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Importance of thorough tissue and cellular level characterization of targeted drugs in the evaluation of pharmacodynamic effects


Autoři: Dustin K. Bauknight aff001;  Victoria Osinski aff003;  Siva Sai Krishna Dasa aff001;  Anh T. Nguyen aff003;  Melissa A. Marshall aff003;  Julia Hartman aff001;  Matthew Harms aff005;  Gavin O’Mahony aff005;  Jeremie Boucher aff005;  Alexander L. Klibanov aff001;  Coleen A. McNamara aff003;  Kimberly A. Kelly aff001
Působiště autorů: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, United States of America aff001;  Cancer Center, University of Virginia, Charlottesville, VA, United States of America aff002;  Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, United States of America aff003;  Department of Pathology, University of Virginia, Charlottesville, VA, United States of America aff004;  Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden aff005;  The Lundberg Laboratory for Diabetes Research, University of Gothenburg, Gothenburg, Sweden aff006;  Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden aff007;  Department of Medicine, Division of Cardiovascular Medicine, University of Virginia, Charlottesville, VA, United States of America aff008
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0224917

Souhrn

Targeted nanoparticle delivery is a promising strategy for increasing efficacy and limiting side effects of therapeutics. When designing a targeted liposomal formulation, the in vivo biodistribution of the particles must be characterized to determine the value of the targeting approach. Peroxisome proliferator-activated receptor (PPAR) agonists effectively treat metabolic syndrome by decreasing dyslipidemia and insulin resistance but side effects have limited their use, making them a class of compounds that could benefit from targeted liposomal delivery. The adipose targeting sequence peptide (ATS) could fit this role, as it has been shown to bind to adipose tissue endothelium and induce weight loss when delivered conjugated to a pro-apoptotic peptide. To date, however, a full assessment of ATS in vivo biodistribution has not been reported, leaving important unanswered questions regarding the exact mechanisms whereby ATS targeting enhances therapeutic efficacy. We designed this study to evaluate the biodistribution of ATS-conjugated liposomes loaded with the PPARα/γ dual agonist tesaglitazar in leptin-deficient ob/ob mice. The ATS-liposome biodistribution in adipose tissue and other organs was examined at the cellular and tissue level using microscopy, flow cytometry, and fluorescent molecular tomography. Changes in metabolic parameters and gene expression were measured by target and off-target tissue responses to the treatment. Unexpectedly, ATS targeting did not increase liposomal uptake in adipose relative to other tissues, but did increase uptake in the kidneys. Targeting also did not significantly alter metabolic parameters. Analysis of the liposome cellular distribution in the stromal vascular fraction with flow cytometry revealed high uptake by multiple cell types. Our findings highlight the need for thorough study of in vivo biodistribution when evaluating a targeted therapy.

Klíčová slova:

Adipose tissue – Drug therapy – Flow cytometry – Insulin – Kidneys – Liposomes – Macrophages – Nanoparticles


Zdroje

1. Zhang H. Onivyde for the therapy of multiple solid tumors. Onco Targets Ther. 2016;9:3001–7. doi: 10.2147/OTT.S105587 27284250; PubMed Central PMCID: PMC4881920.

2. Barenholz Y. Doxil(R)—the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;160(2):117–34. doi: 10.1016/j.jconrel.2012.03.020 22484195.

3. Bulbake U, Doppalapudi S, Kommineni N, Khan W. Liposomal Formulations in Clinical Use: An Updated Review. Pharmaceutics. 2017;9(2):1–33. doi: 10.3390/pharmaceutics9020012 28346375; PubMed Central PMCID: PMC5489929.

4. Working PK, Newman MS, Huang SK, Mayhew E, Vaage J, Lasic DD. Pharmacokinetics, Biodistribution and Therapeutic Efficacy of Doxorubicin Encapsulated in Stealth® Liposomes (Doxil®). Journal of Liposome Research. 1994;4(1):667–87. doi: 10.3109/08982109409037065

5. Bays H, McElhattan J, Bryzinski BS, Group GS. A double-blind, randomised trial of tesaglitazar versus pioglitazone in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2007;4(3):181–93. doi: 10.3132/dvdr.2007.039 17907108.

6. Goldstein BJ, Rosenstock J, Anzalone D, Tou C, Ohman KP. Effect of tesaglitazar, a dual PPAR alpha/gamma agonist, on glucose and lipid abnormalities in patients with type 2 diabetes: a 12-week dose-ranging trial. Curr Med Res Opin. 2006;22(12):2575–90. doi: 10.1185/030079906x154169 17166340.

7. Tonstad S, Retterstol K, Ose L, Ohman KP, Lindberg MB, Svensson M. The dual peroxisome proliferator-activated receptor alpha/gamma agonist tesaglitazar further improves the lipid profile in dyslipidemic subjects treated with atorvastatin. Metabolism. 2007;56(9):1285–92. doi: 10.1016/j.metabol.2007.05.003 17697874.

8. Oakes ND, Thalen P, Hultstrand T, Jacinto S, Camejo G, Wallin B, et al. Tesaglitazar, a dual PPAR{alpha}/{gamma} agonist, ameliorates glucose and lipid intolerance in obese Zucker rats. Am J Physiol Regul Integr Comp Physiol. 2005;289(4):R938–46. doi: 10.1152/ajpregu.00252.2005 16183630.

9. Ljung B, Bamberg K, Dahllof B, Kjellstedt A, Oakes ND, Ostling J, et al. AZ 242, a novel PPARalpha/gamma agonist with beneficial effects on insulin resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker rats. J Lipid Res. 2002;43(11):1855–63. doi: 10.1194/jlr.m200127-jlr200 12401884.

10. Wang YX. PPARs: diverse regulators in energy metabolism and metabolic diseases. Cell Res. 2010;20(2):124–37. doi: 10.1038/cr.2010.13 20101262; PubMed Central PMCID: PMC4084607.

11. Grygiel-Gorniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications—a review. Nutr J. 2014;13:1–10. doi: 10.1186/1475-2891-13-1 24524207; PubMed Central PMCID: PMC3943808.

12. Rizos CV, Elisaf MS, Mikhailidis DP, Liberopoulos EN. How safe is the use of thiazolidinediones in clinical practice? Expert Opin Drug Saf. 2009;8(1):15–32. doi: 10.1517/14740330802597821 19236215.

13. Bailey CJ. Learning from tesaglitazar. Diab Vasc Dis Res. 2007;4(3):161–2. doi: 10.3132/dvdr.2007.036 17907105.

14. Schuster H, Fagerberg B, Edwards S, Halmos T, Lopatynski J, Stender S, et al. Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha/gamma agonist, improves apolipoprotein levels in non-diabetic subjects with insulin resistance. Atherosclerosis. 2008;197(1):355–62. doi: 10.1016/j.atherosclerosis.2007.05.029 17631296.

15. Hamren B, Ohman KP, Svensson MK, Karlsson MO. Pharmacokinetic-pharmacodynamic assessment of the interrelationships between tesaglitazar exposure and renal function in patients with type 2 diabetes mellitus. J Clin Pharmacol. 2012;52(9):1317–27. doi: 10.1177/0091270011416937 22045829.

16. Glassman PM, Muzykantov VR. Pharmacokinetic and Pharmacodynamic Properties of Drug Delivery Systems. J Pharmacol Exp Ther. 2019;370(3):570–80. doi: 10.1124/jpet.119.257113 30837281.

17. Kolonin MG, Saha PK, Chan L, Pasqualini R, Arap W. Reversal of obesity by targeted ablation of adipose tissue. Nat Med. 2004;10(6):625–32. doi: 10.1038/nm1048 15133506.

18. Hossen MN, Kajimoto K, Akita H, Hyodo M, Ishitsuka T, Harashima H. Ligand-based targeted delivery of a peptide modified nanocarrier to endothelial cells in adipose tissue. J Control Release. 2010;147(2):261–8. doi: 10.1016/j.jconrel.2010.07.100 20647023.

19. Hossen MN, Kajimoto K, Akita H, Hyodo M, Harashima H. Vascular-targeted nanotherapy for obesity: unexpected passive targeting mechanism to obese fat for the enhancement of active drug delivery. J Control Release. 2012;163(2):101–10. doi: 10.1016/j.jconrel.2012.09.002 22982237.

20. Xue Y, Xu X, Zhang XQ, Farokhzad OC, Langer R. Preventing diet-induced obesity in mice by adipose tissue transformation and angiogenesis using targeted nanoparticles. Proc Natl Acad Sci U S A. 2016;113(20):5552–7. doi: 10.1073/pnas.1603840113 27140638; PubMed Central PMCID: PMC4878518.

21. Won YW, Adhikary PP, Lim KS, Kim HJ, Kim JK, Kim YH. Oligopeptide complex for targeted non-viral gene delivery to adipocytes. Nat Mater. 2014;13(12):1157–64. doi: 10.1038/nmat4092 25282508.

22. Barnhart KF, Christianson DR, Hanley PW, Driessen WH, Bernacky BJ, Baze WB, et al. A peptidomimetic targeting white fat causes weight loss and improved insulin resistance in obese monkeys. Sci Transl Med. 2011;3(108):108ra12. doi: 10.1126/scitranslmed.3002621 22072637; PubMed Central PMCID: PMC3666164.

23. Kim DH, Woods SC, Seeley RJ. Peptide designed to elicit apoptosis in adipose tissue endothelium reduces food intake and body weight. Diabetes. 2010;59(4):907–15. doi: 10.2337/db09-1141 20103704; PubMed Central PMCID: PMC2844838.

24. Ande SR, Nguyen KH, Nyomba BL, Mishra S. Prohibitin in Adipose and Immune Functions. Trends Endocrinol Metab. 2016;27(8):531–41. doi: 10.1016/j.tem.2016.05.003 27312736.

25. Rajalingam K, Wunder C, Brinkmann V, Churin Y, Hekman M, Sievers C, et al. Prohibitin is required for Ras-induced Raf-MEK-ERK activation and epithelial cell migration. Nat Cell Biol. 2005;7(8):837–43. doi: 10.1038/ncb1283 16041367.

26. Terashima M, Kim KM, Adachi T, Nielsen PJ, Reth M, Kohler G, et al. The IgM antigen receptor of B lymphocytes is associated with prohibitin and a prohibitin-related protein. EMBO J. 1994;13(16):3782–92. 8070406; PubMed Central PMCID: PMC395291.

27. Sharma A, Qadri A. Vi polysaccharide of Salmonella typhi targets the prohibitin family of molecules in intestinal epithelial cells and suppresses early inflammatory responses. Proc Natl Acad Sci U S A. 2004;101(50):17492–7. doi: 10.1073/pnas.0407536101 15576509; PubMed Central PMCID: PMC536020.

28. Ramakrishnan VM, Boyd NL. The Adipose Stromal Vascular Fraction as a Complex Cellular Source for Tissue Engineering Applications. Tissue Eng Part B Rev. 2018;24(4):289–99. doi: 10.1089/ten.TEB.2017.0061 28316259; PubMed Central PMCID: PMC6080106.

29. Kajimoto K, Hossen MN, Hida K, Ohga N, Akita H, Hyodo M, et al. Isolation and culture of microvascular endothelial cells from murine inguinal and epididymal adipose tissues. J Immunol Methods. 2010;357(1–2):43–50. doi: 10.1016/j.jim.2010.03.011 20307543.

30. Church CD, Berry R, Rodeheffer MS. Isolation and study of adipocyte precursors. Methods Enzymol. 2014;537:31–46. doi: 10.1016/B978-0-12-411619-1.00003-3 24480340; PubMed Central PMCID: PMC4276307.

31. Szoka F Jr, Papahadjopoulos D. Procedure for preparation of liposomes with large internal aqueous space and high capture by reverse-phase evaporation. Proc Natl Acad Sci U S A. 1978;75(9):4194–8. doi: 10.1073/pnas.75.9.4194 279908; PubMed Central PMCID: PMC336078.

32. Kulkarni JA, Witzigmann D, Leung J, van der Meel R, Zaifman J, Darjuan MM, et al. Fusion-dependent formation of lipid nanoparticles containing macromolecular payloads. Nanoscale. 2019;11(18):9023–31. doi: 10.1039/c9nr02004g 31021343.

33. Dasa SSK, Suzuki R, Gutknecht M, Brinton LT, Tian Y, Michaelsson E, et al. Development of target-specific liposomes for delivering small molecule drugs after reperfused myocardial infarction. J Control Release. 2015;220(Pt A):556–67. doi: 10.1016/j.jconrel.2015.06.017 26122651.

34. Dasa SSK, Suzuki R, Mugler E, Chen L, Jansson-Lofmark R, Michaelsson E, et al. Evaluation of pharmacokinetic and pharmacodynamic profiles of liposomes for the cell type-specific delivery of small molecule drugs. Nanomedicine. 2017;13(8):2565–74. doi: 10.1016/j.nano.2017.07.005 28754465; PubMed Central PMCID: PMC5673558.

35. Beech JR, Shin SJ, Smith JA, Kelly KA. Mechanisms for targeted delivery of nanoparticles in cancer. Curr Pharm Des. 2013;19(37):6560–74. doi: 10.2174/1381612811319370002 23621529.

36. Penas F, Mirkin GA, Vera M, Cevey A, Gonzalez CD, Gomez MI, et al. Treatment in vitro with PPARalpha and PPARgamma ligands drives M1-to-M2 polarization of macrophages from T. cruzi-infected mice. Biochim Biophys Acta. 2015;1852(5):893–904. doi: 10.1016/j.bbadis.2014.12.019 25557389.

37. Murakami K, Bujo H, Unoki H, Saito Y. Effect of PPARalpha activation of macrophages on the secretion of inflammatory cytokines in cultured adipocytes. Eur J Pharmacol. 2007;561(1–3):206–13. doi: 10.1016/j.ejphar.2006.12.037 17320860.

38. Rakhshandehroo M, Knoch B, Muller M, Kersten S. Peroxisome proliferator-activated receptor alpha target genes. PPAR Res. 2010;2010:1–20. doi: 10.1155/2010/612089 20936127; PubMed Central PMCID: PMC2948931.

39. Kiss-Toth E, Roszer T. PPARgamma in Kidney Physiology and Pathophysiology. PPAR Res. 2008;2008:1–9. doi: 10.1155/2008/183108 19283081; PubMed Central PMCID: PMC2654308.

40. Ruan X, Zheng F, Guan Y. PPARs and the kidney in metabolic syndrome. Am J Physiol Renal Physiol. 2008;294(5):F1032–47. doi: 10.1152/ajprenal.00152.2007 18234957.

41. Osman C, Merkwirth C, Langer T. Prohibitins and the functional compartmentalization of mitochondrial membranes. J Cell Sci. 2009;122(Pt 21):3823–30. doi: 10.1242/jcs.037655 19889967.

42. Salameh A, Daquinag AC, Staquicini DI, An Z, Hajjar KA, Pasqualini R, et al. Prohibitin/annexin 2 interaction regulates fatty acid transport in adipose tissue. JCI Insight. 2016;1(10):1–16. doi: 10.1172/jci.insight.86351 27468426; PubMed Central PMCID: PMC4959783.

43. Schleicher M, Shepherd BR, Suarez Y, Fernandez-Hernando C, Yu J, Pan Y, et al. Prohibitin-1 maintains the angiogenic capacity of endothelial cells by regulating mitochondrial function and senescence. J Cell Biol. 2008;180(1):101–12. doi: 10.1083/jcb.200706072 18195103; PubMed Central PMCID: PMC2213620.

44. Wang YJ, Guo XL, Li SA, Zhao YQ, Liu ZC, Lee WH, et al. Prohibitin is involved in the activated internalization and degradation of protease-activated receptor 1. Biochim Biophys Acta. 2014;1843(7):1393–401. doi: 10.1016/j.bbamcr.2014.04.005 24732013.

45. Stockinger H, Gadd SJ, Eher R, Majdic O, Schreiber W, Kasinrerk W, et al. Molecular characterization and functional analysis of the leukocyte surface protein CD31. J Immunol. 1990;145(11):3889–97. 1700999.

46. McDonnell ME, Ganley-Leal LM, Mehta A, Bigornia SJ, Mott M, Rehman Q, et al. B lymphocytes in human subcutaneous adipose crown-like structures. Obesity (Silver Spring). 2012;20(7):1372–8. doi: 10.1038/oby.2012.54 22395812; PubMed Central PMCID: PMC3682646.

47. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796–808. doi: 10.1172/JCI19246 14679176; PubMed Central PMCID: PMC296995.

48. Pang C, Gao Z, Yin J, Zhang J, Jia W, Ye J. Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity. Am J Physiol Endocrinol Metab. 2008;295(2):E313–22. doi: 10.1152/ajpendo.90296.2008 18492768; PubMed Central PMCID: PMC2519760.

49. Heilbronn LK, Campbell LV. Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr Pharm Des. 2008;14(12):1225–30. doi: 10.2174/138161208784246153 18473870.

50. Feng B, Jiao P, Nie Y, Kim T, Jun D, van Rooijen N, et al. Clodronate liposomes improve metabolic profile and reduce visceral adipose macrophage content in diet-induced obese mice. PLoS One. 2011;6(9):1–11. doi: 10.1371/journal.pone.0024358 21931688; PubMed Central PMCID: PMC3171445.

51. Bu L, Gao M, Qu S, Liu D. Intraperitoneal injection of clodronate liposomes eliminates visceral adipose macrophages and blocks high-fat diet-induced weight gain and development of insulin resistance. AAPS J. 2013;15(4):1001–11. doi: 10.1208/s12248-013-9501-7 23821353; PubMed Central PMCID: PMC3787235.

52. Sugii S, Olson P, Sears DD, Saberi M, Atkins AR, Barish GD, et al. PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization. Proc Natl Acad Sci U S A. 2009;106(52):22504–9. doi: 10.1073/pnas.0912487106 20018750; PubMed Central PMCID: PMC2794650.

53. Wang F, Mullican SE, DiSpirito JR, Peed LC, Lazar MA. Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARgamma. Proc Natl Acad Sci U S A. 2013;110(46):18656–61. doi: 10.1073/pnas.1314863110 24167256; PubMed Central PMCID: PMC3831974.

54. Fagerberg B, Edwards S, Halmos T, Lopatynski J, Schuster H, Stender S, et al. Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia. 2005;48(9):1716–25. doi: 10.1007/s00125-005-1846-8 16001233.


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