectively (P=0.05 by the log-rank test). The median duration of overall survival in the intravenous-therapy and intraperitoneal-therapy groups was 49.7 and 65.6 months, respectively (P=0.03 by the log-rank test). Quality of life was significantly worse in the intraperitoneal-therapy group before cycle 4 and three to six weeks after treatment but not one year after treatment. As compared with intravenous paclitaxel plus cisplatin, intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel improves survival in patients with optimally debulked stage III ovarian cancer.
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Inspired by the multilayer structure of onion, herein, a novel strategy to prepare bionic multilayer hydrogel capsules for inhibiting burst release of doxorubicin (DOX) is reported. The bionic multilayer hydrogel capsules are prepared by the ionotropic crosslinking method. Compared with monolayer hydrogel capsules, the multilayer hydrogel capsules can largely homogenize the distribution of DOX and suppress the concentration gradient of DOX between the outermost hydrogel layer and external environment and the dense cuticular membranes of capsules can restrict the migration and diffusion of DOX. As a result, a significant inhibition of the burst release of DOX can be achieved. Moreover, the bionic multilayer hydrogel capsules demonstrate pH sensitivity and good biocompatibility to human epidermal keratinocyte (HaCaT) cells. This work opens up a new horizon in the burst release of biomaterial-based hydrogels for drug delivery system.
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Background: This study examines the impact of intraoperative macroscopic tumour consistency on short-term and long-term outcomes after cytoreductive surgery (CRS) with intraperitoneal chemotherapy (IPC) for appendiceal adenocarcinoma with peritoneal metastases. Methods: Macroscopic intraoperative tumour consistency was classified in three groups as soft (jelly-like geltatinous tumours), hard (hard tumour nodules without gelatinous features) and intermediate (both soft and hard features). In-hospital mortality, major morbidity, intensive care unit (ICU), high dependency unit (HDU) and total hospital stay, disease-free survival (DFS) and overall survival (OS) were compared. Results: The three groups had similar perioperative short-term outcomes. Patients with soft, intermediate and hard tumours revealed differences in OS (p < 0.001) and DFS (p = 0.03). Multivariable analysis revealed a shorter OS for patients with hard versus soft tumours (HR for hard tumours = 4.43, 95%CI 2.19-9.00). Conclusions: Intraoperative macroscopic tumour consistency may be used as a prognostic marker for survival in patients with appendiceal adenocarcinoma with peritoneal metastases.
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Pumpkin polysaccharide was extracted with hot water, and it was chemically modified with phosphorus oxychloride-pyridine to obtain phosphorylated pumpkin polysaccharides (PP1, PP2) with different degrees of substitution. The degree of substitution of PP1 and PP2 was 0.01 and 0.02, respectively. The scavenging effect of pumpkin polysaccharide and its phosphorylated pumpkin polysaccharides on superoxide anions was determined by pyrogallol autooxidation. The scavenging effect of pumpkin polysaccharide and its phosphorylated pumpkin polysaccharide on hydroxyl radicals was determined by salicylic acid method. The reducing ability of pumpkin polysaccharide and its phosphorylated pumpkin polysaccharide was studied. It showed that the phosphorylated pumpkin polysaccharides with different degrees of substitution had higher scavenging ability to hydroxyl radicals and superoxide anions than the underivatized pumpkin polysaccharide.
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Injectable hydrogels with self-healing and pH-responsive property are appealing for biomedical applications. Herein, we developed a facile and green method to prepare a multifunctional polysaccharide-based hydrogel as a new carrier of drug. The hydrogels were prepared by forming reversible chemical bond between carboxyethyl-modified chitosan (CEC) and aldehyde modified hyaluronic acid (A-HA). The morphology and rheological property of the hydrogels with different solid content were systematically characterized. Owing to the dynamic equilibrium of the Schiff base bonds between amine groups on CEC and aldehyde groups on A-HA, the rapid self-healing performance of hydrogels was confirmed through qualitative and quantitative methods without any external stimulus. The pH-responsive behaviour was demonstrated by equilibrium swelling and in vitro Doxorubicin (Dox) release in PBS medium with various pH. In acidic condition, Dox can be release more rapidly compared with weak alkaline medium. Furthermore, the kill effect of Dox released from hydrogels for cancer cells was investigated. In vitro degradation and cytotoxicity examinations showed that the hydrogel is biodegradable and biocompatible. Therefore, such polysaccharide-based injectable self-healing and pH-responsive hydrogel is a promising candidate as drug delivery carrier.
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Statement of significance: Diabetic wounds, which are a sever type of diabetes, have become one of the most serious clinical problem. There is a great promise in the delivery of adipose stem cells into wound sites using injectable hydrogels that can improve diabetic wound healing. Due to the biocompatibility of poly(ethylene glycol) diacrylate (PEGDA), we developed an in situ RAFT polymerization approach using anti-alcoholi drug - Disulfiram (DS) as a RAFT agent precursor to achieve hyperbranched PEGDA (HP-PEG). HP-PEG can form an injectable hydrogel by crosslinking with thiolated hyaluronic acid (HA-SH). ADSCs can maintain their regenerative ability and be delivered into the wound sites. Hence, diabetic wound healing process was remarkably promoted, including inhibition of inflammation, enhanced angiogenesis and re-epithelialization. Taken together, the ADSCs-seeded injectable hydrogel may be a promising candidate for diabetic wound treatment.
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Carboxymethyl starch-g-polyvinylpyrolidones (CMS-g-PVPs) were prepared by grafting of carboxymethyl starch (CMS) with N-vinylpyrolidone (NVP) using different initiators. The grafting percentage of all the modified starches was determined and the modified starch (CMS-g-PVP-5) with maximum grafting percentage was characterized by elemental analysis, ¹H NMR and FT-IR spectroscopy. Crystallinity and thermal properties of CMS-g-PVP-5 were analysed by XRD and TGA, respectively. CMS-g-PVP-5 was then utilized for the adsorption of Rhodamine 6G (dye) from water under different pH, temperature, adsorbate doze and adsorbent concentration. This modified starch showed good adsorption ability towards Rhodamine 6G. CMS-g-PVP-5 was also applied for the adsorption of ammonia gas and proved an exciting adsorbent for ammonia.
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Nanocellulose refers to a family of novel cellulose materials with the nanosized (2~100 nm) cellulose microfibrils in diameter. Because of the high aspect ratio, large specific surface area, exceptional mechanical properties as well as ease for surface modification, nanocelluose has become a research focus of biosorbent materials areas. In this article, the achievements in the nanocellulose-absorbent materials in recent years are summarized, and the research progress of absorbent materials based on nanocrystalline cellulose (NCC), nanofibrillated cellulose (NFC), and bacterial cellulose (BC) in the aspects of removing dyes, heavy metal ions, CO2 gas, and other pollutants (e.g. antibiotics, aromatic organic compounds, radioactive elements, and volatile organic compounds), are reviewed, respectively. Besides, the existing problems of nanocellulose-based adsorbent materials are discussed, and their future development prospects are presented. © 2017, Editorial Office of Progress in Chemistry. All right reserved.
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Hydrogels based on chitosan/hyaluronic acid/β-sodium glycerophosphate demonstrate injectability, body temperature sensitivity, pH sensitive drug release and adhesion to cancer cell. The drug (doxorubicin) loaded hydrogel precursor solutions are injectable and turn to hydrogels when the temperature is increased to body temperature. The acidic condition (pH 4.00) can trigger the release of drug and the cancer cell (Hela) can adhere to the surface of the hydrogels, which will be beneficial for tumor site-specific administration of drug. The mechanical strength, the gelation temperature, and the drug release behavior can be tuned by varying hyaluronic acid content. The mechanisms were characterized using dynamic mechanical analysis, Fourier transform infrared spectroscopy, scanning electron microscopy and fluorescence microscopy. The carboxyl group in hyaluronic acid can form the hydrogen bondings with the protonated amine in chitosan, which promotes the increase of mechanical strength of the hydrogels and depresses the initial burst release of drug from the hydrogel.
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Hydrogel and porous lyophilized hydrogel have been designed using polyurethane brush with chitosan backbone through grafting. Degree of substitution of grafting has been varied for controlled properties and has been confirmed by 13C NMR, FTIR and UV-vis measurements. Surface modification of chitosan has been done to check the hydrophilic–hydrophobic balance which is reflected in their swelling behavior and contact angle. Porous interconnected three dimensional network structures with controlled size are observed using by scanning electron microscope. Hydrogels or lyophilized hydrogel have sufficient mechanical strength and brush like structure help increasing the fluidity as measured from lesser viscosity under oscillatory shear as compared to pure chitosan and thereby the brush acts like slipping agent. Sustained drug release is achieved using brush copolymer as opposed to burst release noticed in pure chitosan. Controlled drug release phenomenon has been modeled both for hydrogel and lyophilized hydrogel following the Fickian diffusion (n < 0.45). Excellent cytocompatibility of the brush copolymer has been verified through cell line studies using mouse embryonic fibroblast cells. Interestingly, the cells grow nicely within the pores of graft copolymer while predominantly usual cell growth on surface is observed in lyophilized hydrogel of chitosan indicating the effect of brush like modification on chitosan backbone towards better cell proliferation. The developed brush copolymer has the ability to form hydrogel at physiological condition at 37 oC through sol-gel transformation which make them suitable to be used as an injectable hydrogel as evidence from the in vivo experiment using rat model. Hence, developed brush copolymers are promising as potential biomaterials for drug delivery and tissue engineering applications.
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In this study, dextran (Dex) has been cross-linked with epichlorohydrin (Ech) to yield cross-linked hydrogels. These gels were characterized by Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD) analysis, Thermogravimetric analysis (TGA), and Scanning electron microscopy (SEM). The water absorption behavior of gels was studied in simulating gastric fluid (SGF) and simulating intestinal fluid (SIF) at 37?C. The data was interpreted by various kinetic models. The swelling was found to be totally diffusion controlled. The equilibrium data was also used to calculate network parameters. The antidiabetic drug Gliclazide(Glz) was loaded to the gels and its release was investigated in the media of varying pH, to mimic transition from mouth to colon. Finally, the in-vivo study on ?Albino Wistar rats? was carried out to investigate the efficiency of the formulations. The drug-loaded hydrogel was found to be quite effective in reducing the glucose level at lower administration frequency as compared to the plain drug.
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Biological barriers to drug transport prevent successful accumulation of nanotherapeutics specifically at diseased sites, limiting efficacious responses in disease processes ranging from cancer to inflammation. Although substantial research efforts have aimed to incorporate multiple functionalities and moieties within the overall nanoparticle design, many of these strategies fail to adequately address these barriers. Obstacles, such as nonspecific distribution and inadequate accumulation of therapeutics, remain formidable challenges to drug developers. A reimagining of conventional nanoparticles is needed to successfully negotiate these impediments to drug delivery. Site-specific delivery of therapeutics will remain a distant reality unless nanocarrier design takes into account the majority, if not all, of the biological barriers that a particle encounters upon intravenous administration. By successively addressing each of these barriers, innovative design features can be rationally incorporated that will create a new generation of nanotherapeutics, realizing a paradigmatic shift in nanoparticle-based drug delivery.
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To test various formulas and techniques for manufacturing dry-fabricated bio-film (DFBF) that exhibits physical properties advantageous to the use of the DFBF in wound dressings, a DFBF was fabricated by adding chitosan (Chi) and alginate (Alg) to homogenized bacterial cellulose (BC) obtained from vinegar pellicles in vinegar brewing byproducts in this study. The results revealed that the degree of oxidation in DFBF manufactured using hydrogen peroxide oxidized BC (HOBC), with 0.092% carboxyl group content, was lower than that in DFBF manufactured using periodic acid oxidized BC (POBC), but DFBF made using HOBC exhibited higher elongation, rehydration, swelling ratios, and water vapor transmission than that fabricated using POBC. A DFBF composite gel with 98.5% water content possessed appropriate fluidity for molding. After 10 min of rinsing cross-linked HOBC, 72 ppm of calcium remained in the final DFBF, which not only prevented cell toxicity but also demonstrated desirable mechanical and rehydration properties. Overall, the modified DFBF possessed a high rehydration ratio of 51.69% and could absorb and gradually release naringin by up to 80% within 24 h. This modified DFBF has the potential for exudate absorption and the controlled release of medicinal substances at the initial stage of healing when used in wound dressings.
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The intermolecular interaction of prospidinum with gel-forming dextran and starch phosphates has been studied. The sorption equilibria have been studied for cytostatic and the biodegradable hydrogels of polysaccharide phosphates. The concentration coefficients of ion exchange equilibrium and distribution coefficients of prospidinum have been calculated at different degrees of microgel phase filling with the cytostatic, and the relations between the coefficients and the degree of hydrogel swelling have been determined. The ion-exchange and nonexchange contributions to sorption values have been found. The analysis of the distribution coefficients has demonstrated that the concentration of prospidinum sorbed through the nonexchange mechanism is higher than its concentration in an external solution due to the van der Waals interactions between prospidinum cations and macromolecules of polysaccharide phosphates. The Na form of polysaccharide phosphates is the optimal carrier for prospidinum, because this form has a higher density of the total negative charge than their H form has.
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In this work, N-benzyltriazole derivatized dextran was evaluated for its potential as a novel carbohydrate-based adsorbent for the removal of methyl violet dye from water. The modified dextran was synthesized by a click reaction of pentynyl dextran and benzyl azide, and the structure was characterized by nuclear magnetic resonance spectroscopy, elemental analysis, and scanning electron microscopy. Dextran was substituted with a triazole-linked benzyl group. For decolorization of the dye effluent, adsorption is a very effective treatment; here, the driving force is based on hydrogen bonding, pi stacking, and electrostatic interaction between the methyl violet dye and the N-benzyltriazole derivatized dextran. Batch experiments were carried out to investigate the required contact time and the effects of pH, initial dye concentrations, and temperature. The experimental data were analyzed with equilibrium isotherms including the Langmuir, Freundlich, and Temkin models. Based on the Langmuir isotherm, the maximum adsorption capacity was determined to be 95.24 mg of dye per gram of the adsorbent. The adsorption obeyed pseudo-second order kinetics, and a negative ΔG0 value indicated adsorption spontaneous in nature.
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Superabsorbent polymer composites (SAPCs) are very promising and versatile materials for biomedical applications. This study concentrates on the development of novel cellulose-based SAPC, Poly(acrylic acid-co-acrylamide-co−2-acrylamido-2-methyl-1-propanesulfonic acid)-grafted nanocellulose/poly(vinyl alcohol) composite, P(AA-co-AAm-co-AMPS)-g-NC/PVA, as a potential drug delivery vehicle. Amoxicillin was selected as a model drug, which is used for the treatment of Helicobacter pylori induced peptic and duodenal ulcers. P(AA-co-AAm-co-AMPS)-g-NC/PVA was synthesized by graft copolymerization reaction, and FTIR, XRD, SEM, and DLS analyses were performed for its characterization. Equilibrium swelling studies were conducted to evaluate the stimuli-response behavior of the SAPC and found that equilibrium swelling was dependent on pH, contact time, temperature, ionic strength, concentration of crosslinker and PVA. Maximum drug encapsulation efficiency was found out by using different concentrations of amoxicillin. Drug release studies were carried out at simulated gastric and intestinal fluids and the release % was observed as maximum in intestinal fluids within 4 h. The drug release kinetics was investigated using Peppas' potential equation and follows non-Fickian mechanism at pH 7.4. Thus, the drug release experiments indicate that P(AA-co-AAm-co-AMPS)-g-NC/PVA would be a fascinating vehicle for the in vitro administration of amoxicillin into the gastrointestinal tract. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40699.
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Starch was phosphorylated through dry-heating in the presence of pyrophosphate at various conditions, and the characteristics of phosphorylated starch (PS) were examined. Starch phosphorylation increases as the pH increases from 3 to 6, but diminishes at pH 7. Increased temperatures enhance phosphorylation. Data from (31)P NMR suggests that starch phosphorylation occurs mainly at the C3-OH and C6-OH of the glucose residue. The phosphate linkage is mainly due to monostarch monophosphate. Although starch had almost no calcium phosphate-solubilising capacity, this capacity was markedly enhanced by phosphorylation. X-ray diffraction analysis indicates that the crystal structure of hydroxyapatite was not present in the calcium phosphate-PS complex.
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An important component of treatment failure in gastric cancer (GC) is cancer dissemination within the peritoneal cavity and nodal metastasis. Intraperitoneal chemotherapy (IPC) is considered to give a fundamental contribute in treating advanced GC. The purpose of the study is to investigate the effects of IPC in patients with advanced GC. A systematic review with meta-analysis of randomized controlled trials (RCTs) of IPC + surgery vs. control in patients with advanced GC was performed. Twenty prospective RCTs have been included (2145 patients: 1152 into surgery + IPC arm and 993 into control arm). Surgery + IPC improves: 1, 2 and 3-year mortality (OR = 0.31, 0.27, 0.29 respectively), 2 and 3-year mortality in patients with loco-regional nodal metastasis (OR = 0.28, 0.16 respectively), 1 and 2-year mortality rate in patients with serosal infiltration (OR = 0.33, 0.27 respectively). Morbidity rate was increased by surgery + IPC (OR = 1.82). The overall recurrence and the peritoneal recurrence rates were improved by surgery + IPC (OR = 0.46 and 0.47 respectively). There was no statistically significant difference in lymph-nodal recurrence rate. The rate of haematogenous metastasis was improved by surgery + IPC (OR = 0.63). 1, 2 and 3-year overall survival is incremented by the IPC. No differences have been found at 5-year in overall survival rate. 2 and 3-year mortality rates in patients with nodal invasion and 1 and 2-year mortality rates in patients with serosal infiltration are improved by the use of IPC. IPC has positive effect on peritoneal recurrence and distant metastasis. Morbidity rate is incremented by IPC. Loco-regional lymph-nodes invasion in patients affected by advanced gastric cancer is not a contraindication to IPC.
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Dextran microparticles were chemically modified for the attachment of quaternary ammonium groups carrying substituents with different hydrophobicity, in order to obtain amphiphilic cationic hydrogels with different hydrophilic/lipophilic balance. These hydrogels retain various amounts of dyes: Rose Bengal, Brilliant Blue and Vitamin B12, used as models for hydrophobic, amphiphilic and hydrophilic drugs, as a function of their hydrophilic/hydrophobic properties. Bovine serum albumin (BSA) retention by hydrogels occurs in higher amounts at pH 6.9, and is influenced by electrostatic, hydrophobic forces and the swelling of the supports. Tetanus anatoxin is retained by the supports through electrostatic and/or hydrophobic forces, in amounts varying between 110 and 200mg/g. Both proteins are gradually released, through increasing of the eluent ionic strengths. Alpha-tocopherol is retained by the hydrogels preponderantly through hydrophobic forces, in amounts varying between 130 and 300mg/g. Measurement of the scavenging effect proved the antioxidant properties of the included drug. Based on the obtained results, one can appreciate the potential of the synthesized cationic hydrogels as supports for biomolecules or as vaccine adjuvants.
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Polymers and hydrogels have been synthesized which phase separate from aqueous solutions when the temperature is raised through a critical temperature region (LCST). These polymeric systems may be used for the delivery or removal of drugs or other selected molecules and biomolecules. Enzymes immobilized on LCST polymers or within LCST hydrogels may be used in diagnostic assays, biochemical processes or in therapeutics for physiological conditions associated with temperature changes. Antibodies and other binding ligands may also be immobilized on LCST polymers or within LCST hydrogels for therapeutic, diagnostic or separation purposes. This paper describes our ongoing work on these interesting polymers and hydrogels.
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Peritoneal carcinomatosis arising from gastric cancer is mostly associated with poor prognosis. Despite the improvement of survival with modern polychemotherapy, the results are still unsatisfactory. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy might provide an additional therapeutic option for highly selected patients with gastric cancer and peritoneal metastasis leading to improved prognosis. Considering the increased rate of perioperative morbidity and the crucial prognostic role of complete macroscopic cytoreduction, adequate preoperative diagnostics and patient selection are strongly recommended. Further prospective randomized trials are needed to determine the roles of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as part of an interdisciplinary treatment concept.
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Starch was phosphorylated by reaction with mono- and disodium hydrogen orthophosphate under dry conditions in a vacuum oven at 150-180 °C (800 mbar). Studying the different factors affecting the reaction showed that the optimal conditions for starch phosphorylation in the monoester form were: 3 h reaction time, 160 °C reaction temperature and pH 6. The different types of starch gave different degrees of substitution; and amylose bound a higher amount of phosphate than amylopectin under similar reaction conditions. Both ash content and acidity of the phosphorylated starch products increased proportionally with the increase in the degree of substitution while the pH of the different modified starch products was nearly in the same range (pH 6.55—6.75).
Article
The paper describes the synthesis of starch phosphate carbamides by reacting starch with phosphoric acid and urea. A solid state technique in vacuum at elevated temperatures is used. The degree of substitution of phosphate (DSP) and carbamide groups (DSC) can be adjusted by the molar ratio of starch: phosphoric acid: urea, the reaction temperature, and time. The starch derivatives prepared show remarkable swelling if the DSP ranges between 0.2 and 0.3. With increasing content of urea in the reaction mixture the water-holding ability is still significantly improved, which is explained by chemically and especially physically introduced urea into the starch polymer. Furthermore, the ratio of amylose: amylopectin of the starch samples influences both the DS values and the physicochemical properties, e.g., swelling power and multivalent metal ion adsorption of the products. The structure of the new polymers was determined by means of FTIR, 13C- and 31P NMR spectroscopy as well as by gel permeation chromatography (GPC).
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The exponential expression of solute release from polymeric devices can be written in terms of the release mechanism's diffusional and relaxational contributions. The general form of this equation's exponent is related to the geometric shape of the releasing device through its aspect ratio. A methodology is presented for general analysis of the release behavior of controlled release systems using a coupled diffusion/relaxation model.
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Two series of CuO-containing sodium phosphate glasses with 40, and 50 mol% P2O5 were prepared. magic angle spinning nuclear magnetic resonance (MAS-NMR) and Fourier-transformed infrared (FTIR) spectra were applied to characterize the short-range structure of the glasses. NMR spectra reveal the presence of Q2- and Q1-tetrahedral sites in both glass series. The depolymerization of phosphate chains by the addition of CuO was described by the decrease in the concentration of Q2-tetrahedral sites and the increase in that of Q1-tetrahedral sites. The presence of peaks (Q2 site covalently bonded to one copper) in the NMR spectra indicates that a portion of CuO, which acts as a network former, enters the glass network to form covalent POCu linkage in the polyphosphate glasses. The site population increases with increasing CuO content. Almost all the CuO act as network modifiers in the metaphosphate glasses with CuO <30 mol%; the sites only exist in the glasses with high CuO content (≥30 mol%). FTIR analyses reveal the shortening of phosphate chains by the shift of (POP)as band to higher wavenumber due to the addition of CuO. The absorption band of the POCu stretching mode is assigned at around 1080 cm−1.
Article
New results regarding the synthesis and characterization of water-soluble phosphorylated dextran (PDex) are presented. The phosphorylation was made by reaction of dextran with phosphorous acid in molten urea. The structure of phosphorylated product was investigated by elemental analysis, by titration of acidic groups and by FTIR and NMR spectroscopy. It was found that phosphorylated dextran prepared in these conditions is a monobasic dextran phosphate with (H)P(O)(OH) groups. The degree of polymerization of PDex was found comparable to the parent dextran, suggesting that polysaccharide chain was not degraded during phosphorylation. The polyelectrolyte behavior was studied by potentiometric and conductometric titration and by viscometric measurements.
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Injectable and degradable hydrogels are very interesting networks for drug delivery and cell transplantation applications since they can be administered in the human body in a minimally invasive way. In most cases, the crosslinking reaction occurs by photopolymerisation or free radical polymerisation; however, the use of chemical initiators may promote cell death. In the current work, injectable and degradable dextran-based hydrogels were prepared without the use of initiators. Dextran, a natural glucose-containing polysaccharide, was oxidized with sodium periodate (dexOx) and the derivatives characterized by NMR and FTIR spectroscopy's as well as by colorimetric techniques. The oxidized derivatives were crosslinked with adipic acid dihydrazide (AAD), forming a gel within 2–4 min. The obtained hydrogels were characterized by their mechanical properties, swelling and degradation behavior under physiologic conditions. In addition, the hydrogel interior morphology as well as porous structure was evaluated by scanning electron microscopy (SEM) and mercury intrusion porosimetry (MIP). MIP analysis showed that dexOx hydrogels crosslinked with 10% of AAD were macroporous with pore sizes ranging from 0.32 to 0.08 μm. As expected, the average pore size increased during hydrogel degradation as confirmed by SEM and MIP studies.
Article
The simple exponential relation Mt/M∞ = ktn is introduced to describe the general solute release behavior of controlled release polymeric devices, where Mt/M∞ is the fractional solute release, t is the release time, k is a constant, and n is the diffusional exponent characteristic of the release mechanism. It is shown that this equation can adequately describe the release of drugs or other solutes from slabs, spheres, cylinders and discs (tablets), regardless of the release mechanism. It is shown that in cases of pure Fickian release the exponent n has the limiting values of 0.50, 0.45 and 0.43 for release from slabs, cylinders and spheres, respectively. For tablets, and depending on the aspect ratio, i.e., the ratio of diameter to thickness, the Fickian diffusion mechanism is described by 0.43<n< 0.50. For drug release from spherical polymer particles of a wide distribution, the value of the exponent n for Fickian diffusion depends on the width of the distribution.
Article
In situ forming chitosan hydrogels have been prepared via coupled ionic and covalent cross-linking. Thus, different amounts of genipin (0.05, 0.10, 0.15, and 0.20% (w/w)), used as a chemical cross-linker, were added to a solution of chitosan that was previously neutralized with a glycerol-phosphate complex (ionic cross-linker). In this way, it was possible to overcome the pH barrier of the chitosan solution, to preserve its thermosensitive character, and to enhance the extent of cross-linking in the matrix simultaneously. To investigate the contributions of the ionic cross-linking and the chemical cross-linking, separately, we prepared the hydrogels without the addition of either genipin or the glycerol-phosphate complex. The addition of genipin to the neutralized solution disturbs the ionic cross-linking process and the chemical cross-linking becomes the dominant process. Moreover, the genipin concentration was used to modulate the network structure and performance. The more promising formulations were fully characterized, in a hydrated state, with respect to any equilibrium swelling, the development of internal structure, the occurrence of in vitro degradability and cytotoxicity, and the creation of in vivo injectability. Each of the hydrogel systems exhibited a notably high equilibrium water content, arising from the fact that their internal structure (examined by conventional SEM, and environmental SEM) was highly porous with interconnecting pores. The porosity and the pore size distribution were quantified by mercury intrusion porosimetry. Although all gels became degraded in the presence of lysozyme, their degradation rate greatly depended on the genipin load. Through in vitro viability tests, the hydrogel-based formulations were shown to be nontoxic. The in vivo injection of a co-cross-linking formulation revealed that the gel was rapidly formed and localized at the injection site, remaining in position for at least 1 week.
Article
Intraperitoneal (i.p.) administration of paclitaxel (PTX) is a hopeful therapeutic strategy for peritoneal malignancy. Intravenously (i.v.) injected nanoparticle anticancer drugs are known to be retained in the blood stream for a long time and favorably extravasated from vessels into the interstitium of tumor tissue. In this study, we evaluated the effect of i.p. injection of PTX (PTX-30W), which was prepared by solubulization with water-soluble amphiphilic polymer composed of PMB-30W, a co-polymer of 2-methacryloxyethyl phosphorylcholine and n-butyl methacrylate, for peritoneal dissemination of gastric cancer. In a peritoneal metastasis model with transfer of MKN45P in nude mice, the effect of i.p. administration of PTX-30W was compared with conventional PTX dissolved in Cremophor EL (PTX-Cre). The drug accumulation in peritoneal nodules was evaluated with intratumor PTX concentration and fluorescence microscopic observation. PTX-30W reduced the number of metastatic nodules and tumor volume significantly more than did conventional PTX dissolved in Cremophor EL (PTX-Cre), and prolonged the survival time (P < 0.05). PTX concentration in disseminated tumors measured by HPLC was higher in the PTX-30W than in the PTX-Cre group up to 24 h after i.p. injection. Oregon green-conjugated PTX-30W, i.p. administered, preferentially accumulated in relatively hypovascular areas in the peripheral part of disseminated nodules, which was significantly greater than the accumulation of PTX-Cre. I.p. administration of PTX-30W may be a promising strategy for peritoneal dissemination, due to its superior characteristics to accumulate in peritoneal lesions.
Article
Four different cytostatic compounds (prospidium chloride, peptichemio, dacarbazine and mithramycin) have been assayed for their effect on lymphoblastic transformation of spleen cells from mice. The drugs did not affect cell viability at concentrations lower than 0.1-0.2 micrograms/ml (peptichemio and mithramycin) or than 10-20 micrometers/ml (prospidium chloride and dacarbazine). Except for peptichemio, which did not show any marked effect, these cytostatics acted more actively on B cells than on T cells at concentrations of drug not affecting lymphocyte viability. Mithramycin was the most active inhibitor of the mitogen-induced DNA synthesis in the cell. Concentrations of this drug to inhibit the blastogenic response to 50% (IC50) were lower than 0.1 microgram/ml. Inhibition of mitogenesis was less pronounced in the case of dacarbazine (IC50 = 50 and 10 micrograms/ml for T and B cells, respectively), prospidium chloride (IC50 greater than 50 and 50 micrograms/ml for T and B cells) and peptichemio (IC50 = 0.25 and 0.5 microgram/ml for T and B cells, respectively.
Article
Hydrogels are presently under investigation as matrices for the controlled release of bioactive molecules, in particular pharmaceutical proteins, and for the encapsulation of living cells. For these applications, it is often required that the gels degrade under physiological conditions. This means that the originally three-dimensional structure has to disintegrate preferably in harmless products to ensure a good biocompatibility of the hydrogel. In this overview, different chemical and physical crosslinking methods used for the design of biodegradable hydrogels are summarized and discussed. Chemical crosslinking is a highly versatile method to create hydrogels with good mechanical stability. However, the crosslinking agents used are often toxic compounds, which have been extracted from the gels before they can be applied. Moreover, crosslinking agents can give unwanted reactions with the bioactive substances present in the hydrogel matrix. Such adverse effects are avoided with the use of physically crosslinked gels.
Article
Hydrogels are one of the upcoming classes of polymer-based controlled-release drug delivery systems. Besides exhibiting swelling-controlled drug release, hydrogels also show stimuli-responsive changes in their structural network and hence, the drug release. Because of large variations in physiological pH at various body sites in normal as well as pathological conditions, pH-responsive polymeric networks have been extensively studied. This review highlights the use of hydrogels (a class of polymeric systems) in controlled drug delivery, and their application in stimuli-responsive, especially pH-responsive, drug release.
Article
To analyze the factors influencing the prognosis of patients with gastric cancer after surgical treatment, in order to optimize the surgical procedures. A retrospective study of 2 613 consecutive patients with gastric cancer was performed. Of these patients, 2,301 (88.1%) received operations; 196 explorative laparotomy (EL), 130 by-pass procedure (BPP), and 1 975 surgical resection of the tumors (891 palliative resection and 1 084 curative resection). The survival rate was calculated by the actuarial life table method, and the prognostic factors were evaluated using the Cox regression proportional hazard model. Of the patients, 2,450 (93.8%) were followed-up. The median survival period was 4.6 mo for patients without operation, 5.2 mo for EL, 6.4 mo for BPP, and 15.2 mo for palliative resection (P = 0.0001). Of the patients with surgical resection of the tumors, the overall 1, 3 and 5-year survival rates after were 82.7%, 46.3% and 31.1%, respectively, with the 5-year survival rate being 51.2% in patients with curative resection, and 7.8% for those with palliative resection. The 5-year survival rate was 32.5% for patients with total gastrectomy, and 28.3% for those with total gastrectomy plus resection of the adjacent organs. The factors that independently correlated with poor survival included advanced stage, upper third location, palliative resection, poor differentiation, type IV of Borrmann classification, tumor metastasis (N3), tumor invasion into the serosa and contiguous structure, proximal subtotal gastrectomy for upper third carcinoma and D1 lymphadenectomy after curative treatment. The primary lesion should be resected as long as the local condition permitted for stage III and IV tumors, in order to prolong the patients' survival and improve their quality of life after operation. Total gastrectomy is indicated for carcinomas in the cardia and fundus, and gastric cancer involving the adjacent organs without distant metastasis requires gastrectomy with resection of the involved organs.