藥物傳輸中的有序介孔材料-

1、ReviewOrdered mesoporous materials for drug deliveryShaobin WangDepartment of Chemical Engineering,Curtin University of Technology,GPO Box U1987,Perth,WA 6845,Australiaa r t i c l e i n f o Article history:Received 16February 2007Received in revised form 2July 2008Accepted 3July 2008Available online

2、 9July 2008Keywords:Mesoporous materials Drug deliveryStimuli-responsive controlled-release Kineticsa b s t r a c tIn recent years,mesoporous materials,which have unique pore size,higher surface area and pore volume,have been widely employed as carriers for controlled drug delivery.Compared with amo

3、rphous colloidal and porous silica,mesoporous silicas exhibit higher loading of drugs and provide a controlled drug release if modied by functionalisation.In this paper,we review the research work in this area discussing the textural and structural properties of several mesoporous materials such as

4、M41S,SBA,MSU,and HMS in drug loading and release prole.The inuence of functionalisation of mesoporous materials by organ-ics is also discussed.Two systems of drug delivery mechanism,sustained release and stimuli-responsive controlled-release,are compared and drug release kinetics is described.Bioact

5、ivity of various mesopor-ous solids is also presented.2008Elsevier Inc.All rights reserved.Contents 1.Introduction .12.Drug/mesoporous-silica systems for sustained release of various drugs .22.1.M41S based mesoporous materials .22.2.SBA-based mesoporous materials.32.3.HMS-based mesoporous materials.

6、42.4.MSU-based and other mesoporous materials .43.Drug release profile and the kinetics .43.1.Effect of factors influencing the drug release .43.2.Kinetics of drug release.54.Stimuli-responsive control release system.65.Biocompatibility of mesoporous silica/drug system.76.Summary and perspectives .8

7、References .(91.IntroductionOver the past three decades,there has been rapid growth in the area of drug delivery,in searching of new drug delivery systems (NDDS.Both natural and synthetic materials have been tested and proposed as components of NDDS and many efforts have been made to synthesise mate

8、rials with the biological,technological,and mechanical properties ad hoc”for each application in drug delivery 1.In recent years,many types of materials including inorganic silica,carbon materials and layered double hydroxides 24as well as polymeric 57matrix have been employed as substrates for drug

9、 delivery.Amorphous colloidal and porous silicahas been proposed as a drug delivery system on the basis of silica-embedding and biocompatibility 8.In silica-based systems,drugs are known to be adsorbed on commercially available silica.How-ever,direct mixture of both silica sol and the drug results o

10、ften in heterogeneous dispersion of drug through the gel,which can af-fect the release rate of the drug between different samples 9.Controlled drug delivery systems can achieve precisely spatial and temporal delivery of therapeutic agents to the target site.Gen-erally,the controlled drug delivery sy

11、stems can maintain the con-centration of drugs in the precise sites of the body within the optimum range and under the toxicity threshold,which improve the therapeutic efcacy and reduce toxicity.In the past years,con-trolled drug delivery has been developed in polymer-based system and also novel ino

12、rganic materials-based systems 10.1387-1811/$-see front matter 2008Elsevier Inc.All rights reserved.doi:10.1016/j.micromeso.2008.07.002E-mail address:S.auMicroporous and Mesoporous Materials 117(2009 19Contents lists available at ScienceDirectMicroporous and Mesoporous Materials

13、journal homepage:www.elsevi e r.c o m /l o c a t e /m i c r o m e s oFor a controlled-release drug delivery system biodegradability and biocompatibility are the fundamental requirements11.Stud-ies reported in recent years have shown that some crosslinked chitosan microspheres are cytotoxic and may i

14、mpair the biocom-patibility of crosslinked materials.Owing to high chemical and thermal stabilities,large surface areas and good compatibilities with other materials,porous silica has also found wide application in adsorption,enzyme immobilisation and drug delivery.The new developed solgel technolog

15、y offers the possibilities for incorpo-rating biologically active agents within silica gel and for controlling their release kinetics from the gel matrix12.Since the discovery of ordered mesoporous silica materials in 1990s,synthesis and applications of mesoporous solids have re-ceived intensive att

16、ention due to their highly ordered structures, larger pore size,and high surface area.In the past decade,meso-porous materials have found a lot of applications in separation, catalysis,sensors and devices13,14.Due to stable mesoporous structure and well-dened surface properties,mesoporous materi-als

17、 seem ideal for encapsulation of pharmaceutical drug,proteins and other biogenic molecules.In recent years,employing mesopor-ous materials for hosting and further delivering of a variety of mol-ecules of pharmaceutical interest has been appeared15,16.It has been shown that both small and large molec

18、ular drugs can be en-trapped within the mesopores by an impregnation process and lib-erated via a diffusion-controlled mechanism.Table1presents the porous structure of some mesoporous materials,which have been employed for drug delivery.Since the report by Vallet-Regi et al.in2001using MCM-41as a ne

19、w drug delivery system2,a lot of investigations have been done in this area,developing different types of mesoporous mate-rials with varying porous structure and functionality for sustained drug released and stimuli-responsive release.Here,we review the progress of this novel application of mesoporo

20、us materials as car-riers for various drug delivery,comparing the different behaviour of drug/mesoporous-solid systems.We concentrate on the impor-tant factors inuencing the drug loading and release mode as well as the release kinetics.We also discuss the biocompatibility of the drug systems and the

21、ir emerging application for tissue engineering.2.Drug/mesoporous-silica systems for sustained release of various drugsThe denition of drug delivery system can be of a system that is capable of releasing a carried bioactive agent in a specic location at a specic rate.The main aim of this type of syst

22、em is to facilitate the dosage and duration of the drug effect,the minimal harm to the patient and improving human health,since they allow for the reduction of the dosage frequency18.MCM-41as one of the importantly synthesised mesoporous materials,M41S19,has beenrstly employed as drug delivery matri

23、x.MCM-41shows hexagonal arrays of cylindrical mesopores.The structure of the wall of the pores consists of a disordered net-work of siloxane bridges and free silanol groups that could act as reacting nuclei against appropriate guest chemical species,behav-ing as a matrix for controlled adsorption an

24、d liberation of organic molecules.Other groups of mesoporous materials with larger pore size such as SBA including SBA-15,SBA-16,SBA-1,SBA-3,HMS,and MSU were also used for drug delivery.In those new drug/mesopor-ous-solid systems,ibuprofen,an anti-inammatory agent,is the widely tested drug,other dru

25、gs are also employed.Table2summa-rised the results of mesoporous-solid/drug systems and the differ-ent types of mesoporous materials in drug delievery are discussed in the following sections.2.1.M41S based mesoporous materialsTherst investigation using Si-MCM-41for drug delivery sys-tem was reported

26、 by Vallet-Regi and her colleagues2.In the pre-liminary work,two kinds of MCM-41with different pore sizes were tested.The drug employed is ibuprofen.The drug release plots showed a different behaviour depending on the method for charging the drug in the material but not the pore size.In this study,t

27、he in vitro tests were performed under static conditionsTable2Comparison of various mesoporous solid-drug systemsMesoporoussolidSBET(m2/gPorediameter(Drug Loading(wt%ReferenceMCM-41115736Ibuprofen342AlSi-MCM41112443Diunisal8.71AlSi-MCM41112443Naproxen7.31AlSi-MCM41112443Ibuprofen 6.41AlSi-MCM4111244

28、3Ibuprofen Nasalt6.91Si-MCM41121027.9Captopril32.521Si-MCM41-A115725Ibuprofen 2.924Si-MCM41-A102435.9Aspirin 3.8825Si-SBA-1578761Gentamicin20.027Si-SBA-1578788Erythromycin3429Si-SBA-15-C8T55982Erythromycin1329Si-SBA-15-C18ACE7154Erythromycin1529Si-SBA-1560286Ibuprofen14.630Si-SBA-15-APTMS-O57186Ibup

29、rofen16.930Si-SBA-15-APTMS-P47378Ibuprofen20.630Si-SBA-1560286Bovine serumalbumin9.930Si-SBA-15-APTMS-O57186Bovine serumalbumin28.530Si-SBA-15-APTMS-P47378Bovine serumalbumin1.130Si-SBA-1578749Amoxicillin2428 HMS1152Ibuprofen35.933 MCM-41121026.7Ibuprofen74.433 HMS124427.1Ibuprofen96.937 HMS-N-TES10

30、8325.2Ibuprofen76.837 HMS-NN-TES103624.6Ibuprofen74.237 HMS-NNN-TES99024.7Ibuprofen70.937Si-MSU120042Pentapeptide38 MCM-41120033Ibuprofen4131SBA-3100026Ibuprofen3331SBA-1100018Ibuprofen2531SBA-1649085ZnNIA14.332SBA-1649085ZnPCB18.332 MCM-48116636Ibuprofen28.722LP-Ia3d85757Ibuprofen20.122 MCM-4811663

31、6Erythromycin28.022LP-Ia3d85757Erythromycin28.022Table1Porous structure of mesoporous materials16,17Mesoporous solid SpacegroupPore diameter(nmStructureMCM-41P6mm25Hexagonal1D channel MCM-48Ia3d25Bicontinuous3DSBA-15P6mm510Hexagonal1D channelSBA-16Im3m Min16;max49Body centre arrangement of cagesSBA-

32、1Pm3n24Cubic3DSBA-3P6mm242D hexagonalMSU P6mm252D hexagonalHMS P6mm25Hexagonal2S.Wang/Microporous and Mesoporous Materials117(200919(without stirring the solution while the release was taking place and hence diffusion limitations at the external surface of the parti-cles might have overshadowed the

33、inuence of the pore size.Later on,they conducted another investigation focusing on the inuence of pore size of MCM-41materials on drug delivery rate.This study revealed that the delivery rate of ibuprofen in a simulating body uid(SBFsolution decreased as the pore size decreased in the range of2.53.6

34、nm20.Cavallaro et al.1investigated mesoporous silicate as devices for drug delivery.Four anti-inammatory agents such as diunisal, naproxen,ibuprofen and its sodium salt have been used.Drug release studies were also performed at pH1.1and6.8mimicking gastrointestinaluids.Release data suggest that the

35、matrix impregnated with diunisal offers good potential as a system for the modied drug release.Qu et al.21recently studied a water-soluble drug captopril with mesoporous MCM-41system.The drug-loading amount is correlated to the BrunauerEmmettTeller(BETsurface area and surface hydrophilicity and hydr

36、ophobicity of the mesoporous silica material,while drug release proles could be controlled by tailor-ing the surface properties and pore size.Another important mesoporous material of M41S is MCM-48.In contrast with the unidirectional channels present in both MCM-41 and SBA-15,cubic structures with s

37、pace group Ia3d,MCM-48and large pore Ia3d material(LP-Ia3dhave recently attracted much attention due to their unique penetrating bicontinuous channels networks which are very useful for applications requiring easy molecular accessibility and fast molecular transport.However,lit-tle work has been rep

38、orted using these mesoporous materials.Iz-quierdo-Barba et al.22investigated MCM-48and LP-Ia3d with ibuprofen and erythromycin systems for delivery studies.The re-sults showed that the MCM-48and LP-Ia3d are also good carriers for drug delivery.The delivery rate of drugs decreased with the pore size

39、of the matrix and chemical modication of pore surface would also result in a noticeable decrease of the delivery rate.Organic modication of the silicates permits precise control over the surface properties and pore sizes of the mesoporous sieves for specic applications,while at the same time stabili

40、sing the materials towards hydrolysis.Both reactive and passive organic groups can be incorporated in the porous solids by grafting meth-ods or by co-condensation under surfactant control23.For drug delivery based on mesoporous materials,several investigations using organic modied mesoporous silica

41、have also been reported. It is generally found that functionalisation usually will affect the adsorption and delivery.Organic modication with aminopropyl group of two MCM-41 materials having different pore sizes was carried out in order to control the delivery rate of ibuprofen from the siliceous ma

42、trix.It has been found that functionalisation procedure is determinant in both the adsorption of the drug and its release prole.A slower delivery rate has been observed for a two-step method,calcination and functionalisation24.Zeng et al.25carried out a similar study using MCM-41materials modied by

43、organic aminopropyl groups as drug-controlled delivery system of aspirin.The results showed that the releasing properties of this delivery system were affected by the amount of aminopropyl groups on the pore wall and the ordered structure of mesoporous materials.2.2.SBA-based mesoporous materialsSBA

44、-15is another important mesoporous material with large, controlled pore size and highly ordered hexagonal topology26. The pore size of SBA-15is usually6nm in diameter,larger than the3nm pore of MCM-41.Therefore,SBA-15is expected to have less restriction for the delivery of bulky molecules.Doadrio et

45、 al.27investigated the mesoporous silica SBA-15for application as gentamicin drug delivery system.Two procedures were used to evaluate the delivery:calcined powder and disk conformed.No sig-nicant difference between the powder and disk was observed in the tests.The release proles exhibited a pronoun

46、ced initial burst release effect of60%,followed by a very slow release pattern.Val-let-Regi et al.28also tested the antibiotic amoxicillin with a cal-cined SBA-15material.It has been found that the amount of drug incorporated into the porous matrix is strongly dependent upon the solvent,pH,and amoxi

47、cillin concentration,reaching a value of24wt%under optimum conditions.The amoxicillin is released into the solution at a rate which is dependent upon physical state of the material,either powder or disk.Release from powder is fas-ter than that from disk.However,for pure SBA-15,there exist only silan

48、ol groups on the channel walls,and these silanol groups simply form weak intermo-lecular hydrogen bonds with drugs,similar to the case of pure M41S;hence,they are not strong enough to hold drugs and allow them to be released in a sustained manner.Therefore,introduction of functional groups on the su

49、rface of SBA-15to have specic hostguest interactions with drugs will also be important and good for controlled drug delivery.Doadrio et al.29then reported func-tionalisation of SBA-15for controlling drug delivery.They com-pared calcined samples and the samples functionalised with long alkyl chains s

50、uch as octyltrimethoxysilane and octadecyltrime-thoxysilane in delivery patterns.The samples were charged with the macrolide antibiotic erythromycin and the release assays were carried out in vitro.It has been observed that the release rate de-creases as the population of hydrophobicCH2moieties in t

51、he host increases.Song et al.30also reported mesoporous SBA-15materials functionalised with amine groups through postsynthesis and one-pot synthesis as drug matrixes.Ibuprofen(IBUand bovine serum albumin(BSAwere selected as model drugs and loaded onto the unmodied and functionalised SBA-15.It was re

52、vealed that the adsorption capacities and release behaviours of these model drugs were highly dependent on the different surface prop-erties of SBA-15materials.The release rate of ibuprofen from the SBA-15functionalised by postsynthesis was found to be effectively controlled as compared to that from

53、 pure SBA-15and SBA-15func-tionalised by one-pot synthesis due to the ionic interaction be-tween carboxyl groups in ibuprofen and amine groups on the surface of SBA-15.However,the SBA-15functionalised by one-pot synthesis was found to be more favourable for the adsorption and release of BSA due to t

54、he balance of electrostatic interaction and hydrophilic interaction between BSA and the functionalised SBA-15matrix.Andersson et al.31prepared a series of mesoscopically or-dered silicas with different pore sizes,pore connectivity,and pore geometry including MCM-41,SBA-3and SBA-1as carrier matrices

55、for controlled drug delivery systems.Ibuprofen was still used as a model drug,and the release processes were monitored under in vi-tro conditions.The degree of drug loading was dependent on the specic surface area and the pore diameter of the host matrix. The release process was found to be mainly diffusion controlled, but clear differences were observed between the studied materials, which was mainly ascribed to the differences