Journal of Acute Disease (2013)1-12

Contents lists available at ScienceDirect Journal of Acute Disease journal homepa e! """#ja$"eb#or Document hea$in doi: 10.1016/S2221-6189(13)60087-6

%a netic microspheres as ma ical novel $ru $eliver& s&stem! A revie" Satin$er 'a(ar1*) Deepa *atra1) +aman$eep Sin h2) ,jj"al -auti&al2
1 2

Department of .harmac&) Doon valle& /nstitute of .harmac& 0 %e$icine) 'arnal (1ar&ana) Department of .harmac&) 1imachal /nstitute of .harmac&) .aonta Sahib (1#.)
A*S2+AC2

A+2/C34/-56

Article histor&! Received 31 January 2013 Received in revised or! 1" #e$ruary 2013 %cce&'ed 1" (arc) 2013 %vai*a$*e on*ine 20 (arc) 2013

'e&"or$s ! +ar,e'in, (a,ne'ic (icro carriers (a,ne'i'e Revie-

(a,ne'ic !icros&)eres )o*d ,rea' &ro!ise or reac)in, ')e ,oa* o con'ro**ed and si'e s&eci ic dru, de*ivery. (a,ne'ic !icros&)eres as an a*'erna'ive 'ois'radi'iona* radia'ion !e')ods -)ic) uses )i,)*y &ene'ra'in, radia'ions ')a' a$sor$ed ')rou,)ou' ')e $ody. .'s use sys'e!s is *i!i'ed $y 'o/ici'y and side e ec's. 0o- days1 severa* 'ar,e'ed 'rea'!en' inc*udin, !a,ne'ic ie*d1 e*ec'ric ie*d1 u*'rasound1 'e!&era'ure1 23 *i,)' and !ec)anica* orce are $ein, used in !any disease 'rea'!en's (e.,. cancer1 nerve da!a,e1 )ear' and ar'ery1 an'i-dia$e'ic1 eye and o')er !edica* 'rea'!en's). %!on, ')e!1 ')e s'ra'e,y !a,ne'icor'ar,e'ed dru, de*ivery sys'e! is one o ')e !os' a''rac'ive and &ro!isin, de*iverin, ')e dru, 'o ')e s&eci -ays ied si'e. (a,ne'ica**y con'ro**ed dru, 'ar,e'in, is one o ')ees'a$*is) various &ossi$*e o dru, 'ar,e'in,. +)is 'ec)no*o,y is $ased on $indin, an'icancer dru, -i') erro *uid ')a' concen'ra'e ')e4een dru,in'eres' in ')e area o deve*o&!en' in'eres' ('u!or si'e) $y !eans o 'ar,e' !a,ne'ic ie*ds. +)ere )as $een in ')e o a !a,ne'ica**y dru, de*ivery sys'e!. +)ese dru, de*ivery sys'e!s ai! o 'o de*iver ')e dru, a' a ra'e direc'ed $y ')e needs o ')e $ody durin, ')e &eriod 'rea'!en'1 and 'ar,e' ')e ac'ivi'y en'i'y 'o ')e si'e o ac'ion. (a,ne'ic !icros&)eres -ere deve*o&ed 'o overco!e '-o si'e !a5or &ro$*e!s na!e*y: R6S c*earance and 'ar,e' s&eci ici'y. encoun'ered in dru, 'ar,e'in,

1# /ntro$uction (icros&)eres are ree *o-in, &o-ders consis'in, o enca&su*a'ed (dru,s) s&)erica* &ar'ic*es o si7e idea**y *ess ')an 12"& ')a' can $e sus&ended in a8ueous ve)ic*e and in5ec'ed $y an 18 or 16 nu!$er need*e. (a,ne'ic !icros&)eres are su&ra!o*ecu*ar &ar'ic*es ')a' are s!a** enou,) 'o circu*a'e ')rou,)7ca&i**aries -i')ou' &roducin, e!$o*ic occ*usion (9: !) $u' are su icien'*y susce&'i$*e ( erro!a,ne'ic) 'o $e ca&'ured in !icro vesse*s and dra,,ed in'o ')e ad5acen' 'issues $y !a,ne'ic ie*ds o 0."-0.8 +es*a (+). (e')ods o &re&ara'ion o !a,ne'ic !icros&)eres are na!e*y &)ase se&ara'ion e!u*sion &o*y!eri7a'ion (;S6;) and con'inuous so*ven' eva&ora'ion

(<S6). +)e a!oun' and ra'e o dru, de*ivery via !a,ne'ic res&onsive !icros&)eres can $e re,u*a'ed $y varyin, (i) *<orres&ondin, au')or: Sa'inder =a4ar1 >oon 3a**ey .ns'i'u'e o ;)ar!acy ? (edicine1 =arna* (@aryana)1 .ndia. +e*: A91-9017138383 6-(ai*: sa'inder.4a44ar"B,!ai*.co!

Si7e o !icros&)eresC (ii) >ru, con'en'C (iii) (a,ne'i'e

con'en'C (iv) @ydra'ion s'a'eC (v) >ru, re*ease c)arac'eris'ic o carrier. +)e a!oun' o dru, and !a,ne'i'e con 'en' o !icros&)eres needs 'o $e de*ica'e*y $a*anced in order 'o desi,n an e icien' ')era&eu'ic sys'e!. (a,ne'ic !icros&)eres are c)arac'eri7ed or di eren' a''ri$u'es suc) as (i) ;ar'ic*e si7e ana*ysis inc*udin, si7e dis'ri$u'ion1 sur ace 'o&o,ra&)y1 and 'e/'ure e'c. usin, scannin, e*ec'ron !icrosco&y (S6()C (ii) >ru, en'ra&!en'

e iciencyC (iii) D !a,ne'i'e con'en'C (iv) /n vitro !a,ne'ic res&onsivenessC (v) >ru, re*ease. +ar,e'in, $y !a,ne'ic !icros&)eres i.e. incor&ora'ion o !a,ne'ic &ar'ic*es in 'o dru, carriers (;o*y!ers) and usin, an e/'erna**y a&&*ied !a,ne'ic ie*d is one -ay 'o &)ysica**y direc' ')ese !a,ne'ic dru, carriers 'o a desired si'eE1F. >ru, 'ar,e'in, is ')e de*ivery o dru,s 'o rece&'ors or or,an or any o')er s&eci ic &ar' o ')e $ody 'o -)ic) one -is)es 'o de*iver ')e dru, e/c*usive*y. 3arious non!a,ne'ic !icro carriers (nano&ar'ic*es1 !icros&)eres

Satin$er 'a(ar et al#8 Journal of Acute Disease (2013)1-12

and !icro &ar'ic*es e'c.) are success u**y u'i*i7ed or dru, 'ar,e'in, $u' ')ey s)o- &oor si'e s&eci ici'y and are ra&id*y c*eared o $y R6S (re'icu*oendo')e*ia* sys'e!) under nor!a* circu!s'ances. (a,ne'is! &*ays an i!&or'an' ro*e in ')ese cases1 !a,ne'ic &ar'ic*es co!&osed o !a,ne'i'e -)ic) are -e** 'o*era'ed $y ')e $ody1 !a,ne'ic ie*ds are $e*ieved 'o $e )ar!*ess E2F 'o $io*o,ica* sys'e!s and ada&'a$*e 'o any &ar' o ')e $ody . 2& 'o 60D o an in5ec'ed dose can $e de&osi'ed and re*eased in a con'ro**ed !anner in se*ec'ed non re'icu*oendo')e*ia* or,ans. So !a,ne'ic !icro carriers -ere deve*o&ed 'o overco!e '-o !a5or &ro$*e!s encoun'ered in dru, 'ar,e'in, na!e*y R6S c*earance and 'ar,e' si'e s&eci ici'y. (a,ne'is! )as a&&*ica'ion in nu!erous ie*ds *i4e dia,nos'ics1 dru, 'ar,e'in,1 !o*ecu*ar $io*o,y1 ce** iso*a'ion1 ce** &uri ica'ion1 )y&er')er!ia1 and radioi!!unoassayE3F. 2# Concept of tar etin of non tar etin versus ma netic tar etin ma netic

+a$*e 1 s)o-s co!&arison o !a,ne'ic and non !a,ne'ic 'ar,e'in,. 3# Concept an$ principle behin$ ma netic tar etin (a,ne'ic dru, de*ivery $y &ar'icu*a'e carriers is an e icien' !e')od o dru, de*ivery 'o a *oca*i7ed disease si'e. % dru, or ')era&eu'ic radioiso'o&e is enca&su*a'ed in a !a,ne'ic co!&oundC in5ec'ed in'o &a'ien':s $*ood s'rea! ? ')en s'o&&ed -i') a &o-er u* !a,ne'ic ie*d in ')e 'ar,e' area. #i,ure 1 s)o-s re&resen'a'ion o sys'e!ic dru, de*ivery and !a,ne'ic 'ar,e'in,. >e&endin, on ')e 'y&e o dru,1 i' is ')en s*o-*y re*eased ro! !a,ne'ic carriers or con ers a *oca* e ec'1 ')us i' reduces ')e *oss o dru, as ree*y circu*a'in, in $odyE:F. >ru, 'ar,e'in, is a s&eci ic or! o dru, de*ivery -)ere ')e dru, is direc'ed 'o i's si'e ac'ion or a$sor&'ion. +)is cou*d $e a &ar'icu*ar or,an s'ruc'ure1 a ce**1 su$se'or even an in'erce**u*ar re,ion. #i,ure 2 s)o-s !a,ne'ic dru, 'ar,e'in,. 5i ure 2# (a,ne'ic dru, 'ar,e'in,. 3#1# Approaches of tar etin #ive di eren' a&&roac)es o 'ar,e'in, are: (i) <)e!ica* a&&roac)-&rodru,C (ii) <o!&ar'!en' de*iveryC (iii) 0a'ura* 'ar,e'in,C (iv) Gi,and !edia'ed 'ar,e'in,C (v) ;)ysica* 2able 1 <o!&arison o !a,ne'ic and non !a,ne'ic 'ar,e'in,.
S. 0o. 0on !a,ne'ic 'ar,e'in,

5i ure 1# Re&resen'a'ion o sys'e!ic dru, de*ivery and !a,ne'ic 'ar,e'in,.

1.

<a&i**aries o )u!an $ody are in'o in an !icrons1 (a,ne'ic !icros&)eres are in5ec'ed ar'ery ')a' su&&*ies a ,iven si'e. %s ')e so one can easi*y 'ar,e' ')e ca&i**aries !icros&)eres -ou*d $e se*ec'ive*y and !a,ne'ica**y *oca*i7ed a' ')e ca&i**ary *eve*1 ')ey o *un,s1 $*ood1 *iver e'c $y ')e o -ou*d ree *o- access ')rou,) *ar,euse ar'eries. +)us)ave ')e !icros&)eres -ou*d serve ')e !icro as 'i!e-re*ease ca&su*e sys'e! s&)er si''in, in ')e desired *oca'ion. es. 2. 0o !a,ne'ic ie*d s'ren,') needed. % !uc) *o-er !a,ne'ic ie*dnecessary s'ren,') is 'o res'ric' ')e !icros&)eres a' ')e s*o-er !ovin, ve*oci'ies *oo

(a,ne'ic 'ar,e'in,

Satin$er 'a(ar et al#8 Journal of Acute Disease (2013)1-12

3.

0o e ec' o !a,ne'ic ie*d.

$*ood in ca&i**aries. % 'er re!ova* o ')e !a,ne'ic ie*d1 ')e !icros&)eres s'i** con'inued 'o *od,e a' si'e1 ')e 'ar,e' &resu!a$*e $ecause ')ey )ad *od,ed in ')e vascu*ar endo')e*iu!1 &ene'ra'ed in 'o ')e in'ers'i'ia* s&ace1 resu*'in, in ')eir re'en'ion.

a&&roac) o 'ar,e'in,.

3#2# .rinciple of ma netic $ru tar etin 0 principle of ma netic $ru tar etin in cancer ;rinci&*e o !a,ne'ic dru, 'ar,e'in, ? &rinci&*e o !a,ne'ic dru, 'ar,e'in, in cancer are s)o-n in #i,ures 3 ? :.

5i ure 9# ;rinci&*e o !a,ne'ic dru, 'ar,e'in, in cancer. 9# %a netic properties (a,ne'ic &ar'ic*es or $io se&ara'ion consis' o one or !ore !a,ne'ic cores -i') a coa'in, !a'ri/ o &o*y!ers1 si*ica or )ydro/y* a&a'i'e -i') 'er!ina* unc'iona*i7ed ,rou&s. +)e !a,ne'ic core ,enera**y consis's ei')er o !a,ne'i'e (#e3H:) or !a,ne'i'e (,a!!a #e2H3) -i') su&er &ara!a,ne'ic or erro!a,ne'ic &ro&er'ies. So!e !a,ne'ic cores can a*so $e !ade -i') !a,ne'ic erri'es1 suc) as co$a*' erri'e or !an,anese erri'e. 9#1# Super para ma netism Su&er ;ara !a,ne'is! is -)en ')e di&o*e !o!en' o a sin,*e-do!ain &ar'ic*e *uc'ua'es ra&id*y in ')e core due 'o

5i ure 3# ;rinci&*e o !a,ne'ic dru, 'ar,e'in,.

')e ')er!a* e/ci'a'ion so ')a' ')ere is no !a,ne'ic !o!en'

or !acrosco&ic 'i!e sca*es. +)us1 ')ese &ar'ic*es are non!a,ne'ic -)en an e/'erna* !a,ne'ic ie*d is a&&*ied $u' do deve*o& a !ean !a,ne'ic !o!en' in an e/'erna* !a,ne'ic ie*d (#i,ure ")E"F.

5i ure <# #erro!a,ne'ic &ar'ic*es. (a) undero')e *uence !a,ne'ic o an e/'erna* a$sence anin e/'erna* ie*d.!a,ne'ic ie*dC ($) in 5i ure ;# Su&er &ara!a,ne'ic &ar'ic*es. (a) undero')e *uence!a,ne'ic o e/'erna* !a,ne'ic ie*dC ($) in a$sence anin e/'erna* ie*d1 !onodis&erse &ar'ic*e dis'ri$u'ion. 9#2# 5erroma netism # erro!a,ne'is! !eans ')a' ')e &ar'ic*es )ave a &er!anen' !ean !a,ne'ic !o!en'. @ere1 ')e *ar,er e ec'ive !a,ne'ic aniso'ro&y su&&resses ')e ')er!a**y ac'iva'ed !o'ion o ')e core !o!en's. #erro!a,ne'ic &ar'ic*es are ,enera**y reco!!ended or ')eE6F se&ara'ion o >0%/R0% (Si(%I/(;->0%) (#i,ure 6) . ;# %a netite %*so ca**ed as erric errous o/ide1 'ri iron 'e'ra o/ide1 and $*ac4 iron o/ide. (a,ne'ic iron o/ide c)e!ica* or!u*a #eH e203 )avin, a !o*ecu*ar -ei,)' o 231."" -i') a c)e!ica* co!&osi'ion o #eJ72.36D1 HJ27.6:D. +)e #erro !a,ne'ic !a'eria* -)en incor&ora'ed in'o !icros&)eres !a4es ')e! !a,ne'ica**y res&onsive1 so ')a' ')ey can $e concen'ra'ed 'o ')e desired si'e $y a&&*yin, so!e e/'erna* !a,ne'ic ie*d. +o &re&are !a,ne'i'e1 ni'ro,en ,as *us)ed ')rou,) "00 !G round $o''o! *as4 i''ed -i') condenser. <)ar,ed ')e *as4 -i') . 8.9 , (0.1 !o*) o ,oe')i'e1 9.9: , (0.0" !o*) o #e<* :@2H a*on, -i') 2"0 !G deioni7ed -a'er. %dded 2 "0

!G o 2 ( Sodiu! )ydro/ide. Reac'ion !i/'ure -as )ea'ed

')e nano&ar'ic*es sur ace1 'ar,e'ed !edicine1 su&er

'o re *u/ or 12 ). .'s &@ e** ro! 1: (oran,e) in 'o 8-9 ($*ac4 &reci&i'a'es). ;ar'ic*es -as)ed and air driedE718F. <# %aterials use$ in ma netic microspheres +a$*e 2 s)o-s !a'eria*s used in &re&ara'ion o !a,ne'ic !icros&)eresE9F. =# 5actors re ulatin $ru release from microspheres (1) +)e a!oun' $ind ra'e or dru, de*ivery via !a,ne'ica**y res&onsive !icros&)eres is re,u*a'ed $y varyin, ')e si7e o ')e !icros&)eres1 dru, con'en'1 !a,ne'ic con'en'1 and ')eir )ydra'ion s'a'e and dru, re*ease c)arac'ers o ')e carrier. %** ')e ac'ors are in'er-re*a'ed. (2) >ru, con'en' de&ends on si7e. >ru, con'en'1 -)ic) in 'urn is ,overned $y so*u$i*i'y c)arac'ers o dru, and ')eir !e')od o &re&ara'ion. (3) @ydra'ion s'a'e o !a,ne'ic !icros&)eres e ec's ')eir dis'ri$u'ion in ')e $ody. (:) +)e !a,ne'ic con'en' and ')e !a,ni'ude o a&&*ied !a,ne'ic ie*d ,overn ')e re'en'ion o !icros&)eres a' ')e 'ar,e' si'e. (") .n !icros&)eres -i') )i,) !a,ne'ic con'en'1 ')e e/'erna* !a,ne'ic ie*d s'ren,') re8uired is *ess1 $u' i )i,) !a,ne'ic con'en' is &resen' ')an ')e s&ace or dru, avai*a$*e is *ess and )ence ')e !a,ni'ude o !a,ne'ic con'en' and dru, s)ou*d $e de*ica'e*y $a*anced 'o )ave e ec'ive ')era&eu'ic sys'e!s. (a,ne'ic dru, de*ivery $y &ar'icu*a'e carriers is a very e icien' !e')od o de*iverin, a dru, 'o a *oca*i7ed disease si'e. .n !a,ne'ic 'ar,e'in,1 a dru, or ')era&eu'ic radioiso'o&e is $ound 'o a !a,ne'ic co!&ound1 in5ec'ed in'o a &a'ien':s $*ood s'rea!1 and ')en s'o&&ed -i') a &o-er u* !a,ne'ic ie*d in ')e 'ar,e' areaE10F. >e&endin, on ')e 'y&e o dru,C i' is ')en s*o-*y re*eased ro! ')e !a,ne'ic !icros&)eres. .' is ')us &ossi$*e 'o re&*ace *ar,e a!oun's o ree*y circu*a'in, dru, -i') !uc) *o-er a!oun's o 'ar,e'ed !a,ne'ica**y 'o *oca**y diseased si'es1 reac)in, e ec'ive u& 'o severa* o*d increased *oca*i7ed dru, *eve*sE11-13F. #i,ure 7 s)o-s various &rocesses or &re&ara'ion o !a,ne'ic &ar'ic*es vi7. &recursors1 !odi ica'ion o

&ara!a,ne'ic &ar'ic*es &re&ara'ion1 unc'iona*i7a'ion $y ac'ive $io!o*ecu*es.

5i ure =# ;rocesses o &re&ara'ion o !a,ne'ic &ar'ic*es. ># %etho$s of preparation of ma netic microspheres >#1# Selection of $ru s .n ')e se*ec'ion o a dru, or or!u*a'ion o !a,ne'ic !icros&)eres1 o**o-in, &oin's are 'a4en in'o considera'ion: (i) +)e dru, is so dan,erous or *a$i*e ')a' -e canno' a**o- i' 'o circu*a'e ree*y in ')e $*ood s'rea!. (ii) +)e a,en' is so e/&ensive1 ')a' -e canno' a ord 'o -as'e 99.9D o i'. (iii) Re8uires a se*ec'ive1 re,iona* e ec' 'o !ee' *oca*i7ed ')era&eu'ic o$5ec'ive. Re8uires an a*'erna'ive or!u*a'ion essen'ia* 'o con'inue 'rea'!en' in &a'ien' -)ose sys'e!ic ')era&y !us' $e 'e!&orari*y discon'inued due 'o *i e ')rea'enin, 'o/ici'y direc'ed a' se*ec'ive or,ansE1:F. >#2# Continuous solvent evaporation .n ')is !e')od ')e dru, and &o*y!er ( <arrier) are disso*ved in a&&ro&ria'e vo*a'i*e or,anic so*ven' and ')en !a,ne'i'e (i !a,ne'ic !icros&)eres) is added 'o ')is so*u'ion a*on, -i') s'irrin, in order 'o or! a )o!o,eneous sus&ension. +)is sus&ension is added 'o an i!!isci$*e au/i*iary so*u'ion a*on, -i') vi,orous s'irrin,. 0o- ')e vo*a'i*e or,anic so*ven' is eva&ora'ed s*o-*y a' 22-30 ?< 'o or! !icros&)eres. (icros&)eres are ')is cen'ri u,ed and ree7e dried and s'ored a' : ?<E1"-17F. >#3# .hase separation emulsion pol&meri@ation @o!o,enous a8ueous sus&ension is &re&ared $y addin,

2able 2 (a'eria*s used in &re&ara'ion o !a,ne'ic !icros&)eres.

S. 0o.

1. Syn')e'ic &o*y!ers a) Kiode,rada$*e $) 0on $iode,rada$*e 2. 0a'ura* &o*y!ers a) ;ro'eins $) <ar$o)ydra'es

(a'eria* used

+y&es

6/a!&*es

I*yco*ides1 6&o/y &o*y!ers1 &o*yan)ydrides1 Gac'ides ;o*y!e')y*!e')ary*a'e1 %cro*ein1I*ycidy* !e')acry*a'e

c) <)e!ica**y !odi ied car$o)ydra'es

%*$u!in1 Ie*a'in1 <o**a,en

%,arose1 S'arc)1 <)i'osan ;o*yde/'ran1 ;o*ys'arc)

a*$u!in -a'er-so*u$*e dru, and a,en' -i') !a,ne'i'e in

c)i'osan &o*y!erC I*u'ra*de)yde-used as ')e cross-*in4erC

a&&ro&ria'e 8uan'i'y o -a'er (i !a,ne'ic !icros&)eres). +)is a8ueous sus&ension is ')en e!u*si ied in ')e &resence o sui'a$*e e!u*si yin, a,en' 'o or! s&)eres in e!u*sion. +)is a8ueous &ro'eineous s&)ere ')us or!ed in ')e e!u*sion are s'a$i*i7ed ei')er $y )ea'in, a' 1001"0 ?< or $y addin, )ydro&)o$ic cross *in4in, a,en's

*i4e or!a*de)yde1 ,*u'ra*de)yde or 2-3 $u'adiene1 !icros&)eres ')us &roduced are cen'ri u,ed ou' and -as)ed ei')er in e')er or so!e o')er a&&ro&ria'e or,anic so*ven' 'o re!ove e/cess o oi*. (icros&)eres are ree7e
dried and s'ored a' : ?<E1"-17F.

Sodiu! )ydro/ide so*u'ion-used as !ediu!. Syn')esis o !a,ne'ic *uid: % 3"D (-/v) errous su* a'e so*u'ion1 ":D (-/v) erric c)*oride so*u'ion and 36D (-/v) sodiu! )ydro/ide so*u'ion -ere &re&ared usin, dis'i**ed -a'er. +)en ')e erric sa*' and errous sa*' -ere !i/ed1
s'irred and )ea'ed. L)en ')e 'e!&era'ure reac)ed "" ?<1

')e a*4a*ine so*u'ion -as added. +)e !i/'ure -as s'irred or 30 !in1 and ')en " , o &o*ye')y*ene ,*yco*-10000 (;6I10000) -as added. +)e 'e!&era'ure -as raised 'o 80 ?< and

>#9# %ultiple metho$

emulsion

La'er dis&ersi$*e !a,ne'i'e -i') a ;6I/;%% coa'in, -as added 'o ')e KS%-con'ainin, inner -a'er &)ase. 0.2 !G o a 1 !,/!G KS% so*u'ion added 'o a : !G !i/'ure o ><( and 6% a' a ra'io o 3 'o 1 con'ainin, 200 !, o ;GI% ( irs' -/o e!u*sion -as &re&ared usin, a )o!o,eni7er (;o*y'ron ;+10-3"C =ine!a'ica1 Gu7ern1 S-i'7er*and) in an ice $a') a' 26 000 r/!in or 2." !in). #i 'een !G o a 1D ;3% so*u'ion &oured direc'*y in'o ')e &ri!ary e!u*sion and re-e!u*si ied usin, ')e sa!e )o!o,eni7er under ')e sa!e condi'ions or ano')er 2." !in. >#<# Al(aline co precipitation metho$ L/o/- e!u*sion i!!edia'e*y &oured in'o a $ea4er con'ainin, 8" !G o 1D ;3% so*u'ion and s'irred in a )ood under an over)ead +rea' &o*y (acry*ic acidAdiviny*$en7ene) !icros&)eres ;ro&e**er or 2 )1 a**o-in, ')e so*ven' 'o eva&ora'e. -i') di*u'e a8ueous 0aH@ so*u'ion (0." () or )ours a' So*idi ied !icros&)eres )arves'ed $y cen'ri u,a'ion a' 2 sui'a$*e 'e!&era'ure 'o 'rans or! ')e car$o/y*ic acid ,rou&s 'o sodiu! car$o/y*a'es and ')en -as)ed ')orou,)*y -i') -a'er 'o re!ove ')e e/cess 0aH@ 'i** neu'ra* &@. ;ur,ed ')e !icros&)ere sus&ension -i') ni'ro,en or 30 !in. +o ')is sus&ension add an a8ueous so*u'ion o #e<*3 "00 r/!in or 10 !in and -as)ed -i') dis'i**ed -a'er ')ree
'i!es (#i,ure 8)E18119F. and #e<*2 ')a' )ad $een &ur,ed -i') ni'ro,en. S'irred

!ain'ained or 30 !in. +)e !i/'ure -as ')en neu'ra*i7ed -)i*e coo*in,1 and ')e !a,ne'ic *uid -as &re&ared. 1D (-/ -) c)i'osan -as disso*ved in ace'a'e $u er a' &@ :.". +)e disso*ved c)i'osan -as added dro& -ise on ')e !a,ne'ic *uid. #or!ed c)i'osan !a,ne'ic !icros&)eres -ere -as)ed -i') deioni7ed -a'er and soa4ed in 11 31 and " !o* D ,*u'ra*de)yde so*u'ion or 2 )1 and ')en -as)ed -i') deioni7ed -a'erE20F.

5i ure ># ;re&ara'ion o !icros&)eres $y !u*'i&*e e!u*sion !e')od. >#;# Cross lin(in metho$ Rea,en's used: %ce'a'e $u erAused as so*ven' or ')e

')e !i/'ure overni,)' under ni'ro,en a'!os&)ere or ion e/c)an,e. +)e resu*'in, !icros&)eres -ere -as)ed re&ea'ed*y -i') -a'er under ni'ro,en a'!os&)ere 'o re!ove e/cess iron sa*'s. %dded dro& -ise an a8ueous 0aH@ so*u'ion (3 () 'o a sus&ension o ')e !icros&)eres 'a4en u& -i') iron ions under ni'ro,en a'!os&)ere 'o ad5us' ')e &@ va*ue 'o $e M12. +)e !i/'ure -as ')en )ea'ed 'o 60 ?< and 4e&' or ano')er 2 ). +)e resu*'in, !a,ne'ic !icros&)eres -ere sus&ended in an a8ueous @<* so*u'ion (0.1 () 'o 'rans or! ')e A<HH0a 'o A<HH@1 and ')en -as)ed ')orou,)*y -i') -a'er 'o neu'ra* &@1 dried under vacuu! a' "0 ?< overni,)'1 ,ivin, !a,ne'ic E21F !icros&)eres .

>#=# /nverse phase suspension pol&meri@ation metho$ % 2"0 !G ')ree-nec4 *as4 i''ed -i') a !ec)anica* s'irrer used or &er or!in, ')e reac'ion. <on'inuous &)ase inc*udes: 100 !G o cas'or oi* and 10 !G o s&an 80. >e'er!ined a!oun' o i'aconic acid (.%)1 S'yrene (S')1 diviny*$en7ene (>3K) and 01 0N (e')y*ene$isacry*a!ide (K.S) disso*ved co!&*e'e*y in >(SH1 and ')e or,anic &)ase -as added dro& -ise*y in'o ')e *as41 -i') 70 ?< )ea'in, usin, an oi* $a'). %!!oniu! &ersu* a'e (.0.+.%+HR) added

dro& -ise usin, a syrin,e. +)e reac'ion &roceeded or 8 ) -i') con'inuous s'irrin,. +)e resu*'in, !icros&)eres -ere se&ara'ed $y cen'ri u,a'ion. #ur')er -as)ed -i') die')y* e')er and ')en $y deioni7ed -a'er (#i,ure 9)E22F.

')e !icros&)eres are or!ed $y c)e!ica**y cross-*in4in, cys'eine residues o ')e &ro'ein -i') @H2 radica* or!ed around a non-a8ueous dro&*e'. +)e c)e!ica* cross-*in4in, is res&onsi$*e or ')e or!a'ion o ')e !icros&)eres and is a resu*' o ')e c)e!ica* e5ec's o ')e u*'rasound radia'ion on an a8ueous !ediu!. +-o sonoc)e!ica* !e')ods or ')e a$rica'ion o iron o/ide nano&ar'ic*es -ere (i) La'er as ')e so*ven' and (ii) >eca*in as so*ven'. >ecane and iron &en'acar$ony* #e(<H) (7.:32103: () -ere *ayered over a "D -/v &ro'ein" so*u'ion. +)e $o''o! o ')e )i,)-in'ensi'y u*'rasonic )orn -as &osi'ioned a' ')e a8ueous or,anic in'er ace. +)e !i/'ure -as irradia'ed or 3 !in1 e!&*oyin, a &o-er o L1"0 L/ 32c! -i') ')e

5i ure B# Syn')esis o ;(S'-.%->3K) !icros&)eres and (0;S.> !icros&)eres. ;(S'-.%->3K) !icros&)eres: ;(s'yrene-i'aconic aciddiviny*$en7ene) !icros&)eres. (0;S.> !icros&)eres: (a,ne'ic nano&ar'ic*es-coa'ed ; (S'-.%>3K) !icros&)eres.

>#># Sonochemical metho$ + )e !icros&)eres co!&osed o iron o/ide- i**ed and coa'ed ,*o$u*ar $ovine seru! a*$u!in (KS%). +)e !a,ne'ic !icros&)eres -ere &re&ared ro! KS% and iron &en'a car$ony*1 or ro! KS% and iron ace'a'e. ;ro'ein !icros&)eres )ave a -ide ran,e o $io!edica* a&&*ica'ion1 i.e. use as ec)o con'ras' a,en's or sono,ra&)y. +)e !icros&)ere -ere or!ed $y ei')er )ea' dena'ura'ion a' various 'e!&era'ures1 or $y cross *in4in, -i') car$ony* co!&ounds in ')e e')er &)ase. <ross *in4in, -as done as:

ini'ia* 'e!&era'ure o 23 ?< in ')e reac'ion ce**. +)e &@

-as ad5us'ed 'o 7.0 $y addin, @<*. +)is &rocedure -as &er or!ed a,ain -i') an a8ueous so*u'ion o iron ace'a'e1
#e(<@ <H ) 9"D (Si,!a) (7.6621033 (). % 'er ')e syn')esis1
3 2 2

&ar'ic*es -ere se8uen'ia**y -as)ed -i') !e')ano*1 deioni7ed -a'er1 and vacuu! dried a' roo! 'e!&era'ure or 1-2 days 'o yie*d ')e !a,ne'ic &o*y!er !icros&)eresE27F. >#10# 3o"-temperature h&$rothermal metho$ 0.1 , #e3H: -as dis&ersed in ')e a8ueous ,*ucose so*u'ion -i')ou' addi'ives1 ')e )ydro')er!a* reac'ion ca'a*y7ed on*y $y #e3H: -as 4e&' a' 180 ?< or " )E28F. B# Comparison bet"een CS4 an$ .S4. #orcon'inuousso*ven' eva&ora'ion ( < S 6 ) 1 - i d e ran,e o c)e!o')era&eu'ic a,en' -ou*d $e covered $y <S6 'ec)ni8ue1 due 'o avai*a$i*i'y o or,anic so*ven' -i') varyin, &o*ari'y. #or &)ase se&ara'ion e!u*sion &o*y!erisa'ion (;S6;)1 a narro- ran,e o c)e!o')era&eu'ic a,en's can $e incor&ora'ed in'o !icros&)eres $y ;S6; $ecause ')is &rocess re8uired a8ueous so*u$i*i'y o ')e a,en' 'o $e incor&ora'ed in'o ')e !icros&)eres is an essen'ia* &rere8uisi'e or ')is 'ec)ni8ue. 10# Characteri@ation microspheres of ma netic

')e &roduc's -ere se&ara'ed ro! ')e unreac'ed &ro'ein and ro! ')e residues o iron ace'a'e or iron &en'acar$ony* $y cen'ri u,a'ion (1 000 r/!in or " !in). +)e !a,ne'ic !icros&)eres -ere -as)ed a e- 'i!es -i') su icien' vo*u!es o -a'er 'o re!ove ')e residues o ')e &recursorsE2326F . >#B# S"ellin metho$ an$ penetration

#or s-e**in, o &o*y!er !icro &ar'ic*es1 0.2" , o ;S ((icron-si7e &o*ys'yrene) &ar'ic*es -as !i/ed -i') 3" !G o a 0(;/-a'er so*u'ion in a s&eci ic v/v 0(; (0!e')y*2-&yrro*idone)-'o--a'er ra'io. .n *a'er &re&ara'ions o !a,ne'ic !icros&)eres1 S>S (Sodiu! dodecy* su* a'e) -as added 'o ')e 0(;/-a'er so*u'ion. L)enever S>S -as used1 0.02" , o S>S -ere added 'o eac) 0(;/-a'er so*u'ion. +)e 0(;/-a'er !i/'ure -i') ;S s&)eres -as *e ' soa4in, or 2: ) a' roo! 'e!&era'ure -)i*e s'irrin,. 2." !G o ')e su&er&ara!a,ne'ic nano&ar'ic*e dis&ersion (2: !,/!G or o')er s&eci ied concen'ra'ion) -as added 'o ')e !i/'ure o ;S s&)ere and 0(;/-a'er so*u'ion a' 30 ?< -)i*e s)a4in, (a' 1:0 r/!in) or 1-" days 'o a**o- ')e !a,ne'ic nano&ar'ic*es 'o &ene'ra'e in'o ')e in'erior o ')e ;S &ar'ic*es. % 'er-ards1 ')e &o*y!er &ar'ic*es -ere se&ara'ed ro! ')e so*u'ion $y cen'ri u,a'ion. #ina**y1

( 1) ;ar'ic*e si7e ? si7e dis'ri$u'ion: a) Sievin,C $)

11#3# .article si@e $istribution of prepare$ (icrosco&yC c) <ou*'er coun'er ana*ysisC d) Gaser microspheres di rac'ion ana*ysis. (2) Sur ace c)arac'eri7a'ion: a) @i , ) - r e s o * u ' i o n !icrosco&yC $) Scannin, e*ec'ron !icrosco&yC c) Scannin, 'unne*in, !icrosco&y. +)e si7e o !icrosco&y ')e &re&ared !e')od !icros&)eres can $e !easured $y o&'ica* usin, a ca*i$ra'ed s'a,e (3) Sur ace c)ar,e ana*ysis: a) (icro e*ec'ro&)oresisC $) ')e !icro!e'er or rando!*y se*ec'ed sa!&*es o a** ')e or!u*a'ions. Gaser >o&&*er ane!o!e'ry.
)

J (/ 11#9# Dru entrapment capacit& (:) >ensi'y: a) Ku*4 densi'y EKu*4 densi'y (C$) (,/c!3

3$. L)ere1 ( J !ass o &o-der 'a4en1 3$ J $u*4 vo*u!eFC $ +a&&ed densi'y E+a&&ed
densi'y (C') (,/c!3) J (/3'.
)

6 iciency o dru, en'ra&!en'

or eac) $a'c) can $e

L)ere1 ( J -ei,)' o sa!&*e &o-der1 3' J 'a&&ed vo*u!eF.

ca*cu*a'ed in 'er!s o &ercen'a,e dru, en'ra&!en'

S. 0o. %n,*e o re&ose <arr s inde/ (D) @ausner ra'io #*o- c)arac'er

(; > 6).

(") #*o- &ro&er'ies: a) %n,*e o re&ose E%n,*e o Re&ose1 D J 'an-1 ) / r (+a$*e 3)FC $) @ausner ra'io E@ausner ra'io J C'/ C $. L)ere1 C' J 'a&&ed densi'y1 C$ J $u*4 densi'yF. (6) >ru, re*ease &ro i*es: a) /n vitroC $) /n vivo. (7) Sur ace area (8) ;orosi'y (9) @ardness ? ria$i*i'y (10) >ru, con'en' (11) >ru, re*ease &ro i*esE29F. 2able 3 #*o- &ro&er'ies (as &er 2S;30-0#2" s&eci ica'ions).

+)eore'ica* dru, con'en' can $e

de'er!ined $y ca*cu*a'ion assu!in, ')a' ')e en'ire dru, &resen' in ')e &o*y!er so*u'ion used ,e's en'ra&&ed in !icros&)eres and no *oss occurs a' any s'a,e o &re&ara'ion o !icros&)eres. D 6n'ra&!en' J (ac'ua* con'en' / ')eore'ica* con'en') / 100

1. 2. 3. :. ". 6. 7.

2"-30 31-3" 36-:0 :1-:" :6-"" "6-6" M66

910 11-1" 16-20 21-2" 26-31 32-37 38

1.001.121.11 1.18 1.191.2" 1.261.3: 1.3"1.:" 1.:61."9 M1.60

6/ce**en' Iood #air ;assa$*e ;oor 3ery ;oor 3ery 3ery ;oor

!edia. +)e s&ec'ro&)o'o

11#;# /n vitro release $tu$ies /n-vitro $e re*ease can &ers'udies or!ed accordin, 'o 2S; OO.. 'y&e . disso*u'ion a&&ara'us a' sui'a$*e &@ condi'ions. +)e 'e!&era'ure s)ou*d !ain'ained a' (37E 0.") ?$e < and ')e ro'a'ion s&eed o 100 r/!in. +)en " !G o sa!&*e s)ou*d $e -i')dra-n a' various 'i!e in'erva*s and re&*enis)ed -i') an e8ua* vo*u!e o res) disso*u'ion

11# valuati 4 on 11#1# /nteraction stu$& b& 23C8 52/+ 11#1#1# /+ Spectroscopic stu$ies +)e .R s&ec'ra o ')e ree dru, and ')e !icros&)eres -ere recorded. )e iden'ica* &ea4s corres&ondin, 'o ')e unc'iona* ,rou&s and a*$u!in 1 6,, a*$u!in1 @u!an KS% ( seru! a*$u!in) ea'ures con ir! ')a' nei')er ')e &o*y!er nor ')e !e')od o &re&ara'ion )as a ec'ed ')e dru, s'a$i*i'y.
+

11#;#1# 4f (easure! !easure!en is de'er!ined ,iven &@ da i!!ersin, $u er so*u roo! 'e!&e

+)e R va*ues o ')e &re&ared !icros&)eres can $e co!&ared -i') ')e R va*ue o ')e &ure dru,. +)e va*ues indica'e ')e dru, s'a$i*i'y.

11#1#2# 2hin la&er chromato raphic stu$ies +)e dru, s'a$i*i'y in ')e &re&ared !icros&)eres can $e 'es'ed $y ')ea*so +G< !e')od.

ro! ')e $u er so*u'ion and re8uen'*y -ei,)ed a 'er 'ra&&ed -i') a i*'er &a&er 'o re!ove e/cess o -a'er on ')e sur ace. 6SR is ca*cu*a'ed ro! ')e o**o-in, or!u*a Le/ Ld1 -)ere Le is ')e -ei,)' o ')e so*u'ion in e8ui*i$ra'ed s-o**en !icros&)eres a' eac) &rede'er!ined $u er so*u'ion -i') di eren' &@ da'a1 ')e sy!$o* o Ld is ')e sa!e as de ined ear*ier. +)e SR1 (Ls A Ld)/Ld1 is de ined as ')e ra'io o 'o'a* -ei,)' o -a'er in s-o**en !icros&)eres 'o ')e -ei,)' o ')e dried !icros&)eres1 -)ere Ls is ')e -ei,)' o adsor$ed -a'er and Ld is ')e -ei,)' o ')e !icros&)eres a' dry s'a'eE30F.

11#;#2# /n vitro $ru release rate /n vitro dru, re*ease ra'e de'er!ined $y ')e !e')ods: i o**o-in, >ia*ysis !e')odC
<on'inuous co*u!n e*ec'ron !e')odC (iii) >ia*ysis
(ii) ()

11#2# Surface topo raph& b& scannin electron microscop& (S4%) S6(')e o ')e !icros&)eres s)o-s sur ace !or&)o*o,y o ')e ')eir !icros&)eres *i4e s)a&e and si7e.

!e')od. +)e a*$u!in !icros&)eres -ere 'a4en in a unne*C 3 !G o &)os&)a'e $u er (7.3) -as added. +)e !ou') o ')e unne* -as covered -i') ce**o&)ane &a&er and as'ened 'o ru$$er $and. +)e unne* -as ')en inver'ed in'o a $ea4er con'ainin, "0 !G o &)os&)a'e $u er 7.3. 2." !G a*i8uo's -ere -i')dra-n every )a* an )our and re&*aced -i') 2." !G o res) $u er. %*i8uo's -ere -i')dra-n over a &eriod

o 10 ). +)e $u er in c)ina dis) -as con'inuous*y s'irred usin, a !a,ne'ic s'irrer. +)e $u er -as !ain'ained a' 37 ?< .

11#;#3# Continuous column elution metho$ % con'inuous *o- sys'e! si!i*ar 'o ')a' descri$ed $y <)ien -as used. (icros&)eres -ere i!!o$i*i7ed on a
co*u!n con'ainin, a i/ed -ei,)' o ,*ass -a** (3." ,) as su&&or' !a'eria* and 4e&' a' 37 ?<. +)ey -ere su$5ec' 'o a' in'erva*s o )a* an )our. +)e a!oun' o dru, e*u'ed -as es'i!a'ed.

'ar,e' area. (7) %v o i d a n c e o a c u ' e ' o / i c i ' y d i r e c ' e d a , ains' endo')e*iu! and nor!a* &arenc)y!a ce**1 con'ro**ed re*ease -i')in 'ar,e' 'issue or in'erva*s o 30 !in 'o 30 ). as desired1 ada&'a$*e 'o any &ar' o $ody.

13# Disa$vanta es microspheres

of

ma netic

(1) Hne o ')e !a5or *i!i'a'ions o ')is sys'e! is ')e +)is dru, canno' $e 'ar,e'ed 'o dee&-sea'ed or,anis! in ')e $ody. a&&roac) is con ined 'o ')e 'ar,e'in, o dru,s 'o ')e su&er 5oin's.icia* 'issues *i4e s4in1 su&er icia* 'u!ors or ')e (2) +)ro!$osis a' ')e si'e o ca')e'eri7a'ion. +)e so*u$i*i'y o &ar'icu*ar !icros&)eres inso*u$*e s&eci ic (3) +)e un4no-n 'o/ici'y o !a,ne'ic $eads. so*u'ion as !icros&)eres or !icroca&su*es 'o $e in ')a' &ar'icu*ar environ!en' (-a'er or &)os&)a'e $u ers o (:) +)e &ossi$*e un-an'ed *oca*i7a'ion o ')e &roduc' in &@ 7.:) canin $e de'er!ined $y 'a4in, e/cess 8uan'i'y o !icros&)eres "0 !G via*s i**ed -i') -a'er. S)a4ed ')e ')e *iver and ')e re,ions o R6S and ')e dan,erous e ec' o via*s on a &a&er !a,ne'ic #i*'ered ')e so*u'ion ')rou,) L)a'!ann no.1 s'irrer. and dru, concen'ra'ion de'er!ined a' se* - *occu*a'ion o ')e !a,ne'ic &ar'ic*es causin, vascu*ar F &ar'icu*ar !a/ va*ue or ')e &ar'icu*ar dru,. o$s'ruc'ion 'o vi'a* or,ans in ')e $ody . 11#<# Determination of solubilit&
E33F

11#=# Soli$ state b& DSC8G+D +)is 'es's'a'e is done $y an dru,1 O-Ray di rac'o!e'er 'o ind ou' 19# ')e so*id o ')e &o*y!er and dru,-&o*y!er !i/'ure and a*so 'o ind ou' ')e so*id s'a'e o ')e dru, in &re&ared a*$u!in !icros&)eres. +)e c)arac'eri7a'ion o ')e ')e Stora e !icro &ar'icu*a'e carrier is an i!&or'an' &)eno!enon1 -)ic) )e*&s 'o desi,n a sui'a$*e carrier or ')e &ro'eins1 dru, or an'i,en de*ivery. +)ese !icros&)eres )ave di eren' !icros'ruc'ures. +)ese !icros'ruc'ures (icros&)ere sus&ensions s)ou*d no' $e ro7en1 as ree7in, re*ease and ')e s'a$i*i'y o ')e carrierE31132F. de'er!ine ')e is 8 *i4e*y 'o cause irreversi$*e a,,re,a'ion. <o*d s'ora,e (2?S'andard <) is : reco!!ended 'o in)i$i' !icro$ia* ,ro-'). H (non-&ro'ein coa'ed) !icros&)ere sus&ensions do no' con'ain an an'i!icro$ia* a,en'. %** sus&ensions s)ou*d 12# A$vanta es of ma netic microspheres $e )and*ed usin, ase&'ic 'ec)ni8ue. <on'inuous ro**in, (e.,. 3-" r/!in on in a ce** cu*'ure ro**er) is,enera'in, reco!!ended !icros&)eres sus&ension1 -i')ou' oa!'o( 4ee& oa! !ay cause &ar'ic*e *oss ')rou,) $ead en'ra&!en'). . con'inuous ro**in, is no' &ossi$*e1 &ar'ic*es s)ou*d $e (1) !icros&)eres .ncor&ora'ion !a4es o !a,ne'ica**y res&onsive'o !a'eria*s ')orou,)*y resus&ended $e ore use. @i,)er s&eed ro**in, in'o ')e! susce&'i$*e a&&*ied or 2-: )) is ro**in, e ec'ive or ')e resus&ension !a,ne'ic ie*d1 o so!a,ne'ic ')a' ')ey are concen'ra'ed 'o')a' ')e 'ar,e' si'e (30-60 o se''*edr/!in !a'eria*. %,ain1 s&eed is in'ended o 'o $y a&&*ica'ion ie*d e/'erna**y 'o si'e. >ue e ec'ive*y resus&end ')e $eads -i')ou' ,enera'ion 'o ')is1 ra&id c*earance o ')ese !icros&)eres $y R6S is oa!E3:F. &reven'ed. >i de*ivery erence occurs ca&i**ary ne'-or4 so e (2) icien' o dru,!a/i!a**y 'o diseased in 'issue is ac)ieved. (3) (icros&)eres can 'ransi' in'o s&ace crea'in, e/'ra vascu*ar de&o'areas. o e/'ra dru, vascu*ar or sus'ained 1;# 3iterature of $ru s use$ in ma netic re*ease o an dru, -i')in ')e 'ar,e'ed microspheres alon "ith their pol&mers (:) .ncrease o 'u!or 'ar,e'in, !icros&)eres can $e in'erna*i7ed $y 'u!or ce** due 'o 'o nor!a* i's !uc)-increased &)a,ocy'ic ac'ivi'y as co!&ared ce**. So ')e &ro$*e! o across dru, ')e resis'ance due 'o can ina$i*i'y o dru, 'o $e +a$*e : s)o-s dru,s !icros&)eres. a*on, -i') ')eir &o*y!ers used in 'rans&or'ed ce** !e!$rane $e &reven'ed. &re&ara'ion o !a,ne'ic (") <on'ro**ed and &redic'a$*e ra'e o dru, re*ease -i') s!a**er doses o dru, can $e ac)ieved. (6)asGinear $*ood'ove*oci'y insoca&i**aries is 300 'i!es *ess co!&ared ar'eries1 !uc) s!a**er !a,ne'ic ie*d is su icien' 'o re'ain ')e! in ')e ca&i**ary ne'-or4 o 1<# %ar(ete$ ')e pro$ucts 3arious -)ic) &re&ara'ions o !a,ne'ic !icros&)eres are avai*a$*e are c)arac'eri7ed $y ')eir .0<.inna!es1 si7e1 oi* a$s1 re rac'ive inde/ and densi'y s)o-n +a$*e ". 1=# Applications microspheres of ma netic

3arious a&&*ica'ions )ave $een *is'ed in +a$*e 6.

(a,ne'ic !icros&)eres )ave -ide ran,e o a&&*ica'ions.

2able 9 >ru,s and &o*y!ers used in &re&ara'ion o !a,ne'ic !icros&)eres.

S. 0o. 1. 2. 3. :. ". 6. 7. 8. 9. 10. 11. 12. 13. 1:. 1". 16. 17. 18. 19. 20. 21. 22. 23. 2:. 2". 26. 27. >ru, >e/a!e')asone .ndo!e')acin H/an'ra7o*e >ic*o enac sodiu! "-#*uorouraci* >o/oru$icin <andida ru,osa *i&ase (<ar$o/y!e')y*)de/'ran >e/a!e')asone sodiu! &)os&)a'e Si*icon (.3) &)')a*ocyanine deriva'ive "- *uorouraci* ;o*y-*-*ysine !e')o're/a'e >eriva'ive o cyc*o&)os&)a!ide1 %s'a P1 0i!esu*ide Iancic*ovir 3era&a!i* )ydroc)*oride <yc*os&orine % (e')o're/a'e ;i*ocar&ine ni'ra'e >o/oru$icin +a!arind ,u! Gyso7y!e (onoc*ona* ani$odies <yc*os&orine (e'ronida7o*e Gec'in >o/oru$icin *oaded o*a'e ;o*y!er %*$u!in (e')y*!e')acry*a'e <)i'osan 6')y* ce**u*ose 6udra,i' G1001 6udra,i' S1001 6udra,i' ;:13"# and (e')y*ce**u*ose ;o*y (0-iso&ro&y*acry*a!ide) I*ycidy* !e')acry*a'e1 e')y*ene ,*yco* di!e')acry*a'e and viny* ace'a'e I*ycidy* !e')acry*a'e @u!an seru! a*$u!in ;o*y)ydro/y$u'yra'e-co-va*era'e (;@K@3) and &o*y(eca&ro*ac'one) (;<G) <)i'osan ;o*y,*u'ara*de)yde %*$u!in ;o*yviny* a*co)o*1&o*y *ac'ic acid ;o*y (d1G-*ac'ide-co-,*yco*ide (;GI%) Ie*a'in % and <)i'osan ;o*y(d*-*ac'ide-co-,*yco*ide) <a*ciu! &ec'ina'e 6,, a*$u!in ;o*y(acry*ic acid) <)i'osan +ris()ydro/y!e')y*)a!ino!e')ane ;o*ys'yrene ;o*y(ca&ro*ac'one) Ie*a'in @u!an seru! a*$u!in and &o*ys'yrene ;o*y(0-iso&ro&y*acry*a!ide)

2able ; (ar4e'ed or!u*a'ions S. 0o. 1. 2. 3. :. ". 6. 7. 8. 9. 10. 11. 12. 13. 1:. 1". 16. 17. 18. 19. 20. 21. 22. 23. 2:. 2". si'y n3) +rade na!e

6%-209 #*o- $eads S #*o-$eads S6 K;>-800 K;>-"00 K;>-"00+ K;%-"00 K;%-"00O (S;-822 (S;-82" (S;-930 S20;(( +R-1 +R-2 ;H(;-60" ;H(;-610 S;-10 S;-10G S;-"00 <G-2080

+HS;6%RG +HS;6%R +HS;6%R +HS;6%R +HS;6%R

2able < %&&*ica'ions o !a,ne'ic !icros&)eres.

S. 0o.

1. +u!or 'ar,e'in, (i'o/an'rone1 ;ac*i'a/e* E3"F 2. Radioe!$o*isa'ion o *iver and s&*een 'u!ors 186re/188re-,*ass (icros&)eres E36F 3. (a,ne'ic con'ro* o &)ar!aco4ine'ic &ara!e'ers .nsu*in E37F :. (a,ne'ic $iose&ara'ion >yna$eads1 used in iso*a'ion o !R0%1 ,eno!ic >0% and &ro'eins E38F ". <)an,in, ')e 'i!in, and/or e/'en' o dru, a$sor&'ion >ic*o enac sodiu! E39F in s'o!ac) or in'es'ines 6. Radiosynovec'o!y o ar')ri'is 5oin's 3"s-co**oid1 !icros&)eres1169er.ci'ra'e E:0F 7. @y&er')er!ia or 'rea'!en' o cancer <is&*as'in1 ;ac*i'a/e* E:1F 8. >e'ec'ion o !e'as'ases in non-en*ar,ed *y!&) nodes Su&ra!a,ne'ic iron o/ide E:2F 9. Ga$e*ed sand-ic) i!!unoassay #*uoro,enic co!&ound1 %''o;)os(visua* co*or ,enera'in, co!&ound) E:3F 10. >0% de'ec'ion (#i,ure 10) >yna$eads E::F 11. Kac'eria de'ec'ion S're&'avidin coa'ed !a,ne'ic $eads E:"F E:6F 12. <e** se&ara'ion in !icro *uidics c)anne* >yna$eads or se&ara'ion o 1 (e.,.1 &ro'eins1 nuc*eic acids1 an'i,ens and an'i$odies) or ce**s $*ood ce**s1 s'e!s ce**s or $ac'eria)
13. o an'i,ens *ec'in or rece&'ors <e** sur aceand !ar4ers ')e de'ec'ion and *oca*i7a'ion se&ara'ion o red $*ood ce**s (RK<) and *y!&)oid ce**s E:7F

%&&*ica'ion

>ru,s/<arriers &resen'*y in curren' inves'i,a'ion

Re erence

1:. E:8F

.so*a'ion and unc'iona*i'y o cancer ce**s (eu4aryo'ic >yna$eads or $reas' cancer ce**s
ce**s)

21. 22.

1". .!!uno&reci&i'a'ion (iso*a'ion o various &ro'eins) >yna$eads or *i&osacc)aride $indin, &ro'eins E:9F 16. .so*a'ion o ce** co!&ar'!en's o eu4aryo'ic ce**s >yna$eads or Io*,i $odies1endoso!a* vesic*es E:9F 17. Re!ova* o an'i s&er! an'i$odies and s&er! ce**s Ioa' an'i-)u!an i!!uno,*o$u*in E"0F 18. +8 de&*e'ion in a**o,enic 'rans&*an'a'ion dyna$eads or $one !arroE"0F 19. (a,ne'ic se&ara'ion o &o*y (%) !R0% @o!o,eni7a'ion $y !i/'ure o ,uanidiu! ')iocyana'e and &)eno*c)*oro or! 20. (a,ne'o ca&'ure &ro'ein in'erac'ion assays (#i,ure 11) 0i-0+% (ni'ri*oace'ic acid) 'a,,ed !a,ne'ic a,arose $eads )ave $een used or versa'i*e !a,ne'o ca&'ure assays usin, 6/@is-'a,,ed &ro'eins
>ru, 'ar,e'in, <on'race&'ive dru, de*ivery 6*e!en'a* iron &ar'ic*es and ac'iva'ed car$on. (a,ne'ic 'ar,e'ed carriers (1-2 ! in si7e) can adsor$ and desor$s &)ar!aceu'ica* a,en's suc) as do/oru$icin (>HO) >ru, de*ivery is desi,ned res&onsive 'o ')e c)an,es in s'eroid secre'ion durin, !ens'rua* cyc*e

E"1F E"2F
E " E 2

1># Conclusion

(a,ne'is! see!s 'o $e a co!!on unc'ion o o&enin, a nevis'a o a !u*'i-$arrier o !u*'i-s'e& dru, de*ivery. +)eir !ain advan'a,e is ')e 'ar,e'in, o dru, usin, an e/'erna* !a,ne'1 -)ic) can $e acco!&*is)ed very easi*y.

Kac'eria* co*ony

Sus&ension ;< R Kio'in

<e**s/s&eci !ens .!!uno !a,ne'ic Se&ara'ion +)er!o

<yc*e

+)ey are re*a'ive*y youn, dru, de*ivery sys'e!s1 )avin, received a''en'ion ro! ')e ear*y 1990s. .n ')e ear*y days o '-en'ie') cen'ury1 ;au* 6)r*ic) envisioned )is (%I.< K2GG6+ <H0<6;+-')e idea ')a' dru,s reac) ')e ri,)' si'e in ')e $ody1 a' ')e ri,)' 'i!e1 a' ri,)' concen'ra'ion. .' does

Kead

. !

! o $i

*i7a'ion (a,ne'ic se&ara'ion no' e/er' side e ec's1 nei')er on i's -ay 'o ')e ')era&eu'ic 'ar,e'1 no' a' ')e 'ar,e' si'e1 nor durin, ')e c*earance &rocess. +)us !a,ne'ic !icros&)eres )ave ')e &o'en'ia* or ')ese o$5ec'ives. .' is a c)a**en,in, area or u'ure researc) in ')e dru, 'ar,e'in, so !ore researc)es1 *on, 'er! 'o/ici'y

S'rand Se&ar ion@y$rdi7a'ion Reac'i on

+er!ina'ers Iene ;ro$e %rray

<e** *ysis

>e'ec'ion

Goad on ,e*

Iene Se8uencin,

>e'ec' ion s'udy1 and c)arac'eri7a'ion -i** ensure ')e i!&rove!en' o !a,ne'ic dru, de*ivery sys'e!. +)e u'ure )o*ds *o' o 5i ure 10# <once&' o >0% de'ec'ion sys'e! use o &ro!ises in !a,ne'ic !icros&)eres and $y ur')er s'udy ')is !a,ne'ic se&ara'ion-$ased sa!&*e &rocessin, and so*id -i** $e deve*o&ed as nove* and e icien' a&&roac) or 'ar,e'ed dru, de*ivery sys'e!. &)ase se8uencin, 'ec)no*o,ies.

2A 2A

Kind 6/@is-'a,,ed &ro'ein

(i) (ii) (iii) ;ro'ein-&ro'ein ;ro'ein->0% .!!unoassay -0+%-0i -0+%-0i 0+ %0i 2A 0+ %0i

E13F@I e*i 21 Sc)J'' L1 +e**er J1 P$oro-s4i (. Scientific an$

clinical applications of ma netic carriers. 1s' ed. 0e- Qor4:
;*enu! ;ressC 1997.

Kind in'erac'in , &ar'ner

E1:FIa**o J(1 Iu&'a ;=1 @un, <+1 ;rrier >I. (a,ne'ic &ar'ic*es or dru, de*ivery. J .harm Sci 1989C =>: 190.

;ro'ein-&ro'ein in'erac'ion disru&'ed 6*u'e or de'ec'

Go- sa*' 2A -0+%-0i 6> @i 6> +%/ ,) +%/ i!ida7o*e sa*' i!ida7o*e 2A 0+ %0i
2A

-0+%-0i

E1"F.s)ida (1 0a!$u 01 0a,ai +. @i,)*y viscous ,e* oin'!en'

<o*o r or *i,)'

con'ainin, car$o&o* or a&&*ica'ion 'o ora* !ucosa. Chem .harm *ull 1983C 31: :"-61. E16F>e 5a,ar1 L. 3e*')ius @1 ;ra44en KJ1 =uius L Ri54ers I +.

5i ure 11# (a,ne'oca&'ure &ro'ein in'erac'ion assays.

$ac'eria* !a,ne'oso!es. .h&s J Con$ens %atter 2006C 1>: 79-86.

E8F Lec4*er K1 Gu'7 @>. So*id S'a'e .nor,. <)e!. 4ur J %ol Structure 1998C 3;: "31-"::.

Conflict of interest statement Le dec*are ')a' -e )ave no con *ic' o in'eres'. +eferences E1F P ) u = J 1 @ e n d r e n R L 1 J e n s e n = 1 ; i ' ' < I . S y n ' ) e s i s 1 &ro&er'ies1 and $iode,rada'ion o &o*y(113-'ri!e')y*ene car$ona'e). %acromolecules 1991C 29(8): 1736-17:0. E2F ;a'i* S%1 Surya-ans)i @;1 Ka4*i-a* SR1 ;a-ar S;. #erro *uids: a &ro!isin, dru, carrier-a revie-. /nt J .harma +es Dev 2001C 2(10): 2"-28.
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E9F (u4)er5ee S. (a,ne'ic !icros&)eres: a *a'es' a&&roac) in nove* dru, de*ivery sys'e!. J .harm Sci /nnovation 2012C
2<: 21-2". E10F@a e*i 2H. (a,ne'ica**y !odu*a'ed ')era&eu'ic sys'e!s1 /nt J .harm 200:C 2==: 19-2:.

E11FLidder =J1 Senyei %61 Ranney >#. (a,ne'ica**y res&onsive ! i c r o s & ) e r e s a n d o ' ) e r c a r r i e r s o r ' ) e $ i o & ) y s i c a * 'ar,e'in,o an'i'u!ora,en's. A$v .harmacol Chemother 1979C E12FIu&'a ;=1 @un, <+. (a,ne'ica**y con'ro**ed 'ar,e'ed !icro- carrier sys'e!s. 3ife Sciences 1989C 991: 17"-186.
1<: 213-271.

E:F % ,,ar-a* % 1 < ))a5er ; 1 ( a)es)-ari S . ( a,ne'ic dru, de*ivery in ')era&eu'ics. /nt J .harm Sci +es 2012C 3(2):
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Si!u*'aneous de'ec'ion o 1" )u!an cy'o4ines in a sin,*e sa!&*e o s'i!u*a'ed &eri&)era* $*ood !ononuc*ear ce**s. Clin Dia nostic 3ab /mmunol 2003C 10(1): 133-139. E17F< orri,en H . 1 @ ea*y % ( . Surfactants in pharmaceutical pro$ucts an$ s&stems) enc&clope$ia of pharmaceutical technolo &. 3rd ed. Ja!es S-ar$ric4 .n or!a @ea*')care .ncC E18FG ac)!an G % 1 G i$er!an @ % 1 = ani, J G . 2he theor& an$ practice of in$ustrial pharmac&. (u!$ai1 .ndia: 3ar,)ese ;u$*is)in, @ouseC 20021 &. :1:-:1". E19F<o**ins %61 >easy ;K. Kioad)esive *o7en,e or ')e i!&roved de*ivery o ce'y*&yridiniu! c)*oride. J .harm Sci 1998C ;;:
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2712-2717.

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E26F< a/ O 1 = o*'y&in Q 1 ; ro7orov R 1 # e*ner .1 I edan4en % .

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E33F3 i!a* ( 1 % !ares)-ar ; 1 @ e!a!a*ini = 1 S reenivas = .
2001C 39: 66-72. 27:7.

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>e'ec'ion o $io*o,ica* ')rea' a,en's $y i!!uno!a,ne'ic !icros&)ere-$ased so*id &)ase *uoro,enic- and e*ec'ro- c)e!i*u!inescence. *iosens *ioelectron 2000C 19(10-11): E::F#ara, SS. +)era&eu'ic a&&*ica'ions o i!!uno!a,ne'ic ce** se*ec'ion: a revie-. 4ur Cells %ater 2002C 3: 37-:0. E:"F+u S.1 24na*is J1 .r-in ;1 Qu GSG. +)e use o s're&'avidin coa'ed !a,ne'ic $eads or de'ec'in, &a')o,enic $ac'eria $y *i,)' addressa$*e &o'en'io!e'ric sensor. J +api$ %etho$s Autom %icrobiol 2000C >(2): 9"-109. E:6F( o d a 4 0 1 > a ' ' a % 1 I a n , u * y R . < e * * se&ara'ionina!icro *uidicc)an ne* usin, !a,ne'ic!icros&)eres. %icroflui$ -anoflui$ 2008C ;(6): "99-610. E:7F(o*day RS1 Qen S;1 Re!$au! %. %&&*ica'ion o !a,ne'ic !icros&)eres in *a$e**in, and se&ara'ion o ce**s. -ature E:8F0au!e K1 Kor,en 61 Keis4e =. .!!uno!a,ne'ic 'ec)ni8ues o r ' ) e e n r i c ) ! e n ' a n d d e ' e c ' i o n o i s o * a ' e d $ r e a s ' carcino!a ce**s in $one !arro- and &eri&)era* $*ood. J 1ematother 1997C <: 103-11:. E:9F@o-e** =61 <ros$y JR1 Gadins4y (S. (a,ne'ic so*id su&&or' or ce**- ree ana*ysis o vesicu*ar 'rans&or'. .n %dvances in Kio!a,ne'ic Se&ara'ion. 2)*en (1 @o!es 6 and H*svi4 0 E"0F2rs )a e*i. 2he histor& an$ m&ster& of ma netism) scientific an$ clinical applications of ma netic carriers. ;*enu! &ress E"1F< )o!c7yns4i ; 1 S acc)i 0 . S in,*e s'e& !e')od o R 0 % iso*a'ion $y ,uanidiu! ')iocyana'e-&)eno* c)*oro or! e/'rac'ion. Anal *iochem 1987C B: 1"6-162. E"2FSinc*air K. @onin, your c*onin,: ne- c*onin, sys'e!s ,ive &ro'ein e/&ression s'udies a $oos'. Scientist
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