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Mini-Review of Poloxamer as a Biocompatible Polymer for Advanced Drug Delivery

Abstract

Poloxamer is a biocompatible polymer that has already been approved by the US FDA for multiple applications. Poloxamer itself has many grades and functional categories that enable the improvement of both physicochemical and biological properties of drugs. In this minireview, the functional properties of poloxamer for physicochemical modification, such as solubility and stability, and biological response modification, such as neuroprotection, cell apoptosis, efflux pump modification, membrane cell modification, and cellular uptake, are discussed to provide a broader understanding to assist the development of poloxamer-based formulations.

Keywords:
Poloxamer; Biocompatible; Physicochemical Modification and Biological Response Modification

INTRODUCTION

Poloxamer, also known as Pluronic, is a block copolymer that has been used widely in the pharmaceutical industry as a dispersing agent, emulsifying agent, solubilizing agent, tablet lubricant, and wetting agent (Rowe, Sheskey, Quinn, 2009Rowe RC, Sheskey PJ, Quinn ME. Handbook of Pharmaceutical Excipients, Sixth Edition. Pharmaceutical Press. 2009; p.506-509.). Poloxamer is known as a biocompatible polymer (Almeida et al., 2018Almeida M, Magalhães M, Veiga F, Figueiras A. Poloxamers, poloxamines and polymeric micelles: Definition, structure and therapeutic applications in cancer. J Polym Res. 2018;25(1):31. https://doi.org/10.1007/s10965-017-1426-x.
https://doi.org/10.1007/s10965-017-1426-...
; Jeong, 2011Jeong B. Injectable biodegradable materials. Inject Biomater. 2011:323-37. https://doi.org/10.1533/9780857091376.3.323.
https://doi.org/10.1533/9780857091376.3....
), and several types have been approved by the US FDA. Poloxamer is a nonionic polymer consisting of polyoxyethylene- polyoxypropylene copolymers with hydrophilic polyoxyethylene and hydrophobic polyoxypropylene segments (Rowe, Sheskey, Quinn, 2009Rowe RC, Sheskey PJ, Quinn ME. Handbook of Pharmaceutical Excipients, Sixth Edition. Pharmaceutical Press. 2009; p.506-509.). Poloxamer is commercially available in a wide range of grades or types based on the relative amount of propylene and ethylene oxide added during its manufacture. The amphiphilicity of poloxamer gives it a solubilizing capacity and has been intensely studied for improving drug delivery (Bodratti, Alexandridis, 2018Bodratti AM, Alexandridis P. Formulation of poloxamers for drug delivery. J Funct Biomater. 2018;9(1):11. https://doi.org/10.3390/jfb9010011.
https://doi.org/10.3390/jfb9010011...
) via oral, nasal, ophthalmic, and injection routes (Adnet et al., 2020Adnet T, Groo AC, Picard C, Davis A, Corvaisier S, Since M, et al. Pharmacotechnical development of a nasal drug delivery composite nanosystem intended for alzheimer’s disease treatment. Pharmaceutics. 2020;12(3):251. https:// doi.org/10.3390/pharmaceutics12030251.
https:// doi.org/10.3390/pharmaceutics12...
; Bodratti, Alexandridis, 2018Bodratti AM, Alexandridis P. Formulation of poloxamers for drug delivery. J Funct Biomater. 2018;9(1):11. https://doi.org/10.3390/jfb9010011.
https://doi.org/10.3390/jfb9010011...
; Jeong, 2011Jeong B. Injectable biodegradable materials. Inject Biomater. 2011:323-37. https://doi.org/10.1533/9780857091376.3.323.
https://doi.org/10.1533/9780857091376.3....
). To improve the targeting or nontargeting efficacy, several methods have been applied with poloxamers such as the use of polymeric micelles (Gong et al., 2012Gong J, Chen M, Zheng Y, Wang S, Wang Y. Polymeric micelles drug delivery system in oncology. J Control Release . 2012;159(3):312-23. https://doi.org/10.1016/j.jconrel.2011.12.012.
https://doi.org/10.1016/j.jconrel.2011.1...
), mixed micelles (Ćirin, Krstonošić, Poša, 2017Ćirin D, Krstonošić V, Poša M. Properties of poloxamer 407 and polysorbate mixed micelles: Influence of polysorbate hydrophobic chain. J Ind Eng Chem. 2017;47:194-201. https://doi.org/10.1016/j.jiec.2016.11.032.
https://doi.org/10.1016/j.jiec.2016.11.0...
), thermosensitive gels (Adnet et al., 2020Adnet T, Groo AC, Picard C, Davis A, Corvaisier S, Since M, et al. Pharmacotechnical development of a nasal drug delivery composite nanosystem intended for alzheimer’s disease treatment. Pharmaceutics. 2020;12(3):251. https:// doi.org/10.3390/pharmaceutics12030251.
https:// doi.org/10.3390/pharmaceutics12...
), and liposomes (Zarrintaj et al., 2020Zarrintaj P, Ramsey JD, Samadi A, Atoufi Z, Yazdi MK, Ganjali MR, et al. Poloxamer: A versatile tri-block copolymer for biomedical applications. Acta Biomater. 2020;110:37-67. https://doi.org/10.1016/j.actbio.2020.04.028.
https://doi.org/10.1016/j.actbio.2020.04...
). Poloxamer has been shown to be able to improve drug delivery even to the brain across the blood-brain barrier (Bao et al., 2012Bao HJ, Wang T, Zhang MY, Liu R, Dai DK, Wang YQ, et al. Poloxamer-188 attenuates TBI-induced blood-brain barrier damage leading to decreased brain edema and reduced cellular death. Neurochem Res. 2012;37(12):2856-67. https://doi.org/10.1007/s11064-012-0880-4.
https://doi.org/10.1007/s11064-012-0880-...
; Batrakova et al., 2001Batrakova EV, Miller DW, Li S, Alakhov VY, Kabanov a V, Elmquist WF. Pluronic P85 enhances the delivery of digoxin to the brain: in vitro and in vivo studies. J Pharmacol Exp Ther. 2001;296(2):551-7.; Meng et al., 2017Meng X, Liu J, Yu X, Li J, Lu X, Shen T. Pluronic F127 and D-α-Tocopheryl Polyethylene Glycol Succinate (TPGS) mixed micelles for targeting drug delivery across the blood brain barrier. Sci Rep. 2017;7(1):1-12. https://doi.org/10.1038/s41598-017-03123-y.
https://doi.org/10.1038/s41598-017-03123...
; Wang et al., 2014Wang T, Chen X, Wang Z, Zhang M, Meng H, Gao Y, et al. Poloxamer-188 Can Attenuate Blood-Brain Barrier Damage to Exert Neuroprotective Effect in Mice Intracerebral Hemorrhage Model. J Mol Neurosci. 2014;55(1):240-50. https://doi.org/10.1007/s12031-014-0313-8.
https://doi.org/10.1007/s12031-014-0313-...
). With these properties, poloxamer can provide an advantage and solve the issue related to low bioavailability in the brain for drugs targeted to the brain or central nervous system, and cancer drugs to treat metastatic cancer are no exception. This review intends to provide further understanding about the mechanism of poloxamer in improving the physicochemical and biological properties of poloxamer-based drug formulations and delivery.

POLOXAMER FOR PHYSICOCHEMICAL MODIFICATION

Solubility

Poloxamers 188 and 407 were reported to improve solubility, as shown by the dissolution of loratadine prepared by the solid dispersion method. This phenomenon is believed to be a result of the increased wettability and stabilization of the amorphous state with the addition of poloxamer (Rahman et al., 2015Rahman MM, Moniruzzaman M, Haque S, Azad MAK, Islam Aovi F, Ahmeda Sultana N. Effect of Poloxamer on release of poorly water soluble drug Loratadine from solid dispersion: Kneading method. Maced Pharm Bull. 2015;61(1):45-50. https://doi.org/10.33320/maced.pharm.bull.2015.61.01.001.
https://doi.org/10.33320/maced.pharm.bul...
). A similar finding was observed in a bicalutamide solid dispersion with poloxamers 188 and 407 using solvent evaporation and spray drying. There were several changes in the bicalutamide characteristics with the addition of poloxamer in solid dispersions, including improvements in wettability, solubility, and dissolution (Szafraniec et al., 2019Szafraniec J, Antosik A, Knapik-Kowalczuk J, Chmiel K, Kurek M, Gawlak K, et al. The self-assembly phenomenon of poloxamers and its effect on the dissolution of a poorly soluble drug from solid dispersions obtained by solvent methods. Pharmaceutics. 2019;11(3):130. https://doi.org/10.3390/pharmaceutics11030130.
https://doi.org/10.3390/pharmaceutics110...
). The dissolution of tacrolimus was also reported to be increased using the solid dispersion method with poloxamers 188 and 407. This result was due to the conversion of tacrolimus to the amorphous phase, leading to increased solubility (Ha et al., 2012Ha JM, Kang SY, Park CW, Bin SA, Rhee YS, Seo JW, et al. Effect of poloxamer on physicochemical properties of tacrolimus solid dispersion improving water solubility and dissolution rate. J Pharm Investig. 2012;42(4):171-6. https://doi.org/10.1007/s40005-012-0025-4.
https://doi.org/10.1007/s40005-012-0025-...
). Another study confirmed the better characteristics of poloxamer 188 than poloxamer 407 in improving dissolution; this performance was related to the higher proportion of oxyethylene segments in poloxamer 407, which retarded dissolution (Medarević et al., 2016Medarević DP, Kachrimanis K, Mitrić M, Djuriš J, Djurić Z, Ibrić S. Dissolution rate enhancement and physicochemical characterization of carbamazepine-poloxamer solid dispersions. Pharm Dev Technol . 2016;21(3):268-76. https://doi.org/10.3109/10837450.2014.996899.
https://doi.org/10.3109/10837450.2014.99...
). Poloxamer has also been reported to improve the solubility and dissolution of lamotrigine through micellar solubilization. The solubilization, however, decreased with increasing polyethylene oxide (PEO) region proportion in corona micelles and was temperature dependent (Singla et al., 2019Singla P, Singh O, Sharma S, Betlem K, Aswal VK, Peeters M, et al. Temperature-Dependent Solubilization of the Hydrophobic Antiepileptic Drug Lamotrigine in Different Pluronic Micelles - A Spectroscopic, Heat Transfer Method, Small-Angle Neutron Scattering, Dynamic Light Scattering, and in Vitro Release Study. ACS Omega. 2019;4(6):11251-62. https://doi.org/10.1021/acsomega.9b00939.
https://doi.org/10.1021/acsomega.9b00939...
). It was also reported that the solubilization enhancement of nimodipine by poloxamer 407 was higher than that of PEG 6000 due to the surfactant properties of poloxamer, which can form micelles (Kreidel et al., 2012Kreidel RN, Duque MD, Serra CHR, Velasco MVR, Baby AR, Kaneko TM, et al. Dissolution Enhancement and Characterization of Nimodipine Solid Dispersions with Poloxamer 407 or PEG 6000. J Dispers Sci Technol. 2012;33(9):1354-9. https://doi.org/10.1080/01932691.2011.605663.
https://doi.org/10.1080/01932691.2011.60...
). In addition, poloxamer 407 has been shown to increase the solubility of ibuprofen and griseofulvin through a mechanism of micellar solubilization (Dugar, Gajera, Dave, 2016Dugar RP, Gajera BY, Dave RH. Fusion Method for Solubility and Dissolution Rate Enhancement of Ibuprofen Using Block Copolymer Poloxamer 407. AAPS PharmSciTech. 2016;17(6):1428-40. https://doi.org/10.1208/s12249-016-0482-6.
https://doi.org/10.1208/s12249-016-0482-...
; Dutra et al., 2015Dutra LMU, Ribeiro MENP, Cavalcante IM, De Brito DHA, De Moraes Semião L, Da Silva RF, et al. Binary mixture micellar systems of F127 and P123 for griseofulvin solubilisation. Polimeros. 2015;25(5):433-9. https://doi.org/10.1590/0104-1428.1831.
https://doi.org/10.1590/0104-1428.1831...
).

Stability

Poloxamer was reported to increase the chemical and physical stability of drugs or dosage forms. Poloxamer 407/Pluronic F127 has been shown to affect the chemical stability of insulin with increasing poloxamer concentration (Li et al., 2017Li J, Chu MK, Lu B, Mirzaie S, Chen K, Gordijo CR, et al. Enhancing thermal stability of a highly concentrated insulin formulation with Pluronic F-127 for long-term use in microfabricated implantable devices. Drug Deliv Transl Res. 2017;7(4):529-43. https://doi.org/10.1007/s13346-017-0381-8.
https://doi.org/10.1007/s13346-017-0381-...
). Poloxamer was also reported to increase the membrane stability of liposomes, believed to be related to PEO chain length (Li et al., 2020b). A similar result was shown with curcumin-loaded liposomes, where Pluronic F127 improved membrane stability (Li et al., 2020a). In addition, poloxamer 407 has been shown to increase the thermostability of proteins such as interleukin-1 receptor antagonists due to its viscous nature (Akash et al., 2014Akash MSH, Rehman K, Sun H, Chen S. Assessment of release kinetics, stability and polymer interaction of poloxamer 407-based thermosensitive gel of interleukin-1 receptor antagonist. Pharm Dev Technol. 2014;19(3):278-84. https://doi.org/10.3109/10837450.2013.775158.
https://doi.org/10.3109/10837450.2013.77...
). Moreover, Pluronic F68 has been shown to affect the colloidal stability of poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, which was related to the surface coverage of Pluronic/ poloxamer and micellization (Santander-Ortega et al., 2006Santander-Ortega MJ, Jódar-Reyes AB, Csaba N, Bastos- González D, Ortega-Vinuesa JL. Colloidal stability of Pluronic F68-coated PLGA nanoparticles: A variety of stabilisation mechanisms. J Colloid Interface Sci. 2006;302(2):522-9. https://doi.org/10.1016/j.jcis.2006.07.031.
https://doi.org/10.1016/j.jcis.2006.07.0...
). Hydroxyapatite nanoparticles modified by grafting with Pluronic F127 were shown to exhibit increased mechanical properties, crystallinity percentages, and thermal stability compared to those of unmodified hydroxyapatite nanoparticles (Mirhosseini, Haddadi- Asl, Zargarian, 2016Mirhosseini MM, Haddadi-Asl V, Zargarian SS. Fabrication and characterization of polymer-ceramic nanocomposites containing pluronic F127 immobilized on hydroxyapatite nanoparticles. RSC Adv. 2016;6(84):80564-75. https://doi.org/10.1039/c6ra19499k.
https://doi.org/10.1039/c6ra19499k...
).

TABLE I
List of Poloxamers and Functionalities

POLOXAMER FOR BIOLOGICAL RESPONSE MODIFICATION

Neuroprotection

Poloxamer 188 has been shown to contribute to neuroprotection of the blood-brain barrier in traumatic brain injury (TBI). This polymer maintained membrane permeability by (1) reducing the levels of cytochrome-C, caspase-9, and caspase-8, resulting in inhibition of apoptosis, and (2) downregulating aquaporin 4 (AQP4), which is responsible for water channeling across the blood-brain barrier (Bao et al., 2012Bao HJ, Wang T, Zhang MY, Liu R, Dai DK, Wang YQ, et al. Poloxamer-188 attenuates TBI-induced blood-brain barrier damage leading to decreased brain edema and reduced cellular death. Neurochem Res. 2012;37(12):2856-67. https://doi.org/10.1007/s11064-012-0880-4.
https://doi.org/10.1007/s11064-012-0880-...
). AQP4 acts as a selective bidirectional water movement regulator that can facilitate the supply or removal of water from astrocytes, thus affecting blood-brain barrier (BBB) permeability (Verkman et al., 2006Verkman AS, Binder DK, Bloch O, Auguste K, Papadopoulos MC. Threedistinctrolesofaquaporin-4inbrainfunctionrevealed by knockout mice. Biochim Biophys Acta. 2006;1758(8):1085-93. https://doi.org/10.1016/j.bbamem.2006.02.018.
https://doi.org/10.1016/j.bbamem.2006.02...
). In the case of intracerebral hemorrhage (ICH), poloxamer 188 was demonstrated to have a protective effect by preventing BBB disruption via its involvement in maintaining the levels of proteins such as claudin-5, occludin, and zonula occludens-1 and decreasing the expression of nuclear factor kappa B (NF-kB), matrix metalloproteinase (MMP)-2, and MMP-9, leading to the prevention of tight junction (TJ) degradation (Wang et al., 2014Wang T, Chen X, Wang Z, Zhang M, Meng H, Gao Y, et al. Poloxamer-188 Can Attenuate Blood-Brain Barrier Damage to Exert Neuroprotective Effect in Mice Intracerebral Hemorrhage Model. J Mol Neurosci. 2014;55(1):240-50. https://doi.org/10.1007/s12031-014-0313-8.
https://doi.org/10.1007/s12031-014-0313-...
). For MMP-2 and MMP-9, poloxamer showed the opposite action in wound healing, where poloxamer increased the activity of these enzymes, resulting in accelerated autolytic debridement of damaged collagen (Zarrintaj et al., 2020Zarrintaj P, Ramsey JD, Samadi A, Atoufi Z, Yazdi MK, Ganjali MR, et al. Poloxamer: A versatile tri-block copolymer for biomedical applications. Acta Biomater. 2020;110:37-67. https://doi.org/10.1016/j.actbio.2020.04.028.
https://doi.org/10.1016/j.actbio.2020.04...
). Poloxamer 188 was shown to protect against cerebral ischemia in vivo by significantly reducing the number of propidium iodide (PI)-positive labeled cells following ischemia/reperfusion injury. This polymer further repaired HT22 cell membrane rupture induced by Triton X-100. In addition, P188 was found to inhibit ischemia/reperfusion-induced activation of MMP-9 and leakage of molecules (Gu et al., 2013Gu JH, Ge JB, Li M, Xu HD, Wu F, Qin ZH. Poloxamer 188 Protects Neurons against Ischemia/Reperfusion Injury through Preserving Integrity of Cell Membranes and Blood Brain Barrier. PLoS One. 2013;8(4):e61641. https://doi.org/10.1371/journal.pone.0061641.
https://doi.org/10.1371/journal.pone.006...
).

Cell Apoptosis

Poloxamer was demonstrated to have contrary action in multirug-resistant (MDR) cancer cells compared to normal cells, promoting proapoptotic signaling and reducing antiapoptotic defense (Zarrintaj et al., 2020Zarrintaj P, Ramsey JD, Samadi A, Atoufi Z, Yazdi MK, Ganjali MR, et al. Poloxamer: A versatile tri-block copolymer for biomedical applications. Acta Biomater. 2020;110:37-67. https://doi.org/10.1016/j.actbio.2020.04.028.
https://doi.org/10.1016/j.actbio.2020.04...
). This mechanism was based on an increase in the expression of cytochrome-C, caspase 3, and caspase 9 (Alakhova, Kabanov, 2014Alakhova DY, Kabanov AV. Pluronics and MDR reversal: An update. Mol Pharm. 2014;11(8):2566-78. https://doi.org/10.1021/mp500298q.
https://doi.org/10.1021/mp500298q...
; Batrakova, Kabanov, 2008Batrakova EV, Kabanov AV. Pluronic Block Copolymers: Evolution of Drug Delivery Concept from Inert Nanocarriers to Biological Response Modifiers. J Control Release. 2008;130(2):98-106. https://doi.org/10.1016/j.jconrel.2008.04.013.
https://doi.org/10.1016/j.jconrel.2008.0...
; Pitto-Barry, Barry, 2014Pitto-Barry A, Barry NPE. Pluronic® block-copolymers in medicine: From chemical and biological versatility to rationalisation and clinical advances. Polym Chem. 2014;5(10):3291-7. https://doi.org/10.1039/c4py00039k.
https://doi.org/10.1039/c4py00039k...
; Zarrintaj et al., 2020Zarrintaj P, Ramsey JD, Samadi A, Atoufi Z, Yazdi MK, Ganjali MR, et al. Poloxamer: A versatile tri-block copolymer for biomedical applications. Acta Biomater. 2020;110:37-67. https://doi.org/10.1016/j.actbio.2020.04.028.
https://doi.org/10.1016/j.actbio.2020.04...
). Six percent Pluronic F68 was shown to cause G2/M phase arrest, followed by caspase activation and accumulation of apoptotic cells in the K562 cell line (Aoki et al., 2010Aoki N, Tamura M, Ohyashiki JH, Sugaya M, Hisatomi H. Poloxamer 188 enhances apoptosis in a human leukemia cell line. Mol Med Rep. 2010;3(4):669-72. https://doi.org/10.3892/mmr_00000314.
https://doi.org/10.3892/mmr_00000314...
). Moreover, poloxamer 407 hydrogel alone significantly induced apoptosis and promoted the high expression of Annexin-V in the 3T3NIH cell line (Yang et al., 2020Yang X, Yang R, Chen M, Zhou Q, Zheng Y, Lu C, et al. KGF-2 and FGF-21 poloxamer 407 hydrogel coordinates inflammation and proliferation homeostasis to enhance wound repair of scalded skin in diabetic rats. BMJ Open Diabetes Res Care. 2020;8(1):1-13. https://doi.org/10.1136/bmjdrc-2019-001009.
https://doi.org/10.1136/bmjdrc-2019-0010...
). On the other hand, in neural tissue following traumatic brain injury, poloxamer 188 was shown to significantly inhibit apoptosis and necrosis, partly through the inhibition of p38 activation (Serbest et al., 2006Serbest G, Horwitz J, Jost M, Barbee KA. Mechanisms of cell death and neuroprotection by poloxamer 188 after mechanical trauma. FASEB J. 2006;20(2):308-10. https://doi.org/10.1096/fj.05-4024fje.
https://doi.org/10.1096/fj.05-4024fje...
). A similar finding was obtained in the SH-SY5Y cell line when administered poloxamer 188. In this cell line, prevention of apoptosis was indicated to be associated with the prevention of leakage of cathepsins from lysosomes to the cytoplasm (Dong et al., 2019Dong H, Qin Y, Huang Y, Ji D, Wu F. Poloxamer 188 rescues MPTP-induced lysosomal membrane integrity impairment in cellular and mouse models of Parkinson’s disease. Neurochem Int. 2019;126:178-86. https://doi.org/10.1016/j.neuint.2019.03.013.
https://doi.org/10.1016/j.neuint.2019.03...
).

Efflux Pump Modification

Poloxamer was found to inhibit drug efflux by transporter-like Pgp (Batrakova, Kabanov, 2008Batrakova EV, Kabanov AV. Pluronic Block Copolymers: Evolution of Drug Delivery Concept from Inert Nanocarriers to Biological Response Modifiers. J Control Release. 2008;130(2):98-106. https://doi.org/10.1016/j.jconrel.2008.04.013.
https://doi.org/10.1016/j.jconrel.2008.0...
). This effect was mediated by the inhibition of ATPase, leading to ATP depletion and membrane fluidization (Alakhova, Kabanov, 2014Alakhova DY, Kabanov AV. Pluronics and MDR reversal: An update. Mol Pharm. 2014;11(8):2566-78. https://doi.org/10.1021/mp500298q.
https://doi.org/10.1021/mp500298q...
; Gaikwad, Bhatia, 2013Gaikwad VL, Bhatia MS. Polymers influencing transportability profile of drug. Saudi Pharm J. 2013;21(4):327-35. https://doi.org/10.1016/j.jsps.2012.10.003.
https://doi.org/10.1016/j.jsps.2012.10.0...
; Zarrintaj et al., 2020Zarrintaj P, Ramsey JD, Samadi A, Atoufi Z, Yazdi MK, Ganjali MR, et al. Poloxamer: A versatile tri-block copolymer for biomedical applications. Acta Biomater. 2020;110:37-67. https://doi.org/10.1016/j.actbio.2020.04.028.
https://doi.org/10.1016/j.actbio.2020.04...
). Conformational changes in efflux proteins, steric hindrance (Batrakova, Kabanov, 2008Batrakova EV, Kabanov AV. Pluronic Block Copolymers: Evolution of Drug Delivery Concept from Inert Nanocarriers to Biological Response Modifiers. J Control Release. 2008;130(2):98-106. https://doi.org/10.1016/j.jconrel.2008.04.013.
https://doi.org/10.1016/j.jconrel.2008.0...
), and interactions between the amphiphilic structure of poloxamer and the cell membrane are believed to be the main mechanisms of ATP depletion (Alakhova, Kabanov, 2014Alakhova DY, Kabanov AV. Pluronics and MDR reversal: An update. Mol Pharm. 2014;11(8):2566-78. https://doi.org/10.1021/mp500298q.
https://doi.org/10.1021/mp500298q...
). Inhibition of the efflux pump was a concentration-dependent process and was suppressed when the poloxamer concentration increased (Gaikwad, Bhatia, 2013Gaikwad VL, Bhatia MS. Polymers influencing transportability profile of drug. Saudi Pharm J. 2013;21(4):327-35. https://doi.org/10.1016/j.jsps.2012.10.003.
https://doi.org/10.1016/j.jsps.2012.10.0...
). This effect has been suggested to be related to the formation of poloxamer unimers at a level below the critical micelle concentration (Batrakova, Kabanov, 2008Batrakova EV, Kabanov AV. Pluronic Block Copolymers: Evolution of Drug Delivery Concept from Inert Nanocarriers to Biological Response Modifiers. J Control Release. 2008;130(2):98-106. https://doi.org/10.1016/j.jconrel.2008.04.013.
https://doi.org/10.1016/j.jconrel.2008.0...
; Furtado et al., 2018Furtado D, Björnmalm M, Ayton S, Bush AI, Kempe K, Caruso F. Overcoming the Blood-Brain Barrier: The Role of Nanomaterials in Treating Neurological Diseases. Adv Mater. 2018;30(46):e1801362. https://doi.org/10.1002/adma.201801362.
https://doi.org/10.1002/adma.201801362...
). The medium chain length of the polypropylene oxide (PPO) block of poloxamer was found to be more effective than the long-chain type and the highly hydrophobic poloxamer in inhibiting drug efflux in MDR cancer cells without impacting Pgp function and ATP levels (Pitto-Barry, Barry, 2014Pitto-Barry A, Barry NPE. Pluronic® block-copolymers in medicine: From chemical and biological versatility to rationalisation and clinical advances. Polym Chem. 2014;5(10):3291-7. https://doi.org/10.1039/c4py00039k.
https://doi.org/10.1039/c4py00039k...
).

Cell Membrane Integrity Modification

Poloxamer has been shown to decrease the microviscosity of the cell membrane by the integration of hydrophobic chains into cell membranes (Batrakova, Kabanov, 2008Batrakova EV, Kabanov AV. Pluronic Block Copolymers: Evolution of Drug Delivery Concept from Inert Nanocarriers to Biological Response Modifiers. J Control Release. 2008;130(2):98-106. https://doi.org/10.1016/j.jconrel.2008.04.013.
https://doi.org/10.1016/j.jconrel.2008.0...
; Pitto-Barry, Barry, 2014Pitto-Barry A, Barry NPE. Pluronic® block-copolymers in medicine: From chemical and biological versatility to rationalisation and clinical advances. Polym Chem. 2014;5(10):3291-7. https://doi.org/10.1039/c4py00039k.
https://doi.org/10.1039/c4py00039k...
; Zarrintaj et al., 2020Zarrintaj P, Ramsey JD, Samadi A, Atoufi Z, Yazdi MK, Ganjali MR, et al. Poloxamer: A versatile tri-block copolymer for biomedical applications. Acta Biomater. 2020;110:37-67. https://doi.org/10.1016/j.actbio.2020.04.028.
https://doi.org/10.1016/j.actbio.2020.04...
). The interaction of poloxamer with the cell membrane was found to consist of 2 steps: the adsorption of poloxamer onto the membrane surface and the insertion of poloxamer into the membrane. The ability of poloxamer to disrupt membrane activity was shown to be due to the interaction of the hydrophilic chain with the polar head group of the lipid molecule in the cell membrane (Alakhova, Kabanov, 2014Alakhova DY, Kabanov AV. Pluronics and MDR reversal: An update. Mol Pharm. 2014;11(8):2566-78. https://doi.org/10.1021/mp500298q.
https://doi.org/10.1021/mp500298q...
). Poloxamer 188 was suggested to restore the barrier function of the plasma membrane and maintain cell integrity in injured tissues due to the minimization of free diffusion between intracellular and extracellular fluids, facilitated by the binding of the hydrophobic chain of membrane phospholipids with PPO segments and the water phase with PEO segments (Kwiatkowski et al., 2020Kwiatkowski TA, Rose AL, Jung R, Capati A, Hallak D, Yan R, et al. Multiple poloxamers increase plasma membrane repair capacity in muscle and non-muscle cells. Am J Physiol Cell Physiol. 2020;318(2):C253-62. https://doi: 10.1152/ajpcell.00321.2019.
https://doi: 10.1152/ajpcell.00321.2019...
). Administration of poloxamer 188 was shown to restore lysosomal membrane integrity of SH-SY5Y cells and prevent cathepsin leakage (Dong et al., 2019Dong H, Qin Y, Huang Y, Ji D, Wu F. Poloxamer 188 rescues MPTP-induced lysosomal membrane integrity impairment in cellular and mouse models of Parkinson’s disease. Neurochem Int. 2019;126:178-86. https://doi.org/10.1016/j.neuint.2019.03.013.
https://doi.org/10.1016/j.neuint.2019.03...
).

FIGURE 1
Illustration of the poloxamer structure, which is a triblock copolymer (A); Illustration of contradictory conditions where the poloxamer must be in the form of a unimer to be able to inhibit the efflux pump while it must be in the form of a micelle to be able to dissolve the active ingredient (B).

Cellular Uptake

Surface modification by poloxamer 188 and poloxamer 407 has been shown to increase cellular uptake and transport across the BBB of poly(d,l-lactide-co- glycolide) (PLGA)-based nanoparticles (Kulkarni, Feng, 2011Kulkarni SA, Feng SS. Effects of surface modification on delivery efficiency of biodegradable nanoparticles across the blood-brain barrier. Nanomedicine. 2011;6(2):377-94. https://doi.org/10.2217/nnm.10.131.
https://doi.org/10.2217/nnm.10.131...
). Moreover, poloxamer 85 was found to increase cellular uptake in multidrug-resistant human carcinoma cell lines (KBv) but not in human carcinoma cells (KB). This cellular uptake increase was associated with overexpression of P-gP in a multidrug-resistant human carcinoma cell line, the substrate probe of poloxamer (Song et al., 2011Song CK, Balakrishnan P, Shim CK, Chung SJ, Kim DD. Enhanced in-vitro cellular uptake of P-gp substrate by poloxamer-modified liposomes (PMLs) in MDR cancer cells. J Microencapsul. 2011;28(6):575-81. https://doi.org/10.3109/02652048.2011.599436.
https://doi.org/10.3109/02652048.2011.59...
). Cellular uptake by phagocytosis was shown to be affected by the chain of the EO and PO blocks; the longer the EO and PO blocks were, the lower the phagocytic uptake (Rudt, Müller, 1993Rudt S, Müller RH. In vitro phagocytosis assay of nano- and microparticles by chemiluminescence. III. Uptake of differently sized surface-modified particles, and its correlation to particle properties and in vivo distribution. Eur J Pharm Sci. 1993;1(1):31-9. https://doi.org/10.1016/0928-0987(93)90015-3.
https://doi.org/10.1016/0928-0987(93)900...
). Pluronic P85 has been demonstrated to promote cellular uptake by caveolae-mediated endocytosis at a concentration below the CMC, e.g., 0.001%, under which Pluronic 85 assumes a unimer state. However, at concentrations above the CMC, e.g., 0.1%, Pluronic P85 promoted cellular uptake mainly by clathrin-mediated endocytosis (Sahay, Batrakova, Kabanov, 2008Sahay G, Batrakova EV, Kabanov AV. Different internalization pathways of polymeric micelles and unimers and their effects on vesicular transport. Bioconjug Chem. 2008;19(10):2023-9. https://doi.org/10.1021/bc8002315.
https://doi.org/10.1021/bc8002315...
). A polypropyleneimine/pDNA polyplex, which was modified with poloxamer 123, was revealed to exhibit an internalization mechanism by both clathrin-mediated and caveolae-mediated endocytosis (Gu et al., 2016Gu J, Hao J, Fang X, Sha X. Factors influencing the transfection efficiency and cellular uptake mechanisms of Pluronic P123-modified polypropyleneimine/pDNA polyplexes in multidrug resistant breast cancer cells. Colloids Surfaces B Biointerfaces. 2016;140:83-93. https://doi.org/10.1016/j.colsurfb.2015.12.023.
https://doi.org/10.1016/j.colsurfb.2015....
). Another study showed that Pluronic P123 was colocalized to a higher extent by caveolin-1 than by the polyethileneimine/pDNA polyplex (Yang et al., 2008Yang Z, Sahay G, Sriadibhatla S, Kabanov AV. Amphiphilic Block Copolymers Enhance Cellular Uptake and Nuclear Entry of Polyplex-Delivered DNA. Bioconjug Chem . 2008;19(10):1987-94. https://doi.org/10.1021/bc800144a.
https://doi.org/10.1021/bc800144a...
).

DISCUSSION

This review indicates the potential of using poloxamer as a physicochemical and/or biological response modifier. Targeted therapy as the outcome may dictate the grade and concentration of poloxamer that should be used. For example, a poorly soluble drug can be made the target of cellular uptake through caveolae to avoid lysosomal degradation by selecting a type of poloxamer that improves the drug solubility via micellar form or a type that increases caveolae-1 endocytosis via unimer form. An application of formulations derived from targeted drug delivery systems is brain drug delivery, and to that end, multiple factors need to be taken into consideration. These aspects include internalization/cellular uptake, inhibition of Pgp efflux for longer retainment, and neuroprotection ability, contrary to apoptosis.

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  • AUTHOR CONTRIBUTIONS

    All authors contributed to the manuscript.

Publication Dates

  • Publication in this collection
    16 Jan 2023
  • Date of issue
    2022

History

  • Received
    03 Mar 2021
  • Accepted
    29 Aug 2021
Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br