Ultrasound combined blood-brain barrier targeting brain delivery of four-in-one molecular aggregates for the enhancement of anesthetic efficacy and toxicity reduction via propofol-etomidate synergistically inhibition GABA receptor

Abstract

To enhance the anesthetic efficacy and reduce toxic side effects, a strategy is proposed involving the utilization of general anesthetics of Propofol (Pro) and Etomidate (Eto) to synergistic inhibition GABA receptors simultaneously. Four-in-one molecular aggregates were prepared to implement this strategy, which comprised of Pro and Eto with the bridging molecule monoglyceride monooleate (GMO) and surfactant F127 through intermolecular forces. The blood-brain barrier (BBB) targeted lactoferrin (LF) is affixed to their surface, obtaining the final molecular aggregates. By employing lactoferrin enrich aggregates to the BBB, followed by ultrasound combine microbubbles to open the BBB, a remarkable 4.5-fold enhancement in brain drug delivery was achieved. The molecular aggregates group maintained stable parameters of heart rate, diastolic blood pressure, and systolic blood pressure. A notable increase of more than twice therapeutic index (TI) value was observed, implying their higher anesthesia efficiency and reduced toxicity. Electroencephalogram (EEG) experiments demonstrate a significant elevation in the proportion of δ waves from 28% to 80% for aggregates, accompanied by a nearly fivefold reduction in the proportion of θ waves, meaning a significant improvement in synergistic anesthesia effectiveness (interaction index 0.289) with lower drug dosage. Furthermore, mouse immunofluorescence brain slice experiments suggest Pro and Eto enter the GABA receptor simultaneously, resulting in synergistic inhibition of GABA receptors.

Keywords

blood-brain barrier / brain delivery / GABA receptor / molecular aggregates / synergistic anesthetic efficacy

References

[1] A. S. Evers, C. M. Crowder, J. R. Balser, in Goodman & Gilman’s The Pharmacologic Basis of Therapeutics, McGraw-Hill, New York 2006, p.341.

[2] M. Perouansky, H. C. Hemmings, B. Riou, J. Am. Soc. Anesthesiol. 2009, 111, 1365.

[3] E. Bakhtiari, S. H. Mousavi, M. G. Fard, Expert Rev. Clin. Pharmacol. 2021, 14, 889.

[4] M. Legrand, B. Plaud, Anesth. Analg. 2013, 117, 1267.

[5] J. B. Glen, Br. J. Anaesth. 2019, 123, 3.

[6] M. Saraghi, V. M. Badner, L. R. Golden, E. V. Hersh, Compend. Contin. Educ. Dent. 2013, 34, 252.

[7] Y. Miao, Y. Zhang, H. Wan, L. Chen, F. Wang, Biomed. Pharmacother. 2010, 64, 583.

[8] S. Fukami, I. Uchida, M. Takenoshita, T. Mashimo, I. Yoshiya, Eur. J. Pharmacol. 1999, 368, 269.

[9] C. Grasshoff, R. Jurd, U. Rudolph, B. Antkowiak, Mol. Pharmacol. 2007, 72, 780.

[10] P. E. Marik, Curr. Pharm. Des. 2004, 10, 3639.

[11] A. E Rigby-Jones, J. A. Nolan, M. J. Priston, P. M. C. Wright, J. R. Sneyd, A. R. Wolf, J. Am. Soc. Anesthesiol. 2002, 97, 1393.

[12] J. M. Lee, G. Min, J. M. Lee, S. H. Kim, H. S. Choi, E. S. Kim, B. Keum, Y. T. Jeen, H. J. Chun, H. S. Lee, Medicine 2018, 97, e10635.

[13] C. M. Hohl, C. H Kelly-Smith, T. C. Yeung, D. D. Sweet, M. M Doyle-Waters, M. Schulzer, Ann. Emerg. Med. 2010, 56, 105.

[14] S. A. Forman, D. S. Warner, J. Am. Soc. Anesthesiol. 2011, 114, 695.

[15] L. Chen, X. Liang, X. Tan, H. Wen, J. Jiang, Y. Li, Medicine 2019, 98, e15712.

[16] E.-H. Lee, S.-H. Lee, D.-Y. Park, K.-H. Ki, E.-K. Lee, D.-H. Lee, G.-J. Noh, Anesthesiology 2008, 109, 436.

[17] B. I. Valk, M. M. Struys, Clin. Pharmacokinet. 2021, 60, 1253.

[18] A. Vadalouca, E. Raptis, E. Moka, P. Zis, P. Sykioti, I. Siafaka, Pain Pract. 2012, 12, 219.

[19] N. K. Acharya, E. L. Goldwaser, M. M. Forsberg, G. A. Godsey, C. A. Johnson, A. Sarkar, C. DeMarshall, M. C. Kosciuk, J. M. Dash, C. P. Hale, Brain Res. 2015, 1620, 29.

[20] J. Ye, Y. Fan, Y. She, J. Shi, Y. Yang, X. Yuan, R. Li, J. Han, L. Liu, Y. Kang, X. Ji, Adv. Sci. 2024, 1, 2310211.

[21] G. C. Terstappen, A. H. Meyer, R. D. Bell, W. Zhang, Nat. Rev. Drug Discovery 2021, 20, 362.

[22] D. P. Anthony, M. Hegde, S. S. Shetty, T. Rafic, S. Mutalik, B. S. Rao, Life Sci. 2021, 274, 119326.

[23] H. Chen, Y. Qin, Q. Zhang, W. Jiang, L. Tang, J. Liu, Q. He, Eur. J. Pharm. Sci. 2011, 44, 164.

[24] T. Garg, S. Bhandari, G. Rath, A. K. Goyal, J. Drug Target. 2015, 23, 865.

[25] Y. Kang, Z. Mao, Y. Wang, C. Pan, M. Ou, H. Zhang, W. Zeng, X. Ji, Nat. Commun. 2022, 13, 2425.

[26] E. E Konofagou, Y.-S. Tunga, J. Choia, T. Deffieuxa, B. Baseria, F. Vlachosa, Curr. Pharm. Biotechnol. 2012, 13, 1332.

[27] L. Shi, P. Palacio-Mancheno, J. Badami, D. W. Shin, M. Zeng, L. Cardoso, R. Tu, B. M. Fu, Int. J. Nanomed. 2014, 9, 4437.

[28] R. Pandit, L. Chen, J. Götz, Adv. Drug Delivery Rev. 2020, 165-166, 1.

[29] P. Wu, M. Zhu, Y. Li, Z. Ya, Y. Yang, Y. Yuan, W. Dong, S. Guo, S. Lu, L. Zhang, Adv. Funct. Mater. 2021, 31, 2105786.

[30] S. Zhang, S. Zhang, S. Luo, P. Tang, M. Wan, D. Wu, W. Gao, J. Nanobiotechnol. 2022, 20, 1.

[31] J. Ye, Y. Fan, G. Niu, B. Zhou, Y. Kang, X. Ji, Nano Today 2024, 55, 102212.

[32] D. S. Miller, Clin. Pharmacol. Ther. 2015, 97, 395.

[33] J. L. Mikitsh, A.-M. Chacko, Perspect. Med. Chem. 2014, 6, 11.

[34] L. Chen, Z. Mao, Y. Wang, Y. Kang, Y. Wang, L. Mei, X. Ji, Adv. Sci. 2022, 8, 7372.

[35] A. A. Ahmed, S. Dash, Res. J. Pharm. Technol. 2017, 10, 2809.

[36] A. Hassani Najafabadi, S. Azodi-Deilami, M. Abdouss, H. Payravand, S. Farzaneh, J. Mater. Sci. Mater. Med. 2015, 26, 145.

[37] M. Johnsson, J. Barauskas, A. Norlin, F. Tiberg, J. Nanosci. Nanotechnol. 2006, 6, 3017.

[38] X. Li, Y. Zhang, Y. Fan, Y. Zhou, X. Wang, C. Fan, Y. Liu, Q. Zhang, Nanoscale Res. Lett. 2011, 6, 1.

[39] S. A. Kulkarni, S.-S. Feng, Nanomedicine 2011, 6, 377.

[40] M. G. Kim, S. W. Park, J. H. Kim, J. Lee, S. H. Kae, H. J. Jang, D. H. Koh, M. H. Choi, Gastrointest. Endosc. 2017, 86, 452.

[41] Q. Zhang, Y. Chen, R. Lu, Y. Yao, C. Li, Y. Yu, S. Zhang, J. Mater. Chem. B 2020, 8, 2719.

[42] R. H. Fang, C.-M. J. Hu, B. T. Luk, W. Gao, J. A. Copp, Y. Tai, D. E. O’Connor, L. Zhang, Nano Lett. 2014, 14, 2181.

[43] Y. Wang, P. Li, L. Kong, AAPS PharmSciTech 2013, 14, 585.

[44] X. Yuan, J. Shi, Y. Kang, J. Dong, Z. Pei, X. Ji, Adv. Mater. 2024, 36, 2308726.

[45] M. Hamidi, A. Azadi, P. Rafiei, Adv. Drug Delivery Rev. 2008, 60, 1638.

[46] H. Liu, X. Zhou, Y. Wang, M. Yang, X. Xu, A. Wu, J. Drug Delivery Sci. Technol. 2019, 49, 123.

[47] A. Abrahao, Y. Meng, M. Llinas, Y. Huang, C. Hamani, T. Mainprize, I. Aubert, C. Heyn, S. E. Black, K. Hynynen, Nat. Commun. 2019, 10, 4373.

[48] X. Zhang, N. Li, S. Zhang, B. Sun, Q. Chen, Z. He, C. Luo, J. Sun, Med. Res. Rev. 2020, 40, 1754.

[49] T. Zhang, X. Guo, Y. Shi, C. He, C. Duan, Nat. Commun. 2018, 9, 4024.

[50] Q. Wan, Q. Huang, M. Liu, D. Xu, H. Huang, X. Zhang, Y. Wei, Appl. Mater. Today 2017, 9, 145.

[51] J. Barauskas, L. Christerson, M. Wadsäter, F. Lindström, A.-K. Lindqvist, F. Tiberg, Mol. Pharmaceutics 2014, 11, 895.

[52] H. Almeida, M. Amaral, P. Lobão, J. Lobo, J. Pharm. Pharm. Sci. 2012, 15, 592.

[53] Q. Meng, A. Wang, H. Hua, Y. Jiang, Y. Wang, H. Mu, Z. Wu, K. Sun, Int. J. Nanomed. 2018, 13, 705.

[54] K. Meena, R. Meena, S. Nayak, S. Prakash, A. Kumar, J. Anesth. Clin. Res. 2016, 7, 2.

[55] P. A. Nikitina, V. P. Perevalov, Chem. Heterocycl. Compd. 2017, 53, 123.

[56] R. Roger, D. G. Neilson, Chem. Rev. 1961, 61, 179.

[57] R. N. Waterhouse, Mol. Imaging Biol. 2003, 5, 376.

[58] Z. Huang, S. Hua, Y. Yang, J. Fang, Acta Pharmacol. Sin. 2008, 29, 1094.

[59] P. Wu, W. Dong, X. Guo, X. Qiao, S. Guo, L. Zhang, M. Wan, Y. Zong, Adv. Healthcare Mater. 2019, 8, 1900720.

[60] M. Zhu, P. Wu, Y. Li, L. Zhang, Y. Zong, M. Wan, Biomater. Sci. 2022, 10, 3911.

[61] F. Zhang, Y. Kang, L. Feng, G. Xi, W. Chen, N. Kong, W. Tao, T. Luan, S. Koo, X. Ji, Mater. Horiz. 2023, 10, 5474.

[62] A. N. Alatrushi, A. S. Naser, Maced. Vet. Rev. 2021, 44, 203.

[63] J. J. Łuszczki, D. Podgórska, J. Kozińska, M. Jankiewicz, Z. Plewa, M. Kominek, D. Żółkowska, M. Florek-Łuszczki, Pharmacol. Rep. 2021, 73, 111.

[64] L. Hou, H. Tian, Lett. Drug Des. Discovery 2024, 21, 320.

[65] C. L. Krahn, R. P. Raffin, G. S. Santos, L. B. Queiroga, R. L. Cavalcanti, P. Serpa, E. Dallegrave, P. E. Mayorga, A. R. Pohlmann, C. C. Natalini, J. Biomed. Nanotechnol. 2012, 8, 849.

[66] P. L. Purdon, A. Sampson, K. J. Pavone, E. N. Brown, Anesthesiology 2015, 123, 937.

[67] M. Irifune, M. Sugimura, T. Takarada, K. Maeoka, Y. Shimizu, T. Dohi, T. Nishikawa, M. Kawahara, Br. J. Anaesth. 1999, 83, 665.

[68] J. Liu, F. Peng, Y. Kang, D. Gong, J. Fan, W. Zhang, F. Qiu, Int. J. Nanomed. 2021, 16, 5317.

[69] A. Wu, Y. Wang, S. Mina, H. Liu, F. Xie, J. Drug Delivery Sci. Technol. 2018, 46, 156.

[70] R. Cleale, W. Muir, A. Waselau, M. Lehmann, D. Amodie, P. Lerche, J. Vet. Pharmacol. Therap. 2009, 32, 436.

[71] P. L. Purdona, E. T. Piercea, E. A. Mukamelc, M. J. Preraua, J. L. Walsha, K. F. K. Wonga, A. F Salazar-Gomeza, P. G. Harrella, A. L. Sampsona, A. Cimensera, S. Chinga, N. J. Kopelle, C. Tavares-Stoeckela, K. Habeebf, R. Merhara, E. N. Browna, Proc. Natl. Acad. Sci. U. S. A. 2013, 110, E1142.

[72] K. Yuka, I. Masahiro, Y. Taiga, O. Kana, T. Tamayo, O. Aya, K. Hisanobu, I. Serika, S. Utaka, I. Eiji, A. Yukio, O. Yoshiyuki, Anesth. Analg. 2022, 10, 1213.

[73] H. Shaye, A. Ishchenko, J. H. Lam, G. W. Han, L. Xue, P. Rondard, J.-P. Pin, V. Katritch, C. Gati, V. Cherezov, Nature 2020, 584, 298.

[74] X. He, Y. Bai, M. Zeng, Z. Zhao, Q. Zhang, N. Xu, F. Qin, X. Wei, M. Zhao, N. Wu, Z. Li, Y. Zhang, T.-P. Fan, X. Zheng, Pharmacol. Rep. 2018, 70, 69.

[75] N. A. Niessen, J. Balthazart, G. F. Ball, T. D. Charlier, Eur. J. Neurosci. 2013, 38, 3325.

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