Abstract
In part I of this review, the authors showed how poly(amidoamine) (PAMAM)-based dendrimers can be considered as promising delivering platforms for siRNA therapeutics. This is by virtue of their precise and unique multivalent molecular architecture, characterized by uniform branching units and a plethora of surface groups amenable to effective siRNA binding and delivery to e.g., cancer cells. However, the successful clinical translation of dendrimer-based nanovectors requires considerable amounts of good manufacturing practice (GMP) compounds in order to conform to the guidelines recommended by the relevant authorizing agencies. Large-scale GMP-standard high-generation dendrimer production is technically very challenging. Therefore, in this second part of the review, the authors present the development of PAMAM-based amphiphilic dendrons, that are able to auto-organize themselves into nanosized micelles which ultimately outperform their covalent dendrimer counterparts in in vitro and in vivo gene silencing.
Highlights
In its broadest sense, self-assembly describes the natural tendency of physical systems to exchange energy with their surroundings and assume patterns or structures of low free energy
Pharmaceutics 2019, 11, x FOR PEER REVIEW. With these concepts in mind, the authors envisaged the idea of creating small amphiphilic poly(amidoaWmitihnet)he(PseAcMonAceMpt)s-binasmedind,enthderoanutshworhs iecnhv,iusapgoedn athuetoid-oeargoafncirzeaattiionng isnmtoallnaamnopshiizpehdilimc icelles, could mpiomlyi(camthideoacmoivnael)en(PtA, MhiAgMh-)g-beanseedratdieonndrdoenns dwrihmiche,r ucopounntaeurtpoa-orrtgsainnizastiizoen, isnhtoapneanaonsdizefdunction, in particmuilcaerllefos,rcionuvlditrmoimanicdtihne vciovvoalesniRt,NhAighd-geelinveerartyio[n6–d8e]n,darsimseetr ocuoutnbteerlopawr.ts in size, shape and function, in particular for in vitro and in vivo siRNA delivery [6,7,8], as set out below
SchemeS1c.heTmhee c1h. eTmheiccahlesmtriucacltusrtreuoctfutrheeoPfAthMeAPMAM-bAaMse-dbasseeldf-aseslsfe-amssbelminbglinagmapmhpiphhipihliiclicdednedndroronnssbearing a singlebaealkriynlg cahsainignleoaflkvyal rcihaabinleoflevnargiatbhle(1le–n6g)t.h (T1h–6e).tTwhoe twnoonn-oanm-apmhpihpiphhililiicc ddeennddroronsncshcarhaacrtearcizteedrized by a hydrob(p8yh) auilshiecyddparesonpntheagielaitcthipvyeelnretenafeeetrhegnyllyceecncoeolgm(lPypcEoouGln()dPcEshGara)eicnahlas(o7in)s(ha7on)wdannbd(ysbeytehttheexeptpfroreerssdeeenntccaeeiloso)f.ftAhtehdaesposlteoedlPeAfrPMoAmAM[M7A]hwMeiatdhhead (8) used as tnheegpaetrimveissrieofneroefnJochencWomilepyoaunnddSsoanrse, 2a0l1s6o. shown
Summary
The values of the critical micelle concentration (CMC) for the amphiphilic dendrons 1–6 (see STuhpepovratilnugeIsnfoofrmthaetiocnrfiotircdaeltamilsic)ewlleerecfounrtcheenr tirnavteisotniga(tCedMfrCo)mfworhitchhea calmeapr ihnivpehrsileicreldaetinondsrhoinps 1–6 (see bSeutwppeeonrttihneg hIyndfroorpmhaotbiiocntafiol rlendgetthaialsn)dwtheereCMfuCrthwears ionbvtaeisnteigda(tTeadblfero1m). From the values reporte−d17i.n1 ±Ta1b.3le 22, 2th±e1effe−c6t.0iv0e±i0n.t3e6racti−o0n.2b7e±tw0.0e2en th1e6m.9i±ce0l.l5es formed by the different dendrons w4ith siRN−2A2.6(∆±G1.b2ind,e3ff1)±in1cre−a1s2e.s7 w± 0it.4h1incre−a0s.4i1ng± 0a.l0k4yl cha7i.0n±le0n.3gth, the last three dendrons definitely b5eing th−e4s6t.r6o±n1g.e6st s4iR9 N± 1A b−in28d.e9r±s 0in.70the o−rd0.e5r9: ±40
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