Development of PLGA micro- and nanorods with high capacity of surface ligand conjugation for enhanced targeted delivery
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摘要
Particle shape has been recognized as one of the key properties of nanoparticles in biomedical applications including targeted drug delivery. Targeting ability of shape-engineered particles depends largely on targeting ligands conjugated on the particle surface. However, poor capacity for surface ligand conjugation remains a problem in anisotropic nanoparticles made with biodegradable polymers such as PLGA. In this study, we prepared anisotropic PLGA nanoparticles with abundant conjugatable surface functional groups by a film stretching-based fabrication method with poly(ethylene-alt-maleic acid)(PEMA). Scanning electron microscopy images showed that microrods and nanorods were successfully fabricated by the PEMA-based film stretching method. The presence of surface carboxylic acid groups was confirmed by confocal microscopy and zeta potential measurements. Using the improved film-stretching method, the amount of protein conjugated to the surface of nanorods was increased three-fold. Transferrin-conjugated, nanorods fabricated by the improved method exhibited higher binding and internalization than unmodified counterparts. Therefore, the PEMA-based film-stretching system presented in this study would be a promising fabrication method for non-spherical biodegradable polymeric micro-and nanoparticles with high capacity of surface modifications for enhanced targeted delivery.
Particle shape has been recognized as one of the key properties of nanoparticles in biomedical applications including targeted drug delivery. Targeting ability of shape-engineered particles depends largely on targeting ligands conjugated on the particle surface. However, poor capacity for surface ligand conjugation remains a problem in anisotropic nanoparticles made with biodegradable polymers such as PLGA. In this study, we prepared anisotropic PLGA nanoparticles with abundant conjugatable surface functional groups by a film stretching-based fabrication method with poly(ethylene-alt-maleic acid)(PEMA). Scanning electron microscopy images showed that microrods and nanorods were successfully fabricated by the PEMA-based film stretching method. The presence of surface carboxylic acid groups was confirmed by confocal microscopy and zeta potential measurements. Using the improved film-stretching method, the amount of protein conjugated to the surface of nanorods was increased three-fold. Transferrin-conjugated, nanorods fabricated by the improved method exhibited higher binding and internalization than unmodified counterparts. Therefore, the PEMA-based film-stretching system presented in this study would be a promising fabrication method for non-spherical biodegradable polymeric micro-and nanoparticles with high capacity of surface modifications for enhanced targeted delivery.
Particle shape has been recognized as one of the key properties of nanoparticles in biomedical applications including targeted drug delivery. Targeting ability of shape-engineered particles depends largely on targeting ligands conjugated on the particle surface. However, poor capacity for surface ligand conjugation remains a problem in anisotropic nanoparticles made with biodegradable polymers such as PLGA. In this study, we prepared anisotropic PLGA nanoparticles with abundant conjugatable surface functional groups by a film stretching-based fabrication method with poly(ethylene-alt-maleic acid)(PEMA). Scanning electron microscopy images showed that microrods and nanorods were successfully fabricated by the PEMA-based film stretching method. The presence of surface carboxylic acid groups was confirmed by confocal microscopy and zeta potential measurements. Using the improved film-stretching method, the amount of protein conjugated to the surface of nanorods was increased three-fold. Transferrin-conjugated, nanorods fabricated by the improved method exhibited higher binding and internalization than unmodified counterparts. Therefore, the PEMA-based film-stretching system presented in this study would be a promising fabrication method for non-spherical biodegradable polymeric micro-and nanoparticles with high capacity of surface modifications for enhanced targeted delivery.
引文
[1]Park O,Yu G,Jung H,Mok H.Recent studies on micro-/nano-sized biomaterials for cancer immunotherapy.JPharm Investig 2017;47(1):11-18.
[2]Mohtashamian S,Boddohi S.Nanostructured polysaccharide-based carriers for antimicrobial peptide delivery.J Pharm Investig 2017;47(2):85-94.
[3]Choi JH,Lee YJ,Kim D.Image-guided nanomedicine for cancer.J Pharm Investig 2017;47(1):51-64.
[4]Sarisozen C,Pan J,Dutta I,Torchilin VP.Polymers in the co-delivery of siRNA and anticancer drugs to treat multidrug-resistant tumors.J Pharm Investig2017;47(1):37-49.
[5]Albanese A,Tang PS,Chan WC.The effect of nanoparticle size,shape,and surface chemistry on biological systems.Annu Rev Biomed Eng 2012;14:1-16.
[6]Lee SS,Lee YB,Oh IJ.Cellular uptake of poly(dl-lactide-co-glycolide)nanoparticles:effects of drugs and surface characteristics of nanoparticles.J Pharm Investig2015;45(7):659-67.
[7]Yoo JW,Irvine DJ,Discher DE,Mitragotri S.Bio-inspired,bioengineered and biomimetic drug delivery carriers.Nat Rev Drug Discov 2011;10(7):521-35.
[8]Yoo JW,Doshi N,Mitragotri S.Adaptive micro and nanoparticles:temporal control over carrier properties to facilitate drug delivery.Adv Drug Deliv Rev2011;63(14):1247-56.
[9]Hoang NH,Lim C,Sim T,Oh KT.Triblock copolymers for nano-sized drug delivery systems.J Pharm Investig2017;47(1):27-35.
[10]Mitragotri S.In drug delivery,shape does matter.Pharm Res2009;26(1):232-4.
[11]Champion JA,Katare YK,Mitragotri S.Particle shape:a new design parameter for micro-and nanoscale drug delivery carriers.J Control Release 2007;121(1):3-9.
[12]Agarwal R,Singh V,Jurney P,Shi L,Sreenivasan S,Roy K.Mammalian cells preferentially internalize hydrogel nanodiscs over nanorods and use shape-specific uptake mechanisms.Proc Natl Acad Sci USA 2013;110(43):17247-52.
[13]Gavze E,Shapiro M.Motion of inertial spheroidal particles in a shear flow near a solid wall with special application to aerosol transport in microgravity.J Fluid Mech1998;371:59-79.
[14]Thompson AJ,Mastria EM,Eniola-Adefeso O.The margination propensity of ellipsoidal micro/nanoparticles to the endothelium in human blood flow.Biomaterials2013;34(23):5863-71.
[15]Florez L,Herrmann C,Cramer JM,et al.How shape influences uptake:interactions of anisotropic polymer nanoparticles and human mesenchymal stem cells.Small2012;8(14):2222-30.
[16]Gratton SE,Ropp PA,Pohlhaus PD,et al.The effect of particle design on cellular internalization pathways.Proc Natl Acad Sci USA 2008;105(33):11613-18.
[17]Geng Y,Dalhaimer P,Cai S,et al.Shape effects of filaments versus spherical particles in flow and drug delivery.Nat Nanotechnol 2007;2(4):249-55.
[18]Park JH,von Maltzahn G,Zhang L,et al.Systematic surface engineering of magnetic nanoworms for in vivo tumor targeting.Small 2009;5(6):694-700.
[19]Janát-Amsbury M,Ray A,Peterson C,Ghandehari H.Geometry and surface characteristics of gold nanoparticles influence their biodistribution and uptake by macrophages.Eur J Pharm Biopharm 2011;77(3):417-23.
[20]Rolland JP,Maynor BW,Euliss LE,Exner AE,Denison GM,DeSimone JM.Direct fabrication and harvesting of monodisperse,shape-specific nanobiomaterials.J Am Chem Soc 2005;127(28):10096-100.
[21]Xu S,Nie Z,Seo M,et al.Generation of monodisperse particles by using microfluidics:control over size,shape,and composition.Angew Chem 2005;117(5):734-8.
[22]Mathaes R,Winter G,Besheer A,Engert J.Non-spherical micro-and nanoparticles:fabrication,characterization and drug delivery applications.Expert Opin Drug Deliv2015;12(3):481-92.
[23]Champion JA,Katare YK,Mitragotri S.Making polymeric micro-and nanoparticles of complex shapes.Proc Natl Acad Sci USA 2007;104(29):11901-4.
[24]Meyer RA,Meyer RS,Green JJ.An automated multidimensional thin film stretching device for the generation of anisotropic polymeric micro-and nanoparticles.J Biomed Mater Res A 2015;103(8):2747-57.
[25]Kumar S,Anselmo AC,Banerjee A,Zakrewsky M,Mitragotri S.Shape and size-dependent immune response to antigen-carrying nanoparticles.J Control Release2015;220:141-8.
[26]Fan JB,Song Y,Li H,Jia JP,Guo X,Jiang L.Controllable drug release and effective intracellular accumulation highlighted by anisotropic biodegradable PLGE nanoparticles.J Mater Chem B 2014;2(25):3911-14.
[27]Banerjee A,Qi J,Gogoi R,Wong J,Mitragotri S.Role of nanoparticle size,shape and surface chemistry in oral drug delivery.J Control Release 2016;238:176-85.
[28]Barua S,Yoo JW,Kolhar P,Wakankar A,Gokarn YR,Mitragotri S.Particle shape enhances specificity of antibody-displaying nanoparticles.Proc Natl Acad Sci USA2013;110(9):3270-5.
[29]Kolhar P,Anselmo AC,Gupta V,et al.Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium.Proc Natl Acad Sci USA 2013;110(26):10753-8.
[30]Choi JS,Seo K,Yoo JW.Recent advances in PLGA particulate systems for drug delivery.J Pharm Investig 2012;42(3):155-63.
[31]Patil S,Sandberg A,Heckert E,Self W,Seal S.Protein adsorption and cellular uptake of cerium oxide nanoparticles as a function of zeta potential.Biomaterials2007;28(31):4600-7.
[32]Sahoo SK,Panyam J,Prabha S,Labhasetwar V.Residual polyvinyl alcohol associated with poly(D,l-lactide-co-glycolide)nanoparticles affects their physical properties and cellular uptake.J Control Release2002;82(1):105-14.
[33]Eniola AO,Rodgers SD,Hammer DA.Characterization of biodegradable drug delivery vehicles with the adhesive properties of leukocytes.Biomaterials 2002;23(10):2167-77.
[34]Cao J,Naeem M,Noh JK,Lee EH,Yoo JW.Dexamethasone phosphate-loaded folate-conjugated polymeric nanoparticles for selective delivery to activated macrophages and suppression of inflammatory responses.Macromol Res 2015;23(5):485-92.
[35]Keegan ME,Falcone JL,Leung TC,Saltzman WM.Biodegradable microspheres with enhanced capacity for covalently bound surface ligands.Macromolecules2004;37(26):9779-84.
[36]Sunshine JC,Perica K,Schneck JP,Green JJ.Particle shape dependence of CD8+T cell activation by artificial antigen presenting cells.Biomaterials 2014;35(1):269-77.
[37]Govender T,Stolnik S,Garnett MC,Illum L,Davis SS.PLGAnanoparticles prepared by nanoprecipitation:drug loading and release studies of a water soluble drug.J Control Release1999;57(2):171-85.
[38]Lo CT,Van Tassel PR,Saltzman WM.Simultaneous release of multiple molecules from poly(lactide-co-glycolide)nanoparticles assembled onto medical devices.Biomaterials2009;30(28):4889-97.
[39]Choi JS,Cao J,Naeem M,et al.Size-controlled biodegradable nanoparticles:preparation and size-dependent cellular uptake and tumor cell growth inhibition.Colloids Surf BBiointerfaces 2014;122:545-51.
[40]Danhier F,Ansorena E,Silva JM,Coco R,Le Breton A,Préat V.PLGA-based nanoparticles:an overview of biomedical applications.J Control Release 2012;161(2):505-22.
[41]Portlock JCalos M.Site-specific genomic strategies for gene therapy.Curr Opin Mol Ther 2003;5(4):376-82.
[42]Sim T,Lim C,Hoang NH,Oh KT.Recent advance of pH-sensitive nanocarriers targeting solid tumors.J Pharm Investig 2017;47(5):383-94.
[43]Kim CH,Lee SG,Kang MJ,Lee S,Choi YW.Surface modification of lipid-based nanocarriers for cancer cell-specific drug targeting.J Pharm Investig2017;47(3):203-27.
[44]Wilhelm C,Billotey C,Roger J,Pons J,Bacri JC,Gazeau F.Intracellular uptake of anionic superparamagnetic nanoparticles as a function of their surface coating.Biomaterials 2003;24(6):1001-11.
[45]Yang PH,Sun X,Chiu JF,Sun H,He QY.Transferrin-mediated gold nanoparticle cellular uptake.Bioconjug Chem2005;16(3):494-6.
[2]Mohtashamian S,Boddohi S.Nanostructured polysaccharide-based carriers for antimicrobial peptide delivery.J Pharm Investig 2017;47(2):85-94.
[3]Choi JH,Lee YJ,Kim D.Image-guided nanomedicine for cancer.J Pharm Investig 2017;47(1):51-64.
[4]Sarisozen C,Pan J,Dutta I,Torchilin VP.Polymers in the co-delivery of siRNA and anticancer drugs to treat multidrug-resistant tumors.J Pharm Investig2017;47(1):37-49.
[5]Albanese A,Tang PS,Chan WC.The effect of nanoparticle size,shape,and surface chemistry on biological systems.Annu Rev Biomed Eng 2012;14:1-16.
[6]Lee SS,Lee YB,Oh IJ.Cellular uptake of poly(dl-lactide-co-glycolide)nanoparticles:effects of drugs and surface characteristics of nanoparticles.J Pharm Investig2015;45(7):659-67.
[7]Yoo JW,Irvine DJ,Discher DE,Mitragotri S.Bio-inspired,bioengineered and biomimetic drug delivery carriers.Nat Rev Drug Discov 2011;10(7):521-35.
[8]Yoo JW,Doshi N,Mitragotri S.Adaptive micro and nanoparticles:temporal control over carrier properties to facilitate drug delivery.Adv Drug Deliv Rev2011;63(14):1247-56.
[9]Hoang NH,Lim C,Sim T,Oh KT.Triblock copolymers for nano-sized drug delivery systems.J Pharm Investig2017;47(1):27-35.
[10]Mitragotri S.In drug delivery,shape does matter.Pharm Res2009;26(1):232-4.
[11]Champion JA,Katare YK,Mitragotri S.Particle shape:a new design parameter for micro-and nanoscale drug delivery carriers.J Control Release 2007;121(1):3-9.
[12]Agarwal R,Singh V,Jurney P,Shi L,Sreenivasan S,Roy K.Mammalian cells preferentially internalize hydrogel nanodiscs over nanorods and use shape-specific uptake mechanisms.Proc Natl Acad Sci USA 2013;110(43):17247-52.
[13]Gavze E,Shapiro M.Motion of inertial spheroidal particles in a shear flow near a solid wall with special application to aerosol transport in microgravity.J Fluid Mech1998;371:59-79.
[14]Thompson AJ,Mastria EM,Eniola-Adefeso O.The margination propensity of ellipsoidal micro/nanoparticles to the endothelium in human blood flow.Biomaterials2013;34(23):5863-71.
[15]Florez L,Herrmann C,Cramer JM,et al.How shape influences uptake:interactions of anisotropic polymer nanoparticles and human mesenchymal stem cells.Small2012;8(14):2222-30.
[16]Gratton SE,Ropp PA,Pohlhaus PD,et al.The effect of particle design on cellular internalization pathways.Proc Natl Acad Sci USA 2008;105(33):11613-18.
[17]Geng Y,Dalhaimer P,Cai S,et al.Shape effects of filaments versus spherical particles in flow and drug delivery.Nat Nanotechnol 2007;2(4):249-55.
[18]Park JH,von Maltzahn G,Zhang L,et al.Systematic surface engineering of magnetic nanoworms for in vivo tumor targeting.Small 2009;5(6):694-700.
[19]Janát-Amsbury M,Ray A,Peterson C,Ghandehari H.Geometry and surface characteristics of gold nanoparticles influence their biodistribution and uptake by macrophages.Eur J Pharm Biopharm 2011;77(3):417-23.
[20]Rolland JP,Maynor BW,Euliss LE,Exner AE,Denison GM,DeSimone JM.Direct fabrication and harvesting of monodisperse,shape-specific nanobiomaterials.J Am Chem Soc 2005;127(28):10096-100.
[21]Xu S,Nie Z,Seo M,et al.Generation of monodisperse particles by using microfluidics:control over size,shape,and composition.Angew Chem 2005;117(5):734-8.
[22]Mathaes R,Winter G,Besheer A,Engert J.Non-spherical micro-and nanoparticles:fabrication,characterization and drug delivery applications.Expert Opin Drug Deliv2015;12(3):481-92.
[23]Champion JA,Katare YK,Mitragotri S.Making polymeric micro-and nanoparticles of complex shapes.Proc Natl Acad Sci USA 2007;104(29):11901-4.
[24]Meyer RA,Meyer RS,Green JJ.An automated multidimensional thin film stretching device for the generation of anisotropic polymeric micro-and nanoparticles.J Biomed Mater Res A 2015;103(8):2747-57.
[25]Kumar S,Anselmo AC,Banerjee A,Zakrewsky M,Mitragotri S.Shape and size-dependent immune response to antigen-carrying nanoparticles.J Control Release2015;220:141-8.
[26]Fan JB,Song Y,Li H,Jia JP,Guo X,Jiang L.Controllable drug release and effective intracellular accumulation highlighted by anisotropic biodegradable PLGE nanoparticles.J Mater Chem B 2014;2(25):3911-14.
[27]Banerjee A,Qi J,Gogoi R,Wong J,Mitragotri S.Role of nanoparticle size,shape and surface chemistry in oral drug delivery.J Control Release 2016;238:176-85.
[28]Barua S,Yoo JW,Kolhar P,Wakankar A,Gokarn YR,Mitragotri S.Particle shape enhances specificity of antibody-displaying nanoparticles.Proc Natl Acad Sci USA2013;110(9):3270-5.
[29]Kolhar P,Anselmo AC,Gupta V,et al.Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium.Proc Natl Acad Sci USA 2013;110(26):10753-8.
[30]Choi JS,Seo K,Yoo JW.Recent advances in PLGA particulate systems for drug delivery.J Pharm Investig 2012;42(3):155-63.
[31]Patil S,Sandberg A,Heckert E,Self W,Seal S.Protein adsorption and cellular uptake of cerium oxide nanoparticles as a function of zeta potential.Biomaterials2007;28(31):4600-7.
[32]Sahoo SK,Panyam J,Prabha S,Labhasetwar V.Residual polyvinyl alcohol associated with poly(D,l-lactide-co-glycolide)nanoparticles affects their physical properties and cellular uptake.J Control Release2002;82(1):105-14.
[33]Eniola AO,Rodgers SD,Hammer DA.Characterization of biodegradable drug delivery vehicles with the adhesive properties of leukocytes.Biomaterials 2002;23(10):2167-77.
[34]Cao J,Naeem M,Noh JK,Lee EH,Yoo JW.Dexamethasone phosphate-loaded folate-conjugated polymeric nanoparticles for selective delivery to activated macrophages and suppression of inflammatory responses.Macromol Res 2015;23(5):485-92.
[35]Keegan ME,Falcone JL,Leung TC,Saltzman WM.Biodegradable microspheres with enhanced capacity for covalently bound surface ligands.Macromolecules2004;37(26):9779-84.
[36]Sunshine JC,Perica K,Schneck JP,Green JJ.Particle shape dependence of CD8+T cell activation by artificial antigen presenting cells.Biomaterials 2014;35(1):269-77.
[37]Govender T,Stolnik S,Garnett MC,Illum L,Davis SS.PLGAnanoparticles prepared by nanoprecipitation:drug loading and release studies of a water soluble drug.J Control Release1999;57(2):171-85.
[38]Lo CT,Van Tassel PR,Saltzman WM.Simultaneous release of multiple molecules from poly(lactide-co-glycolide)nanoparticles assembled onto medical devices.Biomaterials2009;30(28):4889-97.
[39]Choi JS,Cao J,Naeem M,et al.Size-controlled biodegradable nanoparticles:preparation and size-dependent cellular uptake and tumor cell growth inhibition.Colloids Surf BBiointerfaces 2014;122:545-51.
[40]Danhier F,Ansorena E,Silva JM,Coco R,Le Breton A,Préat V.PLGA-based nanoparticles:an overview of biomedical applications.J Control Release 2012;161(2):505-22.
[41]Portlock JCalos M.Site-specific genomic strategies for gene therapy.Curr Opin Mol Ther 2003;5(4):376-82.
[42]Sim T,Lim C,Hoang NH,Oh KT.Recent advance of pH-sensitive nanocarriers targeting solid tumors.J Pharm Investig 2017;47(5):383-94.
[43]Kim CH,Lee SG,Kang MJ,Lee S,Choi YW.Surface modification of lipid-based nanocarriers for cancer cell-specific drug targeting.J Pharm Investig2017;47(3):203-27.
[44]Wilhelm C,Billotey C,Roger J,Pons J,Bacri JC,Gazeau F.Intracellular uptake of anionic superparamagnetic nanoparticles as a function of their surface coating.Biomaterials 2003;24(6):1001-11.
[45]Yang PH,Sun X,Chiu JF,Sun H,He QY.Transferrin-mediated gold nanoparticle cellular uptake.Bioconjug Chem2005;16(3):494-6.