Sustained Release Of 5-fluorouracil Research Articles

PH-sensitive aminated chitosan/carboxymethyl cellulose/aminated graphene oxide coated composite microbeads for efficient encapsulation and sustained release of 5-fluorouracil

The application of smart pH-sensitive carriers has become an ideal choice for administering drugs with desired release profiles. Although pH-sensitive microbeads offer distinct benefits for delivering anticancer drugs orally, they encounter drawbacks, including low encapsulation efficiency, weak mechanical stability, biocompatibility concerns, and the risk of abrupt release. This study focuses on developing pH-sensitive coated composite microbeads for effective encapsulation and sustained release of 5-fluorouracil (5-FU). Aminated graphene oxide (AmGO) was integrated into carboxymethyl cellulose (CMC) microbeads, which were subsequently coated with an aminated chitosan (AmCs) derivative. Various analysis techniques, including Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), X-ray diffractometer (XRD), X-ray photoelectron spectroscopy (XPS), thermogravimetric analyzer (TGA), zeta potential (ZP), and mechanical testing, were utilized to characterize the microbeads. The AmCs@CMC@AmGO composite microbeads demonstrated a compact structure with enhanced mechanical properties, achieving a maximum Young's modulus value of 35.99 N/mm2 compared to 25.95 N/mm2 for pure CMC microbeads. Moreover, pH-sensitivity and water uptake studies (at pH 1.2 and pH 7.4) revealed significant tunability of the composite microbeads by altering the AmGO and AmCs ratios. The coated composite microbeads encapsulated approximately 86.4 % of 5-FU compared to 47 % for CMC microbeads. The burst release of 5-FU at pH 7.4 was significantly reduced, with sustained release reaching 51 % over 24 h. The predominant release mechanism was Fickian diffusion, which well-described by the Peppas-Sahlin kinetic model. The developed microbeads exposed improved biodegradability and non-toxicity toward normal colon cells, while exhibiting notable toxicity against cancerous cells, emphasizing its potential for anticancer drug delivery.

A green approach for preparation of chitosan/hydroxyapatite/graphitic carbon nitride hydrogel nanocomposite for improved 5-FU delivery

Reducing the side effects of cancer treatment methods is an important issue. The loading efficiency and sustained release of 5-Fluorouracil (5-FU) have been significantly improved by creating a new method. A nanocarrier with pH sensitivity has been developed through the w/o/w emulsification method. It is loaded with 5-FU and comprises of chitosan (CS), hydroxyapatite (HAp), and graphitic carbon nitride (g-C3N4). g-C3N4 nanosheets were incorporated in CS/HAp hydrogel to improve the entrapment and loading efficiency. Drug loading efficiency and entrapment efficiency reached 48 % and 87 %, respectively, and the FTIR and XRD tests verified evidence of the formation of chemical bonds among the drug and nanocarrier. Structural analysis was done using FE-SEM. DLS and zeta potential were employed to obtain average size distribution and surface charge. The release profile of 5-FU in various conditions shows the nanoparticles' pH dependence, and the nanocomposite's controlled release is consistent with the Korsmeyer-Peppas kinetic model. Cell apoptosis and cytotoxicity were evaluated in vitro using flow cytometry and MTT analysis. The biocompatibility of CS/HAp/g-C3N4 against MCF-7 cells was shown by the MTT method and confirmed by flow cytometry. CS/HAp/g-C3N4@5-FU led to the highest apoptosis rate in MCF-7 cells, indicating the nanocarrier's efficiency in killing cancer cells. These data indicate that the designed CS/HAp/g-C3N4@5-FU can be a potential drug for treating cancer cells.

Rapidly separable microneedle patch for the controlled and sustained release of 5-fluorouracil

5-Fluorouracil (5-FU) is frequently used in the treatment of tumors and swollen tissues. However, traditional administration methods can result in poor patient compliance and require to administrate frequently due to the short T1/2 of 5-FU. Herein, the 5-FU@ZIF-8 loaded nanocapsules were prepared using multiple emulsion solvent evaporation methods to enable the controlled and sustained release of 5-FU. To decrease the drug release rate and enhance patient compliance, the obtained pure nanocapsules were added to the matrix to fabricate rapidly separable microneedles (SMNs). The entrapment efficiency (EE%) of 5-FU@ZIF-8 loaded nanocapsules was in the range of 41.55–46.29 %, and the particle size of ZIF-8, 5-FU@ZIF-8, and 5-FU@ZIF-8 loaded nanocapsules were 60 nm, 110 nm, and 250 nm respectively. According to the release study in vivo and in vitro, we concluded that 5-FU@ZIF-8 nanocapsules could achieve the sustained release of 5-FU and that the burst release of nanocapsules could be elegantly handled by incorporating nanocapsules into the SMNs. What's more, the use of SMNs could improve patient compliance due to the rapid separation of needles and backing of SMNs. The pharmacodynamics study also revealed that the formulation would be a better choice for the treatment of scars due to the advantages of painlessness, separation ability, and high delivery efficiency. In conclusion, the SMNs containing 5-FU@ZIF-8 loaded nanocapsules could serve as a potential strategy for some skin diseases therapy with controlled and sustained drug release behavior.

Two cationic iron-based crystalline porous materials for encapsulation and sustained release of 5-fluorouracil.

Iron-based crystalline porous materials (CPMs) emerged as a new class of biodegradable and non-toxic materials of high interest for drug delivery systems (DDSs) due to their high loading capacity and controllable structures. This work constructed two kinds of Fe-CPM coordination polymers (CPM-83 and CPM-85) from typical oxo-centered trimers of the iron octahedra cluster [Fe3O(RCOO)3(TPT)] with two functional modules. The tri-topic pyridine ligand (TPT) occupied the open metal sites of the trinuclear cluster, precluding the attachment of neutralizing anions, leading to three-dimensional frameworks with a positive charge and higher stability. Moreover, the triazine ligand TPT divides the original columnar channel into small domains, improving the adsorption efficiency and maximizing the host-guest interaction. Hence, the suitable pore size and electrostatic force make the materials highly adsorption selective for the anticancer drug 5-fluorouracil (5-Fu). We show that Fe-CPM-83 and Fe-CPM-85 loaded with 5-Fu are efficient drug delivery vehicles with loading content as high as 60.5 (wt%) and 32.8 (wt%) within 2-5 h of loading time. Simultaneously, their sustained release kinetics can be up to 96 hours with a completely different pH-responsive controlled release. The released content is 77% or 85% for each complex, significantly prolonging the release process and decreasing the plasma concentration. The MTT assay was performed on mouse fibroblasts (L929) to demonstrate the satisfactory biocompatibility of the matrix. This work has momentous research significance and application value for developing novel drug-delivery materials.

Fabrication of porous carbon microspheres with numerous spherical microstructures directly from waste Camellia oleifera shells and their application in sustained-release of 5-fluorouracil

Porous carbon microspheres with numerous spherical microstructures were successfully fabricated directly from waste Camellia oleifera shells by hydrothermal carbonization combined with annealing treatment and potassium hydroxide chemical activation technique in the assistance of phloroglucinol. Numerous aromatic carbon microspheres were constructed after hydrothermal carbonization due to the structure-directing effect of phloroglucinol. The spherical microstructures remain intact after suffering from potassium hydroxide chemical activation because the aromatic carbon framework was further graphitized by annealing treatment. The mesoporous carbon microspheres were successfully obtained from microporous carbon microspheres through the secondary potassium hydroxide chemical activation. As valuable porous materials, the as-prepared microporous and mesoporous carbon microspheres were successfully applied to the sustained-release of anticancer drug 5-fluorouracil. The as-prepared microporous and mesoporous carbon microspheres showed some obvious advantages such as low-cost, high-capacity, and strong biological affinity compared with traditional drug sustained-release agent.

Fluorescence imaging enabled urethane-doped citrate-based biodegradable elastomers

The field of tissue engineering and drug delivery calls for new measurement tools, non-invasive real-time assays, and design methods for the next wave of innovations. Based on our recent progress in developing intrinsically biodegradable photoluminescent polymers (BPLPs) without conjugating organic dyes or quantum dots, in this paper, we developed a new type urethane-doped biodegradable photoluminescent polymers (UBPLPs) that could potentially serve as a new tool to respond the above call for innovations. Inherited from BPLPs, UBPLPs demonstrated strong inherent photoluminescence and excellent cytocompatibility in vitro. Crosslinked UBPLPs (CUBPLPs) showed soft, elastic, but strong mechanical properties with a tensile strength as high as 49.41 ± 6.17 MPa and a corresponding elongation at break of 334.87 ± 26.31%. Porous triphasic CUBPLP vascular scaffolds showed a burst pressure of 769.33 ± 70.88 mmHg and a suture retention strength of 1.79 ± 0.11 N. Stable but photoluminescent nanoparticles with average size of 103 nm were also obtained by nanoprecipitation. High loading efficiency (91.84%) and sustained release of 5-fluorouracil (up to 120 h) were achieved from UBPLP nanoparticles. With a quantum yield as high as 38.65%, both triphasic scaffold and nanoparticle solutions could be non-invasively detected in vivo. UBPLPs represent an innovation in fluorescent biomaterial design and may offer great potential in advancing the field of tissue engineering and drug delivery where bioimaging has gained increasing interest.

In vitro and in vivo evaluation of injectable implants for intratumoral delivery of 5-fluorouracil

The aim of this study was to evaluate poly (ε-caprolactone) (PCL)-based injectable implants, which could achieve sustained release of 5-fluorouracil (5-FU) directly to tumors. The implants were prepared by injection molding and the effects of drug loading and poly (ethylene glycol) (PEG) as additive on drug release were investigated. Two implants (PCL/5-FU25% and PCL/PEG5%/5-FU25%) were selected for in vivo evaluation regarding drug distribution in tumor, plasma concentration and antitumor effect. In vitro release test showed that drug release duration varied from 18 to 565 h depending on the compositions of the implant. After intratumoral injection, in vivo release of 5-FU from implants PCL/5-FU25% and PCL/PEG5%/5-FU25% were apparently accelerated. The maximum drug concentrations in tumor were sevenfold and ninefold higher than that attained by intraperitoneal (i.p.) administration of 5-FU solution for the implants PCL/5-FU25% and PCL/PEG5%/5-FU25%, respectively. Drug concentration in plasma was always below 0.1 μg/ml over the entire experimental period. Additionally, the two implants exhibited better tumor growth inhibition as shown by the results that their tumor volumes were approximately twofold smaller than those treated by i.p. administration after 7 days. The present study demonstrated that the injectable 5-FU-loaded implants could minimize drug systemic exposure and exert desirable antitumor activity.

Sustained release of 5-fluorouracil by incorporation into sodium carboxymethylcellulose sub-micron fibers

This work introduces a novel route to the sodium carboxymethylcellulose sub-micron fibers loaded with hydrophilic anticancer drug, 5-fluorouracil (5-Fu). The results show that 5-Fu is successfully incorporated into the biocompatible polymer, sodium carboxymethylcellulose (NaCMC)-based fibers with good stability, desired drug loading content and 100% entrapment efficiency. Furthermore, the drug release rate of the as-prepared drug-loaded fibers could be well controlled. The drug release behavior of the 5-Fu-loaded NaCMC fibers shows a diffusion mechanism, obeying Ritger–Peppas kinetics model. The drug release behavior of the as-prepared products demonstrates their promising application in drug delivery system.

Layer-by-layer assembly of poly( l-glutamic acid)/chitosan microcapsules for high loading and sustained release of 5-fluorouracil

Hollow polyelectrolyte microcapsules based on poly( l-glutamic acid) (PLGA) and chitosan (CS) with opposite charges were fabricated by layer-by-layer (LbL) assembly technique using melamine formaldehyde (MF) microparticles as sacrificial templates. The LbL assembly of polyelectrolytes and the resultant PLGA/CS microcapsules were characterized. A hydrophilic anticancer drug, 5-fluorouracil (5-FU), was chosen to investigate the loading and release properties of the microcapsules. The PLGA/CS microcapsules show high loading capacity of 5-FU under conditions of high drug concentration and salt adding. The high loading can be ascribed to spontaneous deposition of 5-FU induced by hydrogen bonding between 5-FU and PLGA/CS microcapsules. The PLGA/CS microcapsules show sustained release behavior. The release rate of 5-FU drastically slows down after loading in PLGA/CS microcapsules. The 5-FU release from PLGA/CS microcapsules can be best described using Ritger–Peppas or Baker–Londale models, indicating the diffusion mechanism of 5-FU release from the PLGA/CS microcapsules. In vitro cytotoxicity evaluation by the MTT assay shows good cell viability over the entire concentration range of PLGA/CS microcapsules. Therefore, the novel PLGA/CS microcapsules are expected to find application in drug delivery systems because of the properties of biodegradability, high loading, sustained release and cell compatibility.

Endoscopic ultrasonography-guided interstitial chemotherapy in pancreas： a pilot study in canine model

Objective To investigate the feasibility and safety of endoscopic uhrasonography （EUS） guided interstitial chemotherapy for the pancreas in canine model. Methods A therapeutic 19- gauge needle was inserted into the pancreas with EUS guidance, and seeds with sustained release of 5-fluorouracil were implanted into the tissue. After 14 days of clinical observation, the animals were sacrificed and the tissue response to local chemotherapy was examined. Results All the seeds were implanted successfully and no migration was observed. Chemotherapy induced tissue fibrous necrosis was localized in the pancreas without significant complications. The apoptotic index of tissue within 1 cm of the seeds increased. Biochemical parameters were normal in all the dogs. Conclusion EUS-guided implantation of seeds is a safe, simple and minimally invasive technique for interstitial chemotherapy in the pancreas. Key words: Pancreas ; Endoscopic ultrasonography; Chemotherapy ; Flunrouracil

Sustained release of 5-fluorouracil from polymeric nanoparticles.

The use of biodegradable nanoparticles loaded with 5-fluorouracil was investigated as a potential means to sustain the release of this drug. Nanoparticles prepared from four biodegradable polymers were loaded with 5-fluorouracil using three loading concentrations of drug and three different concentrations of added polymer. Washing particles using a centrifugation/re-suspension with ultrasound protocol was found to dislodge the majority of drug, resulting in an over-estimation of incorporation efficiency and low levels of strongly entrapped drug. Increasing the initial 5-fluorouracil concentration before polymer/monomer addition increased the drug loading in both washed and unwashed particles. Increasing the amount of polymer used to make nanoparticles did not increase loadings, but did produce increased amounts of unusable polymer waste. Drug release from nanoparticles was evaluated using a Franz cell diffusion apparatus, which showed an initial burst effect followed by a slower release phase over 24 h. Indeed, nanoparticles prepared from poly(lactide-co-glycolide) released 66% of their 5-fluorouracil payload over this period. It was concluded that 5-fluorouracil-loaded nanoparticles could be readily included into a hydrogel-based delivery system to provide sustained drug release for trans-epithelial drug-delivery applications.

Sustained release of 5-fluorouracil from ethylene acetate copolymer.

Pharmacologic inhibition of fibroblast proliferation and scar formation remains an important consideration in many ophthalmologic surgical procedures. Such inhibition is particularly important in glaucoma filtration surgery. A sustained release system for 5-fluorouracil (5-FU) using ethylene vinyl acetate copolymer (Elvax) was characterized in vitro. 5-FU was incorporated into Elvax discs of 4 mm diameter. Discs were coated to allow sustained and predictable release over a 14 day period. Alteration of coatings, which act as rate-controlling membranes, allowed variation in the pattern of 5-FU release from the core which acts as the drug reservoir. This system for the sustained release of 5-FU may prove valuable in glaucoma surgery where the suppression of cellular proliferation is desired. The non-inflammatory nature of Elvax suggests this compound may provide an alternative means of 5-FU delivery.

Antitumor effect of implanted ethylene-vinyl alcohol copolymer matrices containing anticancer agents on Ehrlich ascites carcinoma and P388 leukemia in mice.

Ethylene-vinyl alcohol (EVAI) copolymer was evaluated as a vehicle for controlled or sustained release of 5-fluorouracil (5-FU) and adriamycin. The variation of initial drug concentration and, to an even greater extent, the variation in comonomer ratio affected the drug release rate as well as the cumulative amount of the drug released. An increase in the ethylene content of the EVAI copolymer decreased drug release. It appears that EVAI copolymer can be used as a membrane for controlling the release of 5-FU or adriamycin. The antitumor activity of EVAI copolymer matrices containing these anticancer agents was evaluated against Ehrlich ascites carcinoma (EAC) in mice on the basis of changes in body weight and animal survival data. Tumor cell injections were performed on day 0 and matrix implantations on day 3, both intraperitoneally. The suppressive effect of matrices containing anticancer agents on the increase in body weight was higher than that of the free drugs. A prolongation of the life span of tumor-bearing mice following implantation of therapeutic matrices was also noted. Implantation of the EVAI copolymer matrix containing an anticancer agent was less effective against the P388 leukemia than the EAC. These results suggest that EVAI copolymer matrices containing anticancer agents may be effective in cancer chemotherapy. Matrices composed of EVAI copolymer could be useful vehicles for implanted delivery systems for anticancer agents.