Elementary processes for the entry of cell-penetrating peptides into lipid bilayer vesicles and bacterial cells
- 219 Downloads
Abstract
Cell-penetrating peptides (CPPs) can translocate across the plasma membrane of living eukaryotic cells and enter the cytosol without significantly affecting cell viability. Consequently, CPPs have been used for the intracellular delivery of biological cargo such as proteins and oligonucleotides. However, the mechanisms underlying the translocation of CPPs across the plasma membrane remain unclear. In this mini-review, we summarize the experimental results regarding the entry of CPPs into lipid bilayer vesicles obtained using three methods: the large unilamellar vesicle (LUV) suspension method, the giant unilamellar vesicle (GUV) suspension method, and the single GUV method. The advantages and disadvantages of these methods are also discussed. Experimental results to date clearly indicate that CPPs can translocate across lipid bilayers and enter the vesicle lumen. Three models for the mechanisms and pathways by which CPPs translocate across lipid bilayers are described: (A) through pores induced by CPPs, (B) through transient prepores, and (C) via formation of inverted micelles. Both the pathway of translocation and the efficiency of entry of CPPs depend on the lipid composition of the bilayer and the type of CPP. We also describe the interaction of CPPs with bacterial cells. Some CPPs have strong antimicrobial activities. There are two modes of action of CPPs on bacterial cells: CPPs can induce damage to the plasma membrane and thus increase permeability, or CPPs enter the cytosol of bacterial cells without damaging the plasma membrane. The information currently available on the elementary processes by which CPPs enter lipid bilayer vesicles and bacterial cells is valuable for elucidating the mechanisms of entry of CPPs into the cytosol of various eukaryotic cells.
Keywords
CPPs Transportan 10 Oligoarginine Large unilamellar vesicle Giant unilamellar vesicle Pore Prepore Leakage Bacterial cellsNotes
Compliance with ethical standards
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Conflict of interest
The authors declare that they have no conflict of interest.
References
- Akimov SA, Volynsky PE, Galimzyanov TR, Kuzmin PI, Pavlov KV, Batishchev OV (2017) Pore formation in lipid membrane I: continuous reversible trajectory from intact bilayer through hydrophobic defect to transversal pore. Sci Rep 7:12152CrossRefPubMedPubMedCentralGoogle Scholar
- Alam JM, Kobayashi T, Yamazaki M (2012) The single giant unilamellar vesicle method reveals lysenin-induced pore formation in lipid membranes containing sphingomyelin. Biochemistry 51:5160–5172CrossRefPubMedGoogle Scholar
- Aota-Nakano Y, Li SJ, Yamazaki M (1999) Effects of electrostatic interaction on the phase stability and structures of cubic phases of monoolein/oleic acid mixture membranes. Biochim Biophys Acta 1461:96–102CrossRefPubMedGoogle Scholar
- Bárány-Wallje E, Keller S, Serowy S, Geibel S, Pohl P, Bienert M, Dathe M (2005) A critical reassessment of penetratin translocation across lipid membranes. Biophys J 89:2513–2521CrossRefPubMedPubMedCentralGoogle Scholar
- Bárány-Wallje E, Gaur J, Lundberg P, Langle Ű, Gräslund A (2007) Differential membrane perturbation caused by the cell penetrating peptide TP10 depending on attached cargo. FEBS Lett 581:2389–2393CrossRefPubMedGoogle Scholar
- Baumgart T, Hess ST, Webb WW (2003) Imaging coexisting fluid domains in biomembrane models coupling curvature and line tension. Nature 425:821–824CrossRefPubMedGoogle Scholar
- Bechara C, Sagan S (2013) Cell-penetrating peptides: 20 years later, where do we stand? FEBS Lett 587:1693–1702CrossRefPubMedGoogle Scholar
- Berlose J-P, Convert O, Derossi D, Brunissen A, Chassaing G (1996) Conformational and associative behaviours of the third helix of antennapedia homeodomain in membrane-mimetic environments. Eur J Biochem 242:372–386CrossRefPubMedGoogle Scholar
- Bigay J, Antonny B (2012) Curvature, lipid packing, and electrostatics of membrane organelles: defining cellular territories in determining specificity. Dev Cell 23:886–895CrossRefPubMedGoogle Scholar
- Binder H, Lindblom G (2003) Charge-dependent translocation of the trojan peptide penetratin across lipid membranes. Biophys J 85:982–995CrossRefPubMedPubMedCentralGoogle Scholar
- Ciobanasu C, Siebrasse J, Kubitscheck U (2010) Cell-penetrating HIV1 TAT peptides can generate pores in model membranes. Biophys J 99:153–162CrossRefPubMedPubMedCentralGoogle Scholar
- Doherty GJ, McMahon HT (2009) Mechanisms of endocytosis. Annu Rev Biochem 78:857–902CrossRefPubMedGoogle Scholar
- Drin G, Déméné H, Temsamani J, Brasseur R (2001) Translocation of the pAntp peptide and its amphipathic analogue AP-2AL. Biochemistry 40:1824–1834CrossRefPubMedGoogle Scholar
- Duchardt F, Fotin-Mieczek M, Schwarz H, Fischer R, Brock R (2007) A comprehensive model for the cellular uptake of cationic cell-penetrating peptides. Traffic 8:848–866CrossRefPubMedGoogle Scholar
- EL-Andaloussi S, Johansson H, Magnusdottir A, Järver P, Lundberg P, Langel Ű (2005) TP10, a delivery vector for decoy oligonucleotides targeting the Myc protein. J Control Release 110:189–201CrossRefPubMedGoogle Scholar
- Elmquist A, Lindgren M, Bartfai T, Langel U (2001) VE-cadherin-derived cell-penetrating peptide, VEC, with carrier functions. Exp Cell Res 269:237–244CrossRefPubMedGoogle Scholar
- El-Sayed A, Futaki S, Harashima H (2009) Delivery of macromolecules using arginine-rich cell-penetrating peptides: ways to overcome endosomal entrapment. AAPS J 11:13–21CrossRefPubMedPubMedCentralGoogle Scholar
- Evans E, Smith BA (2011) Kinetics of hole nucleation in biomembrane rupture. New J Phys 13:095010CrossRefPubMedPubMedCentralGoogle Scholar
- Evans E, Heinrich V, Ludwig F, Rawicz W (2003) Dynamic tension spectroscopy and strength of biomembranes. Biophys J 85:2342–2350CrossRefPubMedPubMedCentralGoogle Scholar
- Fischer R, Köhler K, Fotin-Mleczek M, Brock R (2004) A stepwise dissection of the intracellular fate of cationic cell-penetrating peptides. J Biol Chem 279:12625–12635CrossRefPubMedGoogle Scholar
- Fuertes G, Giménez D, Esteban-Martín S, Sánchez-Muñoz O, Salgado J (2011) A lipocentric view of peptide-i nduced pores. Eur Biophys J 40:399–415CrossRefPubMedPubMedCentralGoogle Scholar
- Futaki S, Suzuki T, Ohashi W, Yagami T, Tanaka S, Ueda K, Sugiura Y (2001) Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery. J Biol Chem 276:5836–5840CrossRefPubMedGoogle Scholar
- Glaser RW, Leikin SL, Chernomordik LV, Pastushenko VF, Sokirko AI (1988) Reversible electrical breakdown of lipid bilayers: formation and evolution of pores. Biochim Biophys Acta 940:275–287CrossRefPubMedGoogle Scholar
- Herce HD, Garcia AE (2007) Molecular dynamics simulations suggest a mechanism for translocation of the HIV-1 TAT peptide across lipid membranes. Proc Natl Acad Sci U S A 104:20805–20810CrossRefPubMedPubMedCentralGoogle Scholar
- Herce HD, Garcia AE, Litt J, Kane RS, Martin P, Enrique N, Rebolledo A, Milesi V (2009) Arginine-rich peptides destabilizes the plasma membrane, consistent with a pore formation translocation mechanism of cell-penetrating peptides. Biophys J 97:1917–1925CrossRefPubMedPubMedCentralGoogle Scholar
- Hille B (1992) Ionic channels of excitable membranes, 2nd edn. Sinauer Association Inc., MassachusettsGoogle Scholar
- Islam MZ, Ariyama H, Alam JM, Yamazaki M (2014a) Entry of cell-penetrating peptide transportan 10 into a single vesicle by translocating across lipid membrane and its induced pores. Biochemistry 53:386–396CrossRefPubMedGoogle Scholar
- Islam MZ, Alam JM, Tamba Y, Karal MAS, Yamazaki M (2014b) The single GUV method for revealing the functions of antimicrobial, pore-forming toxin, and cell-penetrating peptides or proteins. Phys Chem Chem Phys 16:15752–15767CrossRefPubMedGoogle Scholar
- Islam MZ, Sharmin S, Levadnyy V, Shibly SUA, Yamazaki M (2017) Effects of mechanical properties of lipid bilayers on entry of cell-penetrating peptides into single vesicles. Langmuir 33:2433–2443CrossRefPubMedGoogle Scholar
- Karal MAS, Alam JM, Takahashi T, Levadny V, Yamazaki M (2015) Stretch-activated pore of antimicrobial peptide Magainin 2. Langmuir 31:3391–3401CrossRefPubMedGoogle Scholar
- Karal MAS, Levadnyy V, Yamazaki M (2016) Analysis of constant tension-induced rupture of lipid membranes using activation energy. Phys Chem Chem Phys 18:13487–13495CrossRefPubMedGoogle Scholar
- Karatekin E, Sandre O, Guitouni H, Borghi N, Puech P–H, Brochard-Wyart F (2003) Cascades of transient pores in giant vesicles: line tension and transport. Biophys J 84:1734–1749CrossRefPubMedPubMedCentralGoogle Scholar
- Kawamoto S, Takasu M, Miyakawa T, Morikawa R, Oda T, Futaki S, Nagao H (2011) Inverted micelles formation of cell-penetrating peptide studied by coarse-grained simulation: importance of attractive force between cell-penetrating peptides and lipid head group. J Chem Phys 134:095103CrossRefPubMedGoogle Scholar
- Ladokhin AS, Wimley WC, White SH (1995) Leakage of membrane vesicle contents: determination of mechanism using fluorescence requenching. Biophys J 69:1964–1971CrossRefPubMedPubMedCentralGoogle Scholar
- Lakowicz JR (2006) Principles of fluorescence spectroscopy, 3rd edn. Springer, New YorkCrossRefGoogle Scholar
- Levadny V, Tsuboi T, Belaya M, Yamazaki M (2013) Rate constant of tension-induced pore formation in lipid membranes. Langmuir 29:3848–3852CrossRefPubMedGoogle Scholar
- Li SJ, Yamashita Y, Yamazaki M (2001) Effect of electrostatic interactions on phase stability of cubic phases of membranes of monoolein/dioleoylphosphatidic acid mixture. Biophys J 81:983–993CrossRefPubMedPubMedCentralGoogle Scholar
- Lipowsky R, Sackmann E (eds) (1995) Structure and dynamics of membranes. Elsevier Science BV, AmsterdamGoogle Scholar
- Lonhienne TGA, Sagulenko E, Webb RI, Kee K-C, Franke J, Devos DP, Nouwens A, Carroll BJ, Fuerst JA (2010) Endocytosis-like protein uptake in the bacterium Gemmata obscuriglobus. Proc Natl Acad Sic USA 107:12883–12888CrossRefGoogle Scholar
- Luzzati V (1997) Biological significance of lipid polymorphism: the cubic phases. Curr Opin Struct Biol 7:661–668CrossRefPubMedGoogle Scholar
- Madani F, Lindberg S, Langel Ű, Futaki S, Gräslund A (2011) Mechanisms of cellular uptake of cell-penetrating peptides. J Biophysics 2011:414729CrossRefGoogle Scholar
- Magzoub M, Gräslund A (2004) Cell-penetrating peptides: small from inception to application. Q Rev Biophys 37:147–195CrossRefPubMedGoogle Scholar
- McLaughlin S, Murray D (2005) Plasma membrane phosphoinositide organization by protein electrostatics. Nature 438:605–611CrossRefPubMedGoogle Scholar
- Mishra A, Gordon VD, Yang L, Coridan R, Wong GCL (2008) HIV TAT forms pores in membranes by inducing saddle-spray curvature: potential role of bidentate hydrogen bonding. Angew Chem Int Ed 47:2986–2989CrossRefGoogle Scholar
- Mishra A, Lai GH, Schmidt NW, Sun VZ, Rodriguez AR, Tong R, Tang L, Cheng J, Deming TJ, Kamei DT, Wong GCL (2011) Translocation of HIV TAT peptide and analogues induced by multiplexed membrane and cytoskeletal interactions. Proc Natl Acad Sci U S A 108:16883–16888CrossRefPubMedPubMedCentralGoogle Scholar
- Moghal MMR, Islam MZ, Sharmin S, Levadnyy V, Moniruzzaman M, Yamazaki M (2018) Continuous detection of entry of cell-penetrating peptide transportan 10 into single vesicles. Chem Phys Lipids 212:120–129CrossRefPubMedGoogle Scholar
- Moniruzzaman M, Alam JM, Dohra H, Yamazaki M (2015) Antimicrobial peptide lactoferricin B-induced rapid leakage of internal contents from single giant unilamellar vesicles. Biochemistry 54:5802–5814CrossRefPubMedGoogle Scholar
- Moniruzzaman M, Islam MZ, Sharmin S, Dohra H, Yamazaki M (2017) Entry of a six-residue antimicrobial peptide derived from lactoferricin B into single vesicles and Escherichia coli cells without damaging their membranes. Biochemistry 56:4419–4431CrossRefPubMedGoogle Scholar
- Nekhotiaeva N, Elmquist A, Rajarao GK, Hällbrink M, Langel C, Good L (2004) Cell entry and antimicrobial properties of eukaryotic cell-penetrating peptides. FASEB J 18:394–396CrossRefPubMedGoogle Scholar
- Oka T, Tsuboi T, Saiki T, Takahashi T, Alam JM, Yamazaki M (2014) Initial step of pH-jump-induced lamellar to bicontinuous cubic phase transition in dioleoylphosphatidylserine/monoolein. Langmuir 30:8131–8140CrossRefPubMedGoogle Scholar
- Okamoto Y, Masum SM, Miyazawa H, Yamazaki M (2008) Low pH-induced transformation of bilayer membrane into bicontinuous cubic phase in dioleoyl-phosphatidylserine/monoolein membranes. Langmuir 24:3400–3406CrossRefPubMedGoogle Scholar
- Palm C, Netzereab S, Hällbrink M (2006) Quantitatively determined uptake of cell-penetrating peptides in non-mammalian cells with an evaluation of degradation and antimicrobial effects. Peptides 27:1710–1716CrossRefPubMedGoogle Scholar
- Persson D, Thorén PEG, Ksbjörner EK, Goksör M, Lincoln P, Nordén B (2004) Vesicles size-dependent translocation of penetratin analogs across lipid membranes. Biochim Biophys Acta 1665:142–155CrossRefPubMedGoogle Scholar
- Pisa MD, Chassaing G, Swiecicki J-M (2015) Translocation mechanism(s) of cell-penetrating peptides: biophysical studies using artificial membrane bilayers. Biochemistry 54:194–207CrossRefPubMedGoogle Scholar
- Pooga M, Hällbrink M, Zorko M, Langel Ű (1998) Cell penetration by transportan. FASEB J 12:67–77CrossRefPubMedGoogle Scholar
- Pooga M, Kut C, Kihlmark M, Hällbrink M, Fernaeus S, Raid R, Land T, Hallberg E, Bartfai TM, Langel Ű (2001) Cellular translocation of proteins by transportan. FASEB J 15:1451–1453CrossRefPubMedGoogle Scholar
- Qian Z, Dougherty PG, Pei D (2015) Monitoring the cytosolic entry of cell-penetrating peptides using a pH-sensitive fluorophore. Chem Commun 51:2162–2165CrossRefGoogle Scholar
- Qian Z, Martyna A, Hard RL, Wang J, Appiah-Kubi G, Coss C, Phelps MA, Rossman JS, Pei D (2016) Discovery and mechanism of highly efficient cyclic cell-penetrating peptides. Biochemistry 55:2601–2612CrossRefPubMedGoogle Scholar
- Rawictz W, Olbrich KC, McIntosh T, Needham D, Evans E (2000) Effect of chain length and unsaturation on elasticity of lipid bilayers. Biophys J 79:328–339CrossRefGoogle Scholar
- Richard JP, Melikov K, Vivès E, Ramos C, Verbeure B, Gait MJ, Chernomordik LV, Lebleu B (2003) Cell-penetrating peptides. A reevaluation of the mechanism of cellular uptake. J Biol Chem 278:585–590CrossRefPubMedGoogle Scholar
- Rothbard JB, Jessop TC, Wender PA (2005) Adaptive translocation: the role of hydrogen bonding and membrane potential in the uptake of guanidium-rich transporters into cells. Adv Drug Deliv Rev 57:495–504CrossRefPubMedGoogle Scholar
- Sandre O, Moreaux L, Brochard-Wyard F (1999) Dynamics of transient pores in stretched vesicles. Proc Natl Acad Sci U S A 96:10591–10596CrossRefPubMedPubMedCentralGoogle Scholar
- Seddon JM, Templer RH (1995) Polymorphism of lipid-water systems. In: Lipowsky R, Sackmann E (eds) Structure and dynamics of membranes. Elsevier Science BV, Amsterdam, pp 97–160Google Scholar
- Sharmin S, Islam MZ, Karal MAS, Shibly SUA, Dohra H, Yamazaki M (2016) Effects of lipid composition on the entry of cell-penetrating peptide oligoarginine into single vesicles. Biochemistry 55:4154–4165CrossRefPubMedGoogle Scholar
- Soomets U, Lindgren M, Gallet X, Pooga M, Hällbrink M, Elmquist A, Balaspiri L, Zorko M, Pooga M, Brasseur R, Langel Ű (2000) Deletion analogues of transportan. Biochim Biophys Acta 1467:165–176CrossRefPubMedGoogle Scholar
- Stanzl EG, Trantow BM, Vargas JR, Wender PA (2013) Fifteen years of cell-penetrating, guanidinium-rich molecular transporters: basic science, research tools, and clinical applications. Acc Chem Res 46:2944–2954CrossRefPubMedGoogle Scholar
- Sun D, Forsman J, Lund M, Woodward CE (2014) Effect of arginine-rich cell penetrating peptides on membrane pore formation and life-times: a molecular simulation study. Phys Chem Chem Phys 16:20785–20795CrossRefPubMedGoogle Scholar
- Sun D, Forsman J, Woodward CE (2015) Atomistic molecular simulations suggest a kinetic model for membrane translocation by arginine-rich peptides. J Phys Chem B 119:14413–14420CrossRefPubMedGoogle Scholar
- Swiecicki J-M, Bartsch A, Tailhades J, Di Pisa M, Heller B, Chassaing G, Mansuy C, Burlina F, Lavielle S (2014) The efficacies of cell-penetrating peptides in accumulating in large unilamellar vesicles depend on their ability to form inverted micelles. Chembiochem 15:884–891CrossRefPubMedGoogle Scholar
- Takechi Y, Yoshii H, Tanaka M, Kawakami T, Aimoto S, Saito H (2011) Physicochemical mechanism for the enhanced ability of lipid membrane penetration of polyarginine. Langmuir 27:7099–7107CrossRefPubMedGoogle Scholar
- Tamba Y, Yamazaki M (2005) Single giant unilamellar vesicle method reveals effect of antimicrobial peptide, magainin 2, on membrane permeability. Biochemistry 44:15823–15833CrossRefPubMedGoogle Scholar
- Tamba Y, Yamazaki M (2009) Magainin 2-induced pore formation in membrane depends on its concentration in membrane interface. J Phys Chem B 113:4846–4852CrossRefPubMedGoogle Scholar
- Tamba Y, Ohba S, Kubota M, Yoshioka H, Yoshioka H, Yamazaki M (2007) Single GUV method reveals interaction of Tea catechin (−)-epigallocatechin gallate with lipid membranes. Biophys J 92:3178–3194CrossRefPubMedPubMedCentralGoogle Scholar
- Tamba Y, Ariyama H, Levadny V, Yamazaki M (2010) Kinetic pathway of antimicrobial peptide magainin 2-induced pore formation in lipid membranes. J Phys Chem B 114:12018–12026CrossRefPubMedGoogle Scholar
- Tanaka T, Sano R, Yamashita Y, Yamazaki M (2004) Shape changes and vesicle fission of giant unilamellar vesicles of liquid-ordered phase membrane induced by lysophosphatidylcholine. Langmuir 20:9526–9534CrossRefPubMedGoogle Scholar
- Ter-Avetisyan G, Tünnemann G, Nowak D, Nitschke M, Herrmann A, Drab M, Cardoso MC (2009) Cell entry of arginine-rich peptides is independent of endocytosis. J Biol Chem 284:3370–3378CrossRefPubMedPubMedCentralGoogle Scholar
- Terrone D, Sang SLW, Roudaia L, Silvius JR (2003) Penetratin and related cell-penetrating cationic peptides can translocate across lipid bilayers in the presence of a transbilayer potential. Biochemistry 42:13787–13799CrossRefPubMedGoogle Scholar
- Thorén PEG, Persson D, Karlsson M, Nordén B (2000) The Antennapedia peptide penetratin translocates across lipid bilayers—the first direct observation. FEBS Lett 482:265–268CrossRefPubMedGoogle Scholar
- Thorén PEG, Persson D, Ksbjörner EK, Goksör M, Lincoln P, Nordén B (2004) Membrane binding and translocation of cell-penetrating peptides. Biochemistry 43:3471–3489CrossRefPubMedGoogle Scholar
- Vivès E, Brodin P, Lebleu B (1997) A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J Biol Chem 272:16010–16017CrossRefPubMedGoogle Scholar
- Wadia JS, Stan RV, Dowdy SE (2004) Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis. Nat Med 37:147–195Google Scholar
- Walrant A, Matheron L, Cribier S, Chaignepain S, Jobin M-L, Sagan S, Alves ID (2013) Direct translocation of cell-penetrating peptides in liposomes: a combined mass spectrometry quantification and fluorescence detection study. Anal Biochem 438:1–10CrossRefPubMedGoogle Scholar
- Wang T-Y, Sun Y, Muthukrishnan N, Erazo-Oliveras A, Hajjar K, Pellois J-P (2016) Membrane oxidation enables the cytosolic entry of polyarginine cell-penetrating peptides. J Biol Chem 291:7902–7814CrossRefPubMedPubMedCentralGoogle Scholar
- Wheaten SA, Ablan FDO, Spaller BL, Trieu JM, Almeida PF (2013) Translocation of cationic amphipathic peptides across the membranes of pure phospholipid giant vesicles. J Am Chem Soc 135:16517–16525CrossRefPubMedPubMedCentralGoogle Scholar
- Wohlert J, den Otter WK, Edholm O, Briels WJ (2006) Free energy of a trans-membrane pore calculated from atomistic molecular dynamics simulations. J Chem Phys 124:154905CrossRefPubMedGoogle Scholar
- Yamazaki M (2008) The single GUV method to reveal elementary processes of leakage of internal contents from liposomes induced by antimicrobial substances. Adv Planar Lipid Bilayers Liposomes 7:121–142CrossRefGoogle Scholar
- Yamazaki M, Miyazu M, Asano T, Yuba A, Kume N (1994) Direct evidence of induction of interdigitated gel structure in large unilamellar vesicles of dipalmitoylphophatidylcholine by ethanol: studies by excimer method and high-resolution electron cyromicroscopy. Biophys J 66:729–733CrossRefPubMedPubMedCentralGoogle Scholar
- Yandek LE, Pokomy A, Floren A, Knoeike K, Langel Ű, Almeida PFF (2007) Mechanism of the cell-penetrating peptide transportan 10 permeation of lipid bilayers. Biophys J 92:2434–2444CrossRefPubMedPubMedCentralGoogle Scholar
- Yandek LE, Pokomy A, Almeida PFF (2008) Small changes in the primary structure of transportan 10 alter the thermodynamics and kinetics of its interaction with phospholipid vesicles. Biochemistry 47:3051–3060CrossRefPubMedPubMedCentralGoogle Scholar
- Yesylevskyy S, Marrink S-J, Mark AE (2009) Alternative mechanisms for the interaction of the cell-penetrating peptides penetratin and the TAT peptide with lipid bilayers. Biophys J 97:40–49CrossRefPubMedPubMedCentralGoogle Scholar
- Zorko M, Langel Ű (2005) Cell-penetrating peptides: mechanism and kinetics of cargo delivery. Adv Drug Deliv Rev 57:529–545CrossRefPubMedGoogle Scholar