POLYMERS FOR DRUG DELIVERY

Transcription

1 PLYMERS FR DRUG DELIVERY Biodegradable Micro ad Naoparticles Biodegradable Block Copolymer Micelles Biodegradable Targetig Micro ad Naoparticles with Fuctioal Polymers Resposive Polymers PEG Cojugatio (PEGylatio) Polyoxazolie Cojugatio Dedrimers Polymeric Hydrogels for Localized

2 PLYMERS FR DRUG DELIVERY Sigma-Aldrich offers a diverse drug delivery toolbox that icludes ready-to-use polymer ad aoparticle chemistries for directed ad cotrolled delivery of small ad large molecule therapeutics. A major challege i drug developmet is esurig that each ew cadidate is delivered to the right place, at the right time ad i the right amout. Low drug solubility, drug degradatio, drug toxicity, or rapid clearace from the body ca reduce the effectiveess of a otherwise promisig cadidate. Sythetic ad atural polymers are both effective solutios for the delivery of small molecules, proteis, gees, or peptides. Polymer Categories ad Their Applicatios i Drug Cotrolled Ehacemet Biodegradable micro ad aoparticles Biodegradable block copolymer micelles Biodegradable targetig micro ad aoparticles with fuctioal polymers Resposive polymers PEG cojugatio Polyoxazolie cojugatio Dedrimers Polymeric hydrogels for localized delivery Differet polymer types ca be used to cotrol drug release rates, deliver a drug to the desired site of actio, or icrease drug solubility ad reduce toxicity (icrease biocompatibility). Your Parter I Academic Drug Discovery Polymer Drug Techiques is just oe part of Sigma-Aldrich s complete offer for academic Drug Discovery, a uique series of solutios that spa Target ID & Validatio through Pre-Cliical Developmet. Traslatioal Medicie Solutios from Sigma-Aldrich are used by experts ad o-experts alike to facilitate the crossdiscipliary research required for today s drug discovery. TRANSLATINAL RESEARCH SLUTINS To lear more about solutios that cover the etire drug discovery workflow, visit aldrich.com/traslatioal TARGET ID & VALIDATIN LEAD DISCVERY LEAD PTIMIZATIN PRE-CLINICAL DEVELPMENT CLINICAL DEVELPMENT MANUFACTURING 2 Polymers for Drug

3 Biodegradable Micro ad Naoparticles Cotrolled Ehacemet Polymeric micro ad aoparticles are effective carriers that allow for cotrolled ad targeted drug delivery of small molecules, DNA ad proteis i order to improve the bioavailability ad bioactivity of a drug. Polyester-based aoparticles, formed by emulsio or aoprecipitatio techiques ca be desiged to have a rage of degradatio times (see example techique). Particle degradatio ad drug release kietics are cotrolled by the physiochemical properties of the polymer (e.g., molecular weight, hydrophobicity, ad polydispersity). A chemically diverse selectio of biodegradable ad block copolymers ameable to subsequet customizatio allowig the icorporatio/ecapsulatio of highly diverse drug cadidates. Biodegradable sythetic ad atural polymers with varyig rates of degradatio allow for fie-tuig release kietics. Well-defied polymers with arrow PDI to esure reproducible release profiles. A large selectio of exclusive products icludig fast degradig radom PLGA ad ew biodegradable block copolymers. Mixture of aqueous ad o-aqueous phases Cotiuous phase: Water ad Surfactat Disperse phase: Chloroform, Polymer Hydrophobic Payload, e.g., fluorescet dye, drug, etc. Soicatio Formatio of moodisperse chloroform droplets (cotaiig dissolved payload ad polymer) Evaporatio of chloroform Solid polymer particles dispersed i water Example Techique: Biodegradable aoparticles ca be made by emulsio techiques to geerate particles with a cotrolled size ad arrow size distributio. The polymer is dissolved i a orgaic solvet with the drug; a emulsio is formed by the additio of a aqueous phase that cotais a hydrophilic stabilizer. NTE: Hydrophobic drugs should be added directly to the polymer orgaic phase; hydrophilic drugs ca be combied with the polymer phase by soicatio with the polymer solutio. The emulsio is soicated, followed by solvet evaporatio to harde the particles. Particles are the washed, collected ad lyophilized. Polylactides Name Structure Degradatio Time M PDI Prod. No. 5, Poly(L-lactide), PLLA H >3 years 10, Poly(D,L-lactide), PDLLA H <6 moths 20, , , , Poly(lactide-co-glycolide) (PLGA) PLGA Lactide:Glycolide Ratio M w Termial Group Degradatio Time Prod. No. 5:95 * 1.1 dl/g viscosity <4 moths :50 24,000 38,000 acid <3 moths :50 24,000 38,000 ester <3 moths :50 38,000 54,000 acid <3 moths :50 38,000 54,000 ester <3 moths :50 54,000 69,000 ester <3 moths :50 7,000 17,000 acid <3 moths :50 7,000 17,000 ester <3 moths :35 24,000 38,000 acid <5 moths :25 4,000 15,000 acid <6 moths :25 76, ,000 ester <6 moths :15 50,000 75,000 ester <6 moths :15 190, ,000 ester <9 moths For more iformatio, visit sigma-aldrich.com 3

4 Natural Polymers Name Structure Descriptio Viscosity Prod. No. H low molecular weight cp, 1 wt. % i 1% acetic acid (25 C, Brookfield) (lit.) Chitosa H H H NH 2 H NH 2 medium molecular weight high molecular weight cp, 1 wt. % i 1% acetic acid (25 C, Brookfield) (lit.) 800 2,000 cp, 1 wt. % i 1% acetic acid (25 C, Brookfield) (lit.) Algiic acid sodium salt powder cp, 1 % i H 2 (lit.) TRANSLATE DISCVERIES INT THERAPEUTICS Improve accuracy, reproducibility ad cofidece i your drug discovery ad drug delivery research Biodegradable Polymers: polylactide ad polyglycolide (PLA, PGA, PLGA), RESMER, ad chitosa Hydrophilic Polymers: PEGs, poly(2-oxazolie), PNIPAM Cojugated Naomaterials: Au, Ag, iro oxide aoparticles, graphee oxide, ad carbo aotubes Broad Selectio of Polymerizatio Tools: moomers, iitiators, ad CRP agets TRANSLATINAL RESEARCH SLUTINS TARGET ID & VALIDATIN LEAD DISCVERY LEAD PTIMIZATIN PRE-CLINICAL DEVELPMENT CLINICAL DEVELPMENT MANUFACTURING Move your research forward with our polymer therapeutics solutios sigma-aldrich.com/traslatioal 4 Polymers for Drug

5 Biodegradable Block Copolymer Micelles Cotrolled Ehacemet Amphiphilic diblock copolymers cosistig of a hydrophilic block (PEG) ad a hydrophobic block (PLA, PGA, PLGA, PCL), have the capacity to form micelles to ecapsulate hydrophobic drugs i order to icrease drug solubility ad facilitate delivery. The phase segregatio of polymer blocks ito a micellar morphology creates a eviromet where hydrophobic molecules ca dissolve i the hydrophobic core. H 3C CH 2 CH 2 C CH x m CH3 PEG block (hydrophilic) C CH 2 PLGA Block (hydrophobic) y H Hydrophilic Solvet Hydrophilic PEG Hydrophobic Block Hydrophobic Drug Example Techique: Drug loaded micelles are commoly formed by aoprecipitatio. Block copolymer ad drug are dissolved i ad orgaic solvet; the solutio is the added drop-wise ito agitated/stirred water, the orgaic solvet evaporates which causes the amphiphilic copolymers to self-assembly to form micelles. Micelles ca be collected by cetrifugatio, ad lyophilizatio. Biodegradable Block Copolymers Name PEG M B Block M PDI Degradatio Time Prod. No. AB Diblock Copolymers PEG-PDLLA 2,000 2,200 < weeks ,000 5,000 <1.4 >12 moths PEG-PCL 5,000 13,000 <1.4 >12 moths ,000 32,000 <1.4 >12 moths ,000 4,000 < weeks PEG-PLGA 2,000 15,000 < weeks ,000 10,000 < weeks ,000 55,000 < weeks BAB Triblock Copolymers PLA-PEG-PLA 900 1,500 <1.2 >12 moths ,000 1,000 <1.2 >12 moths PLGA-PEG-PLGA (lactide:glycolide 50:50) 1,000 2,000 < weeks PLGA-PEG-PLGA (lactide:glycolide 75:25) 1,000 2,000 < weeks PLGA-PEG-PLGA urethae(lactide:glycolide 1:0.8) 400 6,000 12,000 <2.0 <4 moths PLGA-PEG-PLGA urethae (lactide:glycolide 80:20) 400 6,000 15,000 <2.0 <4 moths PLGA-PEG-PLGA urethae (lactide:glycolide 80:20) 400 8,000 20,000 < PLCL-PEG-PLCL 5,000 5,700 < moths PGA-PEG-PGA (PEG:glycolide 8:92) PGA-PEG-PGA (PEG:glycolide 12:88) For more iformatio, visit sigma-aldrich.com 5

6 Biodegradable Targetig Micro ad Naoparticles with Fuctioal Polymers Cotrolled Ehacemet delivery of drugs ca be achieved through the cojugatio of targetig moieties usig fuctioalized polymers. For example, aoparticles or micelles (i.e., PLGA aoparticles), made with edgroup fuctioalized polymers, ca be grafted to specific targetig peptides, ligads, or atibodies through biocojugatio techiques. Cojugatio with Targetig Moiety Biodegradable polymers with diverse ed-groups ameable to a variety of cojugatio strategies. PLGA Particles Ed-fuctioalized Poly(L-lactide)s Name Structure M PDI Prod. No. Acrylate H CH 2 2, , Acetylee H CH 2, , Amie H NH 2 Azide H N 3 2, , , Maleimide N H 2, , Methacrylate H CH 2 2, , Thiol H SH 2, , Polymers for Drug

7 Resposive Polymers Cotrolled Ehacemet Stimuli-resposive polymers have bee widely employed to eable targeted delivery ad cotrolled release i respose to chages i their eviromet. Stimuli-resposive polymers udergo rapid chages i their microstructure from a hydrophilic to hydrophobic state, triggered by exteral stimuli, icludig heat, ph, ad ioic stregth. Drug delivery systems (micelles, microgels, ad hydrogels) composed of resposive polymers release the drug durig the collapse ad expasio of the etwork i the aqueous eviromet. The most extesively ivestigated temperature/ph sesitive systems are based o poly(n-isopropylacrylamide) (PNIPAM). Temperature- or ph-resposive hydrophilic polymers, such as ed-fuctioalized PNIPAMs, allow for the activatio of a payload upo delivery. Polymeric Micelle-drug Complex Drug Acceleratio ad Cellular Adsorptio Ehacemet Below LCST Above LCST Poly(N-isopropylacrylamide) (PNIPAM) Structure Molecular Weight Prod. No. H 3 C NH M w 20,000 40, Ed-fuctioalized PNIPAM Structure Fuctioal Ed Group Average M Prod. No. Amie 2, , Azide 15, , , Si Carboxylic acid S 7, NH 10, H 3 C N-hydroxylsucciimide (NHS) ester 2, , Maleimide 2, , Triethoxysilae 2, Temperature ad ph Sesitive PNIPAM Copolymers Copolymer Average M LCST Prod. No. Poly(NIPAM-co-BA) BA 12 mol % 30, C Poly(NIPAM-co-BA) BA 5 mol % 30, C Poly(NIPAM-co-MAA-co-DA)* MAA 5 mol %, DA 1 mol % 30,000 60, C Poly(NIPAM-co-MAA)* MAA 5 mol % 30,000 50, C Poly(NIPAM-co-MAA)* MAA 10 mol % 60, C Poly(NIPAM-co-MAA)* MAA 10 mol % 8,000 10, C Poly(NIPAM-co-AA)* AA 15 mol % ** C Poly(NIPAM-co-AAm) AAm 15 mol % 20,000 25, C Poly(NIPAM-co-AAm) AAm 10 mol % 20, C BA: butylacrylate, MAA: methacrylic acid, DA: octadecyl acrylate, AA: acrylic acid, AAm: acrylamide *ph sesitive **Liear hydrogel, viscosity 7,500 12,500 cps (5 wt. % i H 2, 25 C) For more iformatio, visit sigma-aldrich.com 7

8 PEG Cojugatio (PEGylatio) Cotrolled Ehacemet Poor drug solubility ad biocompatibility is a sigificat challege with may ew drug cadidates. Modifyig a drug by attachig a fuctioal PEG ca ehace drug solubility, reduce protei aggregatio, ad decrease immuogeicity. By icreasig the molecular mass of proteis ad peptides ad shieldig them from proteolytic ezymes, PEGylatio improves pharmacokietics. The proper molecular weight selectio of the PEG liker ca sigificatly ehace the solubility ad distributio of a drug cadidate withi a orgaism. A fuctioalized PEG platform ameable to a variety of cojugatio strategies. MALDI-TF verified structures ad degree of fuctioalizatio esures reproducible formulatio. PEGylatio Icreased hydrodyamic size Loger half-life Improved solubility Reduced immuogeecity of drug Moofuctioal mpegs Fuctioal Ed Group PEG M Prod. No. Acrylate Amie Azide MAL NHS Thiol 2, , , , , , , , , , , , , , Polymers for Drug

9 Polyoxazolie Cojugatio Cotrolled Ehacemet Poly(2-oxazolies), low-viscosity PEG alteratives, are biocompatible ad exhibit stealth behavior. Polyoxazolies ca be used for drug cojugatio, similar to PEGylatio. Polyoxazolies ca be used as a alterative to PEGs to address poor drug solubility ad biocompatibility i a drug cadidate. A exclusive selectio of hydrophilic Poly(2-oxazolies) for cojugatio ad tuable water solubility. Poly(oxazolie)s Name Structure M PDI Prod. No. 5, H 3 C H Poly(2-ethyl-2-oxazolie) N 10,000 < , Poly(2-methyl-2-oxazolie), hydroxy termiated N H 2,000 < Poly(2-ethyl-2-oxazolie), alkye termiated moo amie termiated H H 3 C N CH 2, , Dedrimers Cotrolled Ehacemet Dedrimers ca be used as a drug delivery vehicle to address poor bioavailability ad low solubility of small molecules, as well as for multidrug delivery of hydrophobic ad hydrophilic drugs. Dedrimers are highly brached, core-shell aostructures with precise architectures ad low polydispersity. Dedrimers are sythesized i a geeratio-by-geeratio fashio aroud a core uit, resultig i a high level of cotrol over size, brachig poits, ad surface fuctioality. Drugs ca be icorporated ito dedrimer carriers by passive ecapsulatio, where the drug is physically ecapsulated i the iterior or by covalet attachmet of the drug to the dedrimer by chemically reactive fuctioal groups to geerate a drug-dedrimer cojugate. dedrimer drug carriers ca be sythesized by the cojugatio of targetig moieties o the periphery of the dedritic carrier. Hyperbrached PAMAM ad PEG-core dedrimers with a wide selectio of active surface groups for cojugatio. Iterior with multiple braches (geeratios G), well-suited for ecapsulatio of drugs ad aomaterials Core Iterior Surface Surface modified with multiple surface groups * for host-guest iteractios ad fuctioalizatio For more iformatio, visit sigma-aldrich.com 9

10 PEG Dedrimer Structure R R R R CH3 Geeratio Surface Groups No. of Surface Groups PEG M Prod. No. 1 Acetylee 4 6, MG 20, MG H H R R H3C H3C R= R R * R = H H H3C H H 1 Hydroxyl 4 6, MG 20, MG 2 Acetylee 8 6, MG 20, MG 2 Hydroxyl 8 6, MG 20, MG R R R R R= * 3 Acetylee 16 6, MG 20, MG R R H3C R = * R R H H H 3 Hydroxyl 16 6, MG 20, MG H R R CH3 CH3 H3C H3C H3C R R R = H3C H3C H3C H H 4 Hydroxyl 32 6, MG 20, MG R R R R H H PAMAM Dedrimers (ethyleediamie core) Geeratio Surface Groups No. of Surface Groups Prod. No. 0 Amio Amio Amio Amio Amio Amio Amio Amidoethaol Amidoethaol Amidoethaol Amidoethaol Amidoethaol Amidoethaol Polymers for Drug

11 Polymeric Hydrogels for Localized Cotrolled Ehacemet Site-specific, or localized delivery of drugs or bioactive factors ca be achieved usig polymeric hydrogels. Polymer hydrogels ca be desiged with a wide rage of polymers ad crosslikig schemes to make materials that have cotrolled ad sustaied drug release. For example, PEG-based hydrogels, formed from by chemical crosslikig multifuctioal PEGs, have bee used to deliver small molecules ad growth factors. Natural polymers (chitosa), biodegradable polymers (PLGA) ad stimuli-resposive polymers such as PNIPAM have also bee fabricated ito hydrogels for localized ad cotrolled drug, protei, or gee delivery. A selectio of multi-arm ad bifuctioal PEGs ameable to a variety crosslikig strategies to form hydrogels. Heterobifuctioal PEGs Fuctioal Ed Group PEG M Prod. No. HS-PEG-CH 1, NHS-PEG-Bioti 3, NHS-PEG-Maleimide 4, , Amie-PEG-CH 2, , Homobifuctioal PEGs Fuctioal Ed Group PEG M Prod. No. Azide-PEG-Azide 10, , , Amie-PEG-Amie 6, , , Thiol-PEG-Thiol 3, , Multi-arm PEGs Fuctioal Ed Group Number of Arms Prod. No. Amie Carboxylic Hydroxy Succiimidyl glutarate Succiimidyl succiate Thiol *Also see previous product tables: PNIPAM ad PLGA for additioal hydrogel formig polymers For more iformatio, visit sigma-aldrich.com 11

12 PLYMERIC DRUG DELIVERY TECHNIQUES Traslatig Polymer Sciece for Drug A guide to drug delivery solutios usig polymers for cotrolled release, targeted drug delivery ad solubility ehacemet. ystep-by-step methods writte by drug delivery experts highlightig polymer-based methods to solve the most importat drug delivery challeges ysolutios for: Small molecules Nucleic acids Proteis ykey techologies: Drug cojugatio ad PEGylatio Biodegradable aoparticles ad micelles RAFT polymeric carriers for ADCs Dedros Resposive drug delivery systems Polymers for oligoucleotide delivery Request your copy olie at Aldrich.com/ddtechique Eablig Sciece to Improve the Quality of Life rder/customer Service: sigma-aldrich.com/order Techical Service: sigma-aldrich.com/techservice Developmet/Custom Maufacturig Iquiries [email protected] Safety-related Iformatio: sigma-aldrich.com/safetyceter World Headquarters 3050 Spruce St. St. Louis, M (314) sigma-aldrich.com 2015 Sigma-Aldrich Co. LLC. All rights reserved. SIGMA, SAFC, SIGMA-ALDRICH, ALDRICH ad SUPELC are trademarks of Sigma-Aldrich Co. LLC, registered i the US ad other coutries. FLUKA is a trademark of Sigma-Aldrich GmbH, registered i the US ad other coutries. Sigma-Aldrich, Sigma, Aldrich, Supelco, Fluka ad SAFC brad products are sold by affiliated Sigma-Aldrich distributors. Purchaser must determie the suitability of the product(s) for their particular use. Additioal terms ad coditios may apply. Please see product iformatio o the Sigma-Aldrich website at ad/or o the reverse side of the ivoice or packig slip. RRF