Anorectal Pharmacodynamics and In Vitro Drug Release of Clerodendrum bungei Steud.Extract Gel

[Objectives]To determine the optimal preparation technology of Clerodendrum bungei Steud.extract gel by orthogonal test and gel quality test method in General Rule 0114 of Chinese Pharmacopoeia(Volume IV,2020 Edition),and to study its anorectal pharmacodynamics and drug release in vitro.[Methods]Carbomer 940,propylene glycol and absolute ethyl alcohol were selected as the main factors,and the preparation technology of C.bungei Steud.extract gel was optimized by orthogonal test.The mouse model of ulcerative hemorrhoids was established with glacial acetic acid(HAC)and compared with Ma Yinglong musk hemorrhoids ointment.The recovery of trauma was compared between the two groups.At the same time,porcine small intestine was used as semi-permeable membrane to make diffusion cell to simulate anal environment,and the drug release in vitro was studied.[Results]The C.bungei Steud.extract gel was smooth in appearance and good in stability.It could effectively treat anal ulcer in mice and release quickly in vitro.[Conclusions]The formula is reasonable,and the effect of animal experiment is remarkable,which can provide a new treatment plan for ulcerative hemorrhoids.

Development of composite PLGA microspheres containing exenatide-encapsulated lecithin nanoparticles for sustained drug release

This study aimed to prepare poly(D, L-lactic-co-glycolic acid) microspheres(PLGA-Ms)by a modified solid-in-oil-in-water(S/O/W) multi-emulsion technique in order to achieve sustained release with reduced initial burst and maintain efficient drug concentration for a prolonged period of time. Composite PLGA microspheres containing exenatideencapsulated lecithin nanoparticles(Ex-NPs-PLGA-Ms) were obtained by initial fabrication of exenatide-loaded lecithin nanoparticles(Ex-NPs) via the alcohol injection method,followed by encapsulation of Ex-NPs into PLGA microspheres. Compared to Ms prepared by the conventional water-in-oil-in-water(W/O/W) technique(Ex-PLGA-Ms), Ex-NPs-PLGAMs showed a more uniform particle size distribution, reduced initial burst release, and sustained release for over 60 d in vitro. Cytotoxicity studies showed that Ms prepared by both techniques had superior biocompatibility without causing any detectable cytotoxicity.In pharmacokinetic studies, the effective drug concentration was maintained for over 30 d following a single subcutaneous injection of two types of Ms formulation in rats, potentially prolonging the therapeutic action of Ex. In addition, administration of Ex-NPs-PLGA-Ms resulted in a more smooth plasma concentration-time profile with a higher area under the curve(AUC) compared to that of Ex-PLGA-Ms. Overall, Ex-NPs-PLGA-Ms prepared by the novel S/O/W method could be a promising sustained drug release system with reduced initial burst release and prolonged therapeutic efficacy.

Influence of Sorbitan Monooleate on Morphology and Drug Release Behavior of Emulsion Electrospinning Polycaprolactone Nanofibers

Ultrafine polycaprolactone(PCL)fibers containing watersoluble drug tetracycline hydrochloride(Tet)were prepared by emulsion electrospinning.Sorbitan monooleate(Span80)was added as an essential additive to form stable water/oil emulsions and fabricate fibers with core-sheath structure.Different concentrations of Span80(0-40 g/L)were used to investigate the stability of emulsion and size of dispersed droplets.The scanning electron microscope(SEM)images indicated that the morphology of the fibers with Span80 were beaded-free with diameters of 200-400 nm,and Span80 enhanced the spinnability of electrospinning solution.The laser scanning confocal microscope(LSCM)images indicated that Tet was well encapsulated into the core region of the PCL fibers.The transmission electron microscope(TEM)image showed the formation of core-sheath structure.The loading efficiency(LE)and entrapment efficiency(EE)of Tet were calculated and release profiles in artificial saliva buffer solution(pH=6.8)were also analyzed.The results revealed that LE and EE of fibers with Span80decreased with the increase of its concentration.Fibers with coresheath structure had a longer effective release lifetime than without Span80.The increase of Span80 resulted in higher hydrophilicity of fibers and faster release rate of Tet.

Hollow MnO_2/GNPs serving as a multiresponsive nanocarrier for controlled drug release

In this work,hollow manganese dioxide/gold nanoparticle(MnO2/GNPs)hybrid drug nanocarriers were prepared by coupling the gold nanoparticles(GNPs)with hollow structure manganese dioxide(MnO2).Among them,GNPs have been used as near-infrared(NIR)-responsive element for photothermal effect under NIR laser irradiation.The glutathione(GSH)-responsive and p H-responsive performances of drug release were derived from hollow MnO2.Particularly,Doxorubicin hydrochloride(DOX)can be loaded into hollow MnO2/GNPs with the drug loading efficiency up to 82.0%.Moreover,the photothermal effect and GSH-/pH-responsive properties of hollow MnO2/GNPs were investigated.The hollow MnO2/GNPs possessed satisfactory drug release efficiency(ca.87.4%of loaded drug released in 12 h)and have high photothermal conversion efficiency,multiresponsive properties,and degradability.Finally,the kinetics of drug release was discussed in detail.Thus,our finding highlights that the multiresponsive nanocarriers are of great potential in the field of drug controlled release.

Synthesis and Drug Release Properties of Thermosensitive Poly(N-vinylacetamide-co-vinylacetate) Hydrogels

Thermosensitive poly[N-vinylacetamide-co-vinylacetate][P（NVA-co-VAc）] hydrogels were prepared via free radical copolymerization from hydrophilic NVA and hydrophobic VAc in the presence of butylenes-bis （N-vinylacetamide）（Bis-NVA） as crosslinker. Scanning electron microscopy（SEM） images reveal that the as-prepared hydrogels were of three-dimensional network with irregular cave structure. The prepared hydrogels with more NVA in the feed swelled faster and the swelling ratio of the hydrogels gradually decreased with temperature increasing from 10 °C to 60 °C. The dynamic swelling studies indicate that the swelling process of the hydrogels was controlled by diffusion of water molecules considered as Fickian-controlled case. The adsorption amount of model drug, sodium salicylate（SS） was higher in the hydrogels containing more NVA units, whose corresponding release could reach equilibrium in about 6 h.

Fabrication and Drug Release Property of Silk Fibroin-Based Weft-Knitted Stents

This paper was to develop a weft-knitted stent coated by a drng-loaded electro-spun fibrous membrane and then investigate its morphology, mechan/cal properties and in vitro drug release property. This work was started by weft-knitting of an inner layer of such stent using polydioxanone （PDO） and silkf＇dment. Subsequently, 5-fluorouracil （5-FU） and curcnmin（CUR） loaded silk fibroin （SF） membranes were coated on the surface of the weft- knitted stent using electro-spinning technique to endow the drug delivery funct/on of the stent. The results show that the radial compression strength and c/renmferentlal expanding strength can reach above （9.1±0.4） cN/cm2 and （205.0± 0.2） cN/mm, respectively. The drug releasing behaviors can be sustained for 400 h. It is concluded that the stents have potential application as anintestinal stent in the future.

POLYCAPROLACTONE-POLY (ETHYLENE GLYCOL) BLOCK COPOLYMER Ⅲ DRUG RELEASE BEHAVIOR

The drug release behavior of degradable polymer--polycaprolactone-poly (ethyleneglycol)block copolymer(PCE) in vitro was investigated by using 5-Fluoro-uracil (5-Fu) asa model drug under a condition of pH 7. 4 at 37C. It is found that the release rate of 5-Fufrom PCE increased with increasing polyether content of the copolymer. The results showthat the increasing polyether content of the copolymer caused increasing hydrophilicity anddecreasing crystallinity of the PCE copolymer. Thus, the drug release behavior and thedegradable property of the PCE can be controlled by adjusting the composition of thecopolymer.

Microwave-assisted Polymerization of ε-Caprolactone with Maleic Acid as Initiator and Drug Release Behavior of Ibuprofen-Poly(ε-caprolactone) System

Poly(e-caprolactone) (PCL) with weight-average molar mass over 10000 g/mol was synthesized by microwave-assisted ring-opening polymerization of e-caprolactone (e-CL) with maleic acid (MA) as initiator (2.45 GHz, 360 W, 85 min). Ibuprofen-PCL controlled release system was prepared directly by the ROP of e-CL in its mixture with ibuprofen. The release of ibuprofen from the system was sustained and steady.

Development of NAMI-A-loaded PLGA-mPEG Nanoparticles:Physicochemical Characterization, in vitro Drug Release and in vivo Antitumor Efficacy

NAMI-A[imidazolium trans-tetrachloro(dimethylsulfoxide)imidazoleruthenium(Ⅲ)] shows extraordinary activities against metastatic tumors. However, the hydrolysis of NAMI-A to produce dimethyl sulfoxide(DMSO) could reduce anti-metastatic activity. To enhance the circulation time and the anti-metastatic effect of NAMI-A, NAMI-A-loaded nanoparticles were prepared by the double emulsion method and characterized by scanning electron microscopy for surface morphology, laser light scattering for size and zeta potential for surface charges. Controlled release of NAMI-A was observed in a sustained manner. Compared with free NAMI-A, NAMI-A-loaded nanoparticles exhibited superior antitumor effect by delaying tumor growth in T739 mice. PLGA-mPEG nanoparticles are promising for further studies as drug delivery carriers.

Regulation of drug release performance using mixed doxorubicin-doxorubicin dimer nanoparticles as a pH-triggered drug self-delivery system

A mixed drug self-delivery system(DSDS)with high drug content(>50%)was developed to regulate pHtriggered drug release,based on two doxorubicin(DOX)-DOX dimmers:D-DOX_(ADH) and D-DOX_(car) conjugated with acid-labile dynamic covalent bonds(hydrazone and carbamate,respectively)and stabilized with PEGylated D-DOX_(ADH)(D-DOX_(ADH)-PEG).Owing to the different stability of the dynamic covalent bonds in the two dimers and the noncovalent interaction between them,pH-triggered drug release could be easily regulated by adjusting the feeding ratios of the two DOX-DOX dimers in the mixed DSDS.Similar in vitro cellular toxicity was achieved with the mixed DSDS nanoparticles prepared with different feeding ratios.The mixed DSDS nanoparticles had a similar DOX content and diameter but different drug releasing rates.The MTT assays revealed that a high anti-tumor efficacy could be achieved with the slowrelease mixed DSDS nanoparticles.

Swelling and Drug Release Characteristics of Poly （methacrylic acid-co-poloxamer） hydrogels

Poly (methacrylic acid-co-poloxamer) hydrogel networks were synthesized byfree-radical solution polymerization, and the dynamic swelling and in vitro release properties ofmodel drugs, dextromethorphan hydrobromide (DMP) and vitamin B_(12) (VB_(12)) were studied. Thesegels exhibited pH-dependant swelling and sustained drug release properties, and the water uptakerate and drug release rate in neutral or basic media were higher than that in acidic media. Theresults showed that the water uptake followed non-Fickian or zero order process in neutral or basicmedia, and the release of model drugs from hydrogels of appropriate composition was of zero orderkinetics over a period of several hours.

Novel Gelatin-Adriamycin Sustained Drug Release System for Intravesical Therapy of Bladder Cancer

To reduce recurrence in the patients with bladder cancer after tumor removal through open surgery or transurethral resection, a form of gelatin adriamycin sustained drug release system was developed and its release kinetics both in vitro and in vivo , its efficacy in inhibiting BIU 87 bladder tumor cell growth in vitro and its safety in vivo were studied. The results showed that this system controlled adriamycin release over a period of 21 days in vitro and significantly inhibited BIU 87 cell growth. When this system was injected into rabbit bladder, it sustained adriamycin release for 12 days and the released drug could diffuse 1 cm around the injection point. No major complications were observed except minor acute nonspecific cystitis that could be tolerated well by the animals. This study suggests the possibility of applying this system locally in treating bladder cancer..

Synthesis and Characterization of a Novel pH-sensitive Complex for Drug Release

A novel pH-sensitive complex was prepared by using oxidized konjac glucomannan and 4-aminosalicylic acid （4-ASA） through glutaraldehyde as a cross-linking agent. The product was characterized by FTIR and 13C NMR spectra, and the thermogravimetric analysis was also studied. The drug release studies in vitro showed that the amount of 4-ASA released from the complex was about 4%, 56% and 17% after 12 h at pH 1.2, 6.8 and 7.4, respectively. The data demonstrate that the rate of the drug release of the complex can be more effectively controlled by pH value. The results showed that the novel pH-sensitive complex could be potentially useful for colon-targeting drug delivery system.

Tussah Silk Fibroin Porous Scaffolds Prepared with a Mild Self-assembly Process for Controlled Drug Release

Besides excellent biodegradability and biocompatibility,a useful tissue engineering scaffold should provide favorable surface properties,outstanding mechanical strength and controlled drug release property. In this paper,a mild process to prepare porous tussah silk fibroin( TSF) scaffolds from aqueous solution was described. The n-butanol was used to control the self-assembly of tussah silk. The scaffolds with different TSF concentrations and the same volume showed differences in pore size and distribution. The maximum porosity of the poprepared porous scaffolds was 80% in this paper. And the pore size of the prepared porous scaffolds with different concentrations was between 10μm and 230 μm. X-ray diffraction( XRD) analysis revealed that amorphous TSF was crystallized to β-sheet secondary structure upon gelatin. The TSF scaffolds for controlled drug release was studied and the result showed that the time of drug release was significantly longer. The produced TSF scaffolds with sustained drug release have potential application in tissue engineering.

SYNTHESIS AND DRUG RELEASE OF CROSSLINKING POLYPHOSPHATES

A new class of crosslinking polyphosphates were synthesized characterizedby IR 1HNMR, 31PNMR spectroscopy as well as elemental analysis. In vitrodegradation of the polyphosphates obtained and the release of antineoplastic drugMethotrexate (MTX) and contraceptive Levonorgestrel (LNG ) by nsing thesepolymers as matrix were studied. Zero order release rate was rkserved in the case ofLNG release.

Injectable“cocktail”hydrogel with dual-stimuli-responsive drug release,photothermal ablation,and drug-antibody synergistic effect

The combination of the first-line standard chemotherapeutic drug doxorubicin hydrochloride(DOX)and the molecular-targeted drug Herceptin(HCT)has emerged as a promising strategy for human epidermal growth receptor 2(HER-2)overexpressing breast cancer treatment.However,insufficient drug accumulation and severe cardiotoxicity are two major challenges that limit its clinical application.Herein,an in situ forming gold nanorods(AuNRs)-sodium alginate(ALG)hybrid hydrogel encapsulating DOX and HCT was engineered for tumor synergistic therapy involving injectable,dual-stimuli-responsive drug release,photothermal ablation,and drug-antibody synergistic therapy.The photothermal agent AuNRs,anticancer drug DOX,and anticancer antibody HCT were mixed in ALG solution,and after injection,the soluble ALG was quickly transformed into a hydrogel in the presence of Ca^(2+)in the body.Significantly,the hybrid hydrogel exhibits an extremely high photothermal conversion efficiency of 70%under 808 nm laser irradiation.The thermal effect can also provide photothermal stimulation to trigger the drug release from the gel matrix.In addition,the drug release rate and the releasing degree are also sensitive to the pH.In vitro studies demonstrated that the PEI-AuNR/DOX/HCT/ALG hydrogel has facilitated the therapeutic efficiency of each payload and demonstrated a strong synergistic killing effect on SK-BR-3 cells.In vivo imaging results showed that the local drug delivery system can effectively reduce the nonspecific distribution in normal tissues and increase drug concentration at tumor sites.The proposed hydrogel system shows significant clinical implications by easily introducing a sustainable photothermal therapy and a potential universal carrier for the local delivery of multiple drugs to overcome the challenges faced in HER-2 overexpressing cancer therapy.

pH-sensitive KHA/CMC-Fe^(3+)@CS hydrogel loading and the drug release properties of riboflavin

To improve drug utilization,reduce the drug administration frequency,increase the release time,and reduce the drug side effects in the human body,we prepared(KHA/CMC-Fe^(3+))@CS hydrogel spheres using green and natural potassium humate(KHA),carboxymethyl cellulose(CMC),and chitosan(CS)as raw materials and Fe3+as a crosslinking agent,and loaded them with riboflavin for drug sustainedrelease study using the drop ball method.The tests with FTIR,SEM,TG,and X-ray diffractometer showed that the coordination among KHA,CMC,and Fe^(3+)formed a three-dimensional network structure,where cs was encapsulated on the surface of the hydrogel spheres via noncovalent bonding,resulting in good thermal stability.The stability,drug loading,swelling,and in vitro release of the(KHA/CMC-Fe^(3+))@CS hydrogel spheres were investigated.The results showed that the hydrogel spheres were significantly pH-sensitive,with 11.16 g/g higher swelling in an alkaline environment(pH=7.4)than that in an acidic environment(pH=1.2).The swelling and drug release process of the hydrogel spheres were analyzed using mathematical models,concluding that the hydrogel swelling follows Schott second-order swelling kinetics,and the drug release mechanism was Fickian delivery mode.

Yeast-Controlled Double-Shelled CacO_(3)/CaF_(2)Hollow Nanospheres with Hierarchically Porous for Sustained pH-Sensitive Drug Release

Hierarchically porous materials(HP materials)are believed one of the most hopeful matrix materials because of their distinctive multimodal pore structures and tremendous application potentials in the field of biomedicine.However,green and facile synthesis of hierarchically porous nanomaterials with beneficial water dispersibility and biocompatibility is still a great challenge.Herein,a novel biomimetic strategy is proposed to prepare the cell-tailored double-shelled HPCaCO_(3)/CaF_(2) hollow nanospheres under the mediation of yeast cells.The biomolecules derived from the secretion of yeast cells are used as conditioning and stabilizing agents to control the biosynthesis of the HPCaCO_(3)/CaF_(2) materials,which exhibit excellent water dispersibility and favorable biocompatibility.The double-shelled CaCO_(3)/CaF_(2) nanospheres hold hierarchically porous structure and have abundant pore channel and large specific surface area,showing high drug-loading and a prolonged drug sustainable release profile by the pore-by-pore diffusion pattern of the hierarchical pores.Otherwise,the HPCaCO_(3) with pH-sensitivity could controllably release drug doxorubicin hydrochloride(DOX)at the acidic tumor microenvironment.Both in vitro and in vivo results demonstrate that HPCaCO_(3)/CaF_(2) has the sustainable pH-sensitive drug release property,showing an enhanced therapeutic effect.Summarily,this study provides a biomimetic strategy to synthesize the hierarchically porous double-shelled hollow nanomaterials for applying in sustainable drug delivery system.

Phase-change composite filled natural nanotubes in hydrogel promote wound healing under photothermally triggered drug release

It is of great importance to treat a bacterial-infected wound by a smart dressing capable of delivering antibiotics in a smart manner without causing drug resistance.The construction of smart release nanocontainers responsive to near-infrared(NIR)laser irradiation in an on-demand and stepwise way is a promising strategy for avoiding the emergence of multidrug-resistant bacteria.Here,we develop a hydrogel composite made of alginate and nanotubes with an efficient NIR-triggered release of rifampicin and outstanding antibacterial ability.This composite hydrogel is prepared through co-encapsulating antibacterial drug(rifampicin),NIR-absorbing dye(indocyanine green),and phase-change materials(a eutectic mixture of fatty acids)into halloysite nanotubes,followed by incorporation into alginate hydrogels,allowing the in-situ gelation at room temperature and maintaining the integrity of drug-loaded nanotubes.Among them,the eutectic mixture with a melting point of 39℃ serves as the biocompatible phase-change material to facilitate the NIR-triggered drug release.The resultant phase-change material gated-nanotubes exhibit a prominent photothermal efficiency with multistep drug release under laser irradiation.In an in vitro assay,composite hydrogel provides good antibacterial potency against Staphylococcus aureus,one of the most prevalent microorganisms of dangerous gas gangrene.A bacterial-infected rat full-thickness wound model demonstrates that the NIR-responsive composite hydrogel inhibits the bacteria colonization and suppresses the inflammatory response caused by bacteria,promoting angiogenesis and collagen deposition to accelerate wound regeneration.The NIR-responsive composite hydrogel has a great po-tential as an antibacterial wound dressing functionalized with controlled multistep treatment of the infected sites.

Size-transformable nanoparticles with sequentially triggered drug release and enhanced penetration for anticancer therapy

There are several limitations to the application of nanoparticles in the treatment of cancer,including their low drug loading,poor colloidal stability,insufficient tumor penetration,and uncontrolled release of the drug.Herein,gelatin/laponite(LP)/doxorubicin(GLD)nanoparticles are developed by crosslinking LP with gelatin for doxorubicin delivery.GLD shows high doxorubicin encapsulation efficacy(99%)and strong colloidal stability,as seen from the unchanged size over the past 21 days and reduced protein absorption by 48-fold compared with unmodified laponite/doxorubicin nanoparticles.When gelatin from 115 nm GLD reaches the tumor site,matrix metallopeptidase-2(MMP-2)from the tumor environment breaks it down to release smaller 40 nm LP nanoparticles for effective tumor cell endocytosis.As demonstrated by superior penetration in both in vitro three-dimensional(3D)tumor spheroids(138-fold increase compared to the free drug)and in vivo tumor models.The intracellular low pH and MMP-2 further cause doxorubicin release after endocytosis by tumor cells,leading to a higher inhibitory potential against cancer cells.The improved anticancer effectiveness and strong in vivo biocompatibility of GLD have been confirmed using a mouse tumor-bearing model.MMP-2/pH sequentially triggered anticancer drug delivery is made possible by the logical design of tumor-penetrating GLD,offering a useful method for anticancer therapy.