Advances and Applications of Metal-Organic Framework Nanomaterials as Oral Delivery Carriers: A Review.

Oral administration is a commonly used, safe, and patient-compliant method of drug delivery. However, due to the multiple absorption barriers in the gastrointestinal tract (GIT), the oral bioavailability of many drugs is low, resulting in a limited range of applications for oral drug delivery. Nanodrug delivery systems have unique advantages in overcoming the multiple barriers to oral absorption and improving the oral bioavailability of encapsulated drugs. Metal-organic frameworks (MOFs) are composed of metal ions and organic linkers assembled by coordination chemistry. Unlike other nanomaterials, nanoscale metal-organic frameworks (nano-MOFs, NMOFs) are increasingly popular for drug delivery systems (DDSs) due to their tunable pore size and easily modified surfaces. This paper summarizes the literature on MOFs in pharmaceutics included in SCI for the past ten years. Then, the GIT structure and oral drug delivery systems are reviewed, and the advantages, challenges, and solution strategies possessed by oral drug delivery systems are discussed. Importantly, two major classes of MOFs suitable for oral drug delivery systems are summarized, and various representative MOFs as oral drug carriers are evaluated in the context of oral drug delivery systems. Finally, the challenges faced by DDSs in the development of MOFs, such as biostability, biosafety, and toxicity, are examined.

Preparation and pharmacokinetics of glycyrrhetinic acid and cell transmembrane peptides modified with liposomes for liver targeted-delivery.

The article presents a hepatocellular carcinoma cell surface-specific ligand glycyrrhetinic acid (GA) and cell-penetrating peptide (TAT) with good cell membrane penetration to modify the anti-tumor drug pingyangmycin (PYM) liver delivery system, which achieve targeted delivery of drugs and improve anti-tumor efficiency. In this study, we synthesized the pingyangmycin liposome modified by glycyrrhetinic acid and cell penetrating peptide(GA-TAT-PYM-L) and evaluated the anti-tumor effect of GA-TAT-PYM-Lin vitro. Using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenylte-trazolium bromidecell proliferation method, GA-TAT-PYM-L had a stronger inhibitory effect on HepG2 cells than the free drug PYM at the same concentration. Acridine orange-ethidium bromide staining assays showed that GA-TAT-PYM-L had stronger apoptosis promotion effects on HepG2 cells in comparison to PYM. Pharmacokinetic studies indicated that, compared with PYM, GA-TAT-PYM-L enhanced mean residence time (MRT0-∞) and area under curve (AUC0-∞) by about 2.79-fold and 2.45-fold. TheT1/2was prolonged to 140.23 ± 14.13 min. Tissue distribution results showed that the PYM concentrations in livers from the GA-TAT-PYM-L group were always higher than other tissues at each monitoring period after 5 min, indicating that GA-TAT-PYM-L can achieve liver targeting.

An insight into the in vivo imaging potential of curcumin analogues as fluorescence probes.

Curcumin and its derivatives have good electrical and optical properties due to the highly symmetric structure of delocalized π electrons. Apart from that, curcumin and its derivatives can interact with numerous molecular targets, thereby exerting less side effects on human body. The fluorescence emission wavelength and fluorescence intensity of curcumin can be enhanced by modifying its π-conjugated system and ß-diketone structure. Some curcumin-based fluorescent probes have been utilized to detect soluble/insoluble amyloid-ß protein, intracranial reactive oxygen species, cysteine, cancer cells, etc. Based on the binding characteristics of curcumin-based fluorescent probes with various target molecules, the factors affecting the fluorescence intensity and emission wavelength of the probes are analyzed, in order to obtain a curcumin probe with higher sensitivity and selectivity. Such an approach will be greatly applicable to in vivo fluorescence imaging.

Fabrication and Characterization of Taurine Functionalized Graphene Oxide with 5-Fluorouracil as Anticancer Drug Delivery Systems.

Recently, nanocarrier systems for cancer drugs, especially GO-based drug delivery systems, have become a boon for cancer patients. In this study, we choose Tau to functionalize the GO surface to improve its biocompatibility. Firstly, nano-scale GO was synthesized by the modified Hummer's method and ultrasonic stripping method. The taurine-modified graphene oxide carrier (Tau-GO) was synthesized by chemical method to obtain Tau-GO that has a good dispersibility and stability in water, with a zeta potential of - 38.8 mV and a particle size of 242 nm. Based on the encapsulation efficiency evaluation criteria, the optimal formulation was determined to combine Tau-GO and 5-FU by non-covalent bonding. The 5-FU-Tau-GO was more stable in neutral environment than in acidic environment, and with a certain PH response and sustained release effect. In vivo, we compared oral and intravenous administrations of 5-FU and 5-FU-Tau-GO, respectively, using pharmacokinetic tests and related parameters and showed that 5-FU-Tau-GO oral or intravenous administration prolongs the action time of 5-FU in the body and improves its bioavailability. In addition, the inhibition of HepG2 cells that was measured by the MTT assay, showed that the IC50 value of 5-FU was 196 ± 8.73 µg/mL, and the IC50 value of 5-FU-Tau-GO was 65.2 ± 0.7 µg/mL, indicating that 5- FU-Tau-GO is more potent against HepG2 cells and has a stronger inhibitory effect on cancer cells. The effect on cell morphology that was measured using the AO/EB staining also showed that 5-FU-Tau-GO not only disrupted cells, but also significantly induced apoptosis compared to 5-FU. We also verified by computer aided design that Tau-GO can bind better to 5-FU than to the unmodified GO, and that the formed 5-FU-Tau-GO system is more stable, and conducive to the transfer and release of 5-FU in vivo.

A pH-sensitive and sustained-release oral drug delivery system: the synthesis, characterization, adsorption and release of the xanthan gum-graft-poly(acrylic acid)/GO-DCFP composite hydrogel.

In this study, graphene oxide (GO) was successfully prepared using the improved Hummers method, and the prepared GO powder was dissolved in distilled water and subjected to ultrasonic stripping. Diclofenac potassium (DCFP) was selected as a model drug to systematically evaluate the adsorption mechanism of DCFP by GO. Different reaction models were constructed to fit the adsorption kinetics and adsorption isotherms of DCFP on GO, in order to further explore the underlying adsorption mechanism. The results demonstrated that the pseudo-second-order kinetic model and Freundlich model could better delineate the adsorption process of DCFP by GO. Both π-π stacking and hydrophobic interaction were mainly involved in the adsorption process, and there were electrostatic interaction and hydrogen bonding at the same time. Then, the xanthan gum-graft-poly(acrylic acid)/GO (XG-g-PAA/GO) composite hydrogel was synthesized by in situ polymerization as a slow-release drug carrier. For this reason, a XG-g-PAA/GO-DCFP composite hydrogel was synthesized, and its in vitro drug release and pharmacokinetic data were assessed. The results showed that the synthesized XG-g-PAA/GO composite hydrogel had a certain mechanical strength and uniform color, indicating that GO is evenly distributed in this composite hydrogel. Moreover, the results of a swelling ratio test demonstrated that the swelling ratios of the XG-g-PAA/GO composite hydrogel were significantly increased with increasing pH values, implying that this material is sensitive to pH. The in vitro drug release experiment showed that the cumulative release of DCFP after 96 h was significantly higher in artificial intestinal fluid than in artificial gastric fluid. These findings indicate that the XG-g-PAA/GO-DCFP composite hydrogel exhibits pH sensitivity under physiological conditions. Besides, the results of in vivo pharmacokinetic analysis revealed that the t 1/2 of DCFP group was 2.03 ± 0.35 h, while that of the XG-g-PAA/GO-DCFP composite hydrogel group was 10.71 ± 2.04 h, indicating that the synthesized hydrogel could effectively prolong the drug action time. Furthermore, the AUC(0-t) of the DCFP group was 53.99 ± 3.18 mg L-1 h-1, while that of the XG-g-PAA/GO-DCFP composite hydrogel group was 116.79 ± 14.72 mg L-1 h-1, suggesting that the bioavailability of DCFP is greatly enhanced by this composite hydrogel. In conclusion, this study highlights that the XG-g-PAA/GO-DCFP composite hydrogel can be applied as a sustained-release drug carrier.

Glycyrrhetinic acid modified MOFs for the treatment of liver cancer.

Liver cancer remains a major cause of cancer-related death across the globe. Nano medicines have emerged as promising candidates to improve liver cancer chemotherapy. In this study, a glycyrrhetinic acid (GA) modified metal-organic framework-based drug delivery system (GA-MOFs) was developed to enhance the liver targeting ability of 5-FU. The physicochemical properties of GA-MOFs regarding particle size, size distribution and morphology were evaluated. The results showed that the obtained 5-FU@GA-MOFs had an octahedral structure, a uniform particle size distribution, and a diameter of ∼200 nm. In vitro release experiments demonstrated that 5-FU@GA-MOFs exhibited a pH-dependent release pattern. MTT assays indicated that 5-FU-loaded GA-MOFs showed greater cytotoxicity towards HepG2 cells when compared to 5-FU alone at the same dose. In vivo tissue distribution demonstrated that the 5-FU@GA-MOFs significantly increased the accumulation of 5-FU in the liver. In vivo imaging analysis further manifested the liver targeting ability of GA-MOFs. Taken together, these results suggested that GA-modified MOFs showed promising potential as liver-targeting nanocarriers for the delivery of anti-tumor drugs.

Chitosan modified metal-organic frameworks as a promising carrier for oral drug delivery.

Metal-organic frameworks (MOFs) are composed of both organic linkers and metallic ions, which have emerged as excellent drug delivery agents for the treatment of cancer and other diseases. Currently, MOF studies are mainly focused on intravenous administration, while studies dedicated to oral administration are relatively scarce. In this study, five MOFs, namely UiO-66, UiO-66-NH2, UiO-66-COOH, UiO-67 and Zr-NDC, were synthesized, of which Zr-NDC had the largest drug loading capacity for 5-FU. Next, a chitosan (CS) modified Zr-NDC was developed to provide a strong impetus for the oral administration of 5-FU. In vitro release experiments of fluorescein isothiocyanate (FITC)-labeled chitosan demonstrated that the cumulative release rates of FITC-labeled chitosan in artificial gastric juice and artificial intestinal fluid were about 20% and 90%, respectively. The in vitro drug release profiles showed that under the protection of CS-MOF, the release of 5-FU into an acidic environment was only 20%, but the release in artificial intestinal fluid reached 70%. Pharmacokinetic analysis revealed that the coating of chitosan on the surface of MOFs exerted a controlled drug release effect, and further improved the oral bioavailability of 5-FU. These findings suggest that CS coating can break through the limitation of MOF intolerance to acid. It is expected that CS-MOF@5-FU can serve as a potential drug delivery system for the oral administration of 5-FU.

Spectroscopic investigation of the anticancer alkaloid piperlongumine binding to human serum albumin from the viewpoint of drug delivery.

Piperlongumine (PL) is a very promising natural agent with a high potential for cancer treatment. To overcome the poor water solubility of PL, there is a need to develop a novel water-soluble formulation in which PL is non-covalently bound to human serum albumin (HSA). PL binding to HSA was studied by various spectroscopic techniques under simulated physiological conditions. Spectroscopic evidence showed that the interaction of PL with HSA could form a PL-HSA complex. The binding constant (Ka ) values increased with increasing temperature, and a similar dependence was observed for the number of binding sites (n) values. The number of PL molecules bound to HSA reached 8.1 when the temperature was raised to 308 K. Thermodynamic calculation results suggested that the binding reaction occurred spontaneously but was an entropy-driven process, and hydrophobic forces played a major role in stabilizing the complex. Furthermore, PL binding induced conformational and microenvironmental changes in HSA. Displacement studies indicated that PL and warfarin had separate binding regions in site I. Therefore, it would be possible to develop a novel water-soluble formulation involving PL and HSA. This study may provide some valuable information in terms of improving the poor water solubility of PL.

The increased binding affinity of curcumin with human serum albumin in the presence of rutin and baicalin: A potential for drug delivery system.

The impacts of rutin and baicalin on the interaction of curcumin (CU) with human serum albumin (HSA) were investigated by fluorescence and circular dichroism (CD) spectroscopies under imitated physiological conditions. The results showed that the fluorescence quenching of HSA by CU was a simultaneous static and dynamic quenching process, irrespective of the presence or absence of flavonoids. The binding constants between CU and HSA in the absence and presence of rutin and baicalin were 2.268×10(5)M(-1), 3.062×10(5)M(-1), and 3.271×10(5)M(-1), indicating that the binding affinity was increased in the case of two flavonoids. Furthermore, the binding distance determined according to Förster's theory was decreased in the presence of flavonoids. Combined with the fact that flavonoids and CU have the same binding site (site I), it can be concluded that they may simultaneously bind in different regions in site I, and formed a ternary complex of flavonoid-HSA-CU. Meanwhile, the results of fluorescence quenching, CD and three-dimensional fluorescence spectra revealed that flavonoids further strengthened the microenvironmental and conformational changes of HSA induced by CU binding. Therefore, it is possible to develop a novel complex involving CU, flavonoid and HSA for CU delivery. The work may provide some valuable information in terms of improving the poor bioavailabiliy of CU.

Multi-spectroscopic methods investigation on the interaction of tenoxicam with DNA.

Non-steroidal anti-inflammatory drugs (NSAIDs) show chemopreventive and chemosuppressive effects on various cancer cell lines. They exert anticancer activities by inhibiting both at the protein level and/or at the transcription level. Thus, in this paper, the interaction between tenoxicam (TXM) and calf thymus DNA (ct-DNA) was investigated by UV-visible light, fluorescence, viscosity experiments and DNA melting studies. The results showed that TXM could bind to ct-DNA in the groove binding mode. The binding constants were 7.67 × 10(3) and 5.48 × 10(3) M(-1) at 293 and 300 K, respectively. Furthermore, the calculated thermodynamic parameters suggested that hydrogen bonds or van der Waals force might play an important role in the binding of TXM to ct-DNA. The obtained results should give new insight into the pharmacological activity of TXM.

Protein damage and reactive oxygen species generation induced by the synergistic effects of ultrasound and methylene blue.

The sonodynamic damage to protein in the presence of methylene blue (MB) and the various influencing factors including ultrasonic irradiation time and MB concentration on the damage of protein were studied by fluorescence and absorption spectra. In addition, the mechanisms of the synergistic effects of ultrasound and MB were studied by oxidation-extraction photometry with several reactive oxygen species (ROS) scavengers. The results indicated that the damage of protein induced by the synergistic effects of ultrasound and MB were more serious than those that ultrasound or MB alone was applied. The damage of protein could be mainly due to the generation of ROS. The damage degree of protein increased with the increase of ultrasonic irradiation time and MB concentration because of the increased quantities of ROS generation. Both (1)O2 and ·OH were the important mediators of the ultrasound-inducing protein damage in the presence of MB.

Synthesis of three rimantadine schiff bases and their biological effects on serum albumin.

Three new rimantadine Schiff bases (RSBs) were prepared, and then the interaction of RSBs with bovine serum albumin (BSA) was investigated using fluorescence, synchronous fluorescence, UV-vis absorption spectroscopy under physiological conditions. The results showed that the three RSBs effectively quenched the intrinsic fluorescence of BSA via static quenching. Binding constant (K a), number of binding sites (n), and the binding distance (r) between three RSBs and BSA were calculated by Stern-Volmer equation and Förster's theory in this study. According to the results of displacement experiments of site probes, it was considered that the binding sites were located in hydrophobic cavities in sub-domains IIA of BSA. What is more, synchronous fluorescence studies indicated that the hydrophobicity around tryptophan residues was increased with the addition of rimantadine-o-vanillin (ROV) and rimantadine-4-methoxy-salicylaldehyde (RMS), while there was no apparent change with the addition of rimantadine-salicylaldehyde (RS).

Synthesis and antiproliferative effect of novel curcumin analogues.

Novel curcumin analogues with α,ß-unsaturated ketone moiety and/or α,ß-saturated ketone structure were synthesized from curcumin via alkylation at the central carbon and the phenolic hydroxy groups, and hydrogenation of α,ß-unsaturated ketone moiety. The antiproliferative activities were tested in five human solid tumor cell lines in vitro. Most of the compounds exhibited increased antiproliferative activities comparing with that of curcumin. Structure-activity relationship (SAR) analysis revealed that the α,ß-unsaturated ketone structure was not required for antiproliferative activity of these curcumin analogues. Among these compounds, 1,7-bis(3-methoxy-4-(3-(4-methylpiperazinyl-1-yl)propoxy)phenyl)-4,4-dibenzylheptane-3,5-dione (16f) was the most effective one with IC50 value below 1 µM, which was 9- to 81-fold more potent than curcumin.

The influence of ultrasound on the fluoroquinolones antibacterial activity.

In this work, the antibacterial effect of fluoroquinolones (FQs) upon Escherichia coli (E.coli) was measured with and without application of 40 kHz ultrasound (US) stimulation. The research results demonstrated that simultaneous application of 40 kHz US apparently enhanced the antibacterial effectiveness of FQs. That is, the synergistic effect was observed and the bacterial viability was reduced when FQs and US were combined. In addition, various influencing factors, such as FQs drug concentration, US irradiation time and solution temperature, on the inhibition of E.coli were also investigated. The antibacterial activity was enhanced apparently with increasing of FQs drug concentration, US irradiation time and solution temperature. Furthermore, we discussed preliminarily the mechanism of US enhanced antibacterial activity. Results show that US can activate FQs to produce reactive oxygen species (ROS) indeed, which are mainly determined as superoxide radical anion (·O(2)(-)) and hydroxyl radical (·OH).

Spectroscopic investigation on protein damage by ciprofloxacin under ultrasonic irradiation.

In recent years, sonodynamic activities of many drugs have attracted more and more attention of researchers. The correlative study will promote the development of sonodynamic therapy (SDT) in anti-tumor treatment. In this work, bovine serum albumin (BSA) was used as a protein model to investigate the intensifying effects of ciprofloxacin (CPFX) ultrasonically induced protein damage by UV-vis and fluorescence spectra. Meanwhile, the conformation of BSA is changed upon the addition of CPFX and metal ions under ultrasound (US) so that the damaging site of BSA is considered. Various influencing factors, such as US irradiation time, metal ions, solution temperature and ionic strength, on the ultrasonically induced BSA damage are discussed. It was showed that CPFX could enhance ultrasonically induced BSA damage. The damage degree of BSA was aggravated with the increasing of US irradiation time, solution temperature, ionic strength as well as the addition of metal ions. Furthermore, the reactive oxygen species (ROS) in reaction system were detected by oxidation-extraction photometry (OEP). Experimental results also showed that US could activate CPFX to produce ROS, which were mainly determined as superoxide radical anion (.O2-) and hydroxyl radical (.OH).

Synthesis and characterization of polymer eight-coordinate (enH2)[YIII(pdta)(H2O)](2)·10H2O as well as the interaction of [YIII(pdta)(H2O)]2(2-) with BSA.

The eight-coordinate (enH2)[YIII(pdta)(H2O)](2)·10H2O (en=ethylenediamine and H4pdta=1,3-propylenediamine-N,N,N',N'-tetraacetic acid) was synthesized, meanwhile its molecular and crystal structures were determined by single-crystal X-ray diffraction technology. The interaction between [Y(III)(pdta)(H2O)]2(2-) and bovine serum albumin (BSA) was investigated by UV-vis and fluorescence spectra. The results indicate that [YIII(pdta)(H2O)]2(2-) quenched effectively the intrinsic fluorescence of BSA via a static quenching process with the binding constant (Ka) of the order of 10(4). Meanwhile, the binding and damaging sites to BSA molecules were also estimated by synchronous fluorescence. Results indicate that the hydrophobic environments around Trp and Tyr residues were all slightly changed. The thermodynamic parameters (ΔG=-25.20 kJ mol(-1), ΔH=-26.57 kJ mol(-1) and ΔS=-4.58 J mol(-1) K(-1)) showed that the reaction was spontaneous and exothermic. What is more, both ΔH and ΔS were negative values indicated that hydrogen bond and Van der Waals forces were the predominant intermolecular forces between [YIII(pdta)(H2O)]2(2-) and BSA.

Spectrometric studies on the sonodynamic damage of protein in the presence of levofloxacin.

Taking bovine serum albumin (BSA) as typical molecules, the sonodynamic damage of protein in the presence of Levofloxacin (LVFX) and its mechanism were studied by fluorescence and UV-vis spectra. Various influencing factors such as ultrasonic irradiation time, pH value, ionic strength and solution temperature on the damage of BSA were also discussed. The results showed that ultrasound can enhance the damage of LVFX on BSA. The damage degree of BSA was aggravated with the increase of ultrasonic irradiation time, solution temperature and ionic strength, whereas decreased with the increase of solution pH value. Furthermore, the reactive oxygen species (ROS) in reaction system were studied by oxidation and extraction photometry. Experimental results showed that the amounts of superoxide anion radical (·O(2)(-)) and hydroxyl radical (·OH) were significantly more than that of singlet oxygen ((1)O(2)) in the presence of LVFX under ultrasonic irradiation.