Preparation, characterization, and biodistribution of glutathione PEGylated nanoliposomal doxorubicin for brain drug delivery with a post-insertion approach

Document Type : Original Article

Authors

1 Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

3 Warwick Medical School, University of Warwick, Coventry, UK

4 Department of Medical Nanotechnology, Shiraz University of Medical Sciences, Shiraz, Iran

5 Biosun Pharmed Pharmaceuticals Company, Tehran, Iran

6 Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): Brain cancer treatments have mainly failed due to their inability to cross the blood-brain barrier. Several studies have confirmed the presence of glutathione (GSH) receptors on BBB’s surface, as a result, products like 2B3-101, which contain over 5% pre-inserted GSH PEGylated liposomal Doxorubicin, are being tested in clinical trials. Here we conducted the PEGylated nanoliposomal Doxorubicin particles that are covalently attached to the glutathione using the post-insertion technique. Compared with the pre-insertion approach, the post-insertion method is notably simpler, faster, and more cost-effective, making it ideal for large-scale pharmaceutical manufacturing. 
Materials and Methods: The ligands of the DSPE PEG(2000) Maleimide-GSH were introduced in the amounts of 25, 50, 100, 200, and 400 on the available Caelyx. Following physicochemical evaluations, animal experiments such as biodistribution, fluorescence microscopy, and pharmacokinetics were done. 
Results: In comparison with Caelyx, the 200L and 400L treatment arms were the most promising formulations. We showed that nanocarriers containing 40 times fewer GSH micelles than 2B3-101 significantly increased blood-brain barrier penetrance. Due to the expressed GSH receptors on tissues as an endogenous antioxidant, Doxorubicin will likely concentrate in the liver, spleen, heart, and lung in comparison with Caelyx, according to other tissue analyses. 
Conclusion: The post-insertion technique was found a successful approach with more pharmaceutical aspects for large-scale production. Moreover, further investigations are highly recommended to determine the efficacy of 5% post-inserted GSH targeted nanoliposomes versus 2B3-101 as a similar formulation with a different preparation method.

Keywords

References

1. Chen R, Smith-Cohn M, Cohen AL, Colman H. Glioma Subclassifications and Their Clinical Significance. Neurotherapeutics 2017; 14:284-297.
2. Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, et al. The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol 2014; 16:896-913.
3. Pallavicini G, Berto GE, Di Cunto F. Precision Revisited: Targeting Microcephaly Kinases in Brain Tumors. Int J Mol Sci 2019; 20.
4. Salcman M. Surgical resection of malignant brain tumors: who benefits? Oncology (Williston Park) 1988; 2:47-56, 59-60, 63.
5. Lara-Velazquez M, Al-Kharboosh R, Jeanneret S, Vazquez-Ramos C, Mahato D, Tavanaiepour D, et al. Advances in Brain Tumor Surgery for Glioblastoma in Adults. Brain Sci 2017; 7.
6. Stupp R, Brada M, van den Bent MJ, Tonn JC, Pentheroudakis G. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014; 25 Suppl 3:iii93-101.
7. Perry JR, Laperriere N, O’Callaghan CJ, Brandes AA, Menten J, Phillips C, et al. Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma. N Engl J Med 2017; 376:1027-1037.
8. Kotecha R, Gondi V, Ahluwalia MS, Brastianos PK, Mehta MP. Recent advances in managing brain metastasis. F1000Res 2018; 7.
9. Mercadante V, Al Hamad A, Lodi G, Porter S, Fedele S. Interventions for the management of radiotherapy-induced xerostomia and hyposalivation: A systematic review and meta-analysis. Oral Oncol 2017; 66:64-74.
10. Brown PD, Ahluwalia MS, Khan OH, Asher AL, Wefel JS, Gondi V. Whole-Brain Radiotherapy for Brain Metastases: Evolution or Revolution? J Clin Oncol 2018; 36:483-491.
11. Ikonomidou C. Chemotherapy and the pediatric brain. Molecular and Cellular Pediatrics 2018; 5:8.
12. Eide S, Feng ZP. Doxorubicin chemotherapy-induced “chemo-brain”: Meta-analysis. Eur J Pharmacol 2020; 881:173078.
13. Makwana V, Karanjia J, Haselhorst T, Anoopkumar-Dukie S, Rudrawar S. Liposomal doxorubicin as targeted delivery platform: Current trends in surface functionalization. Int J Pharm 2021; 593:120117.
14. Pugazhendhi A, Edison T, Velmurugan BK, Jacob JA, Karuppusamy I. Toxicity of Doxorubicin (Dox) to different experimental organ systems. Life Sci 2018; 200:26-30.
15. O’Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 2004; 15:440-449.
16. Yamaguchi N, Fujii T, Aoi S, Kozuch PS, Hortobagyi GN, Blum RH. Comparison of cardiac events associated with liposomal doxorubicin, epirubicin and doxorubicin in breast cancer: a Bayesian network meta-analysis. Eur J Cancer 2015; 51:2314-2320.
17. Björnmalm M, Thurecht KJ, Michael M, Scott AM, Caruso F. Bridging Bio-Nano Science and Cancer Nanomedicine. ACS Nano 2017; 11:9594-9613.
18. Golali E, Jaafari MR, Khamesipour A, Abbasi A, Saberi Z, Badiee A. Comparison of in vivo Adjuvanticity of Liposomal PO CpG ODN with Liposomal PS CpG ODN: Soluble Leishmania Antigens as a Model. Iran J Basic Med Sci 2012; 15:1032-1045.
19. Moghimi SM, Szebeni J. Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog Lipid Res 2003; 42:463-478.
20. Cattel L, Ceruti M, Dosio F. From conventional to stealth liposomes: a new Frontier in cancer chemotherapy. J Chemother 2004; 16 Suppl 4:94-97.
21. Mahendra A, James HP, Jadhav S. PEG-grafted phospholipids in vesicles: Effect of PEG chain length and concentration on mechanical properties. Chem Phys Lipids 2019; 218:47-56.
22. Samiei A, Tamadon AM, Samani SM, Manolios N, Sarvestani EK. Engraftment of plasma membrane vesicles into liposomes: A new method for designing of liposome-based vaccines. Iran J Basic Med Sci 2014; 17:772-778.
23. Fang J, Nakamura H, Maeda H. The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev 2011; 63:136-151.
24. Golombek SK, May JN, Theek B, Appold L, Drude N, Kiessling F, et al. Tumor targeting via EPR: Strategies to enhance patient responses. Adv Drug Deliv Rev 2018; 130:17-38.
25. Kumari S, Ahsan SM, Kumar JM, Kondapi AK, Rao NM. Overcoming blood brain barrier with a dual purpose Temozolomide loaded Lactoferrin nanoparticles for combating glioma (SERP-17-12433). Scientific Reports 2017; 7:6602.
26. Haumann R, Videira JC, Kaspers GJL, van Vuurden DG, Hulleman E. Overview of Current Drug Delivery Methods Across the Blood-Brain Barrier for the Treatment of Primary Brain Tumors. CNS Drugs 2020; 34:1121-1131.
27. Jena L, McErlean E, McCarthy H. Delivery across the blood-brain barrier: nanomedicine for glioblastoma multiforme. Drug Deliv Transl Res 2020; 10:304-318.
28. Thangudu S, Cheng FY, Su CH. Advancements in the Blood-Brain Barrier Penetrating Nanoplatforms for Brain Related Disease Diagnostics and Therapeutic Applications. Polymers (Basel) 2020; 12.
29. Chertok B, Moffat BA, David AE, Yu F, Bergemann C, Ross BD, et al. Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors. Biomaterials 2008; 29:487-496.
30. Lundy DJ, Lee KJ, Peng IC, Hsu CH, Lin JH, Chen KH, et al. Inducing a Transient Increase in Blood-Brain Barrier Permeability for Improved Liposomal Drug Therapy of Glioblastoma Multiforme. ACS Nano 2019; 13:97-113.
31. Ferraris C, Cavalli R, Panciani PP, Battaglia L. Overcoming the Blood-Brain Barrier: Successes and Challenges in Developing Nanoparticle-Mediated Drug Delivery Systems for the Treatment of Brain Tumours. Int J Nanomedicine 2020; 15:2999-3022.
32. Li J, Zhao J, Tan T, Liu M, Zeng Z, Zeng Y, et al. Nanoparticle Drug Delivery System for Glioma and Its Efficacy Improvement Strategies: A Comprehensive Review. Int J Nanomedicine 2020; 15:2563-2582.
33. Boyd BJ, Galle A, Daglas M, Rosenfeld JV, Medcalf R. Traumatic brain injury opens blood-brain barrier to stealth liposomes via an enhanced permeability and retention (EPR)-like effect. J Drug Target 2015; 23:847-853.
34. Löscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx 2005; 2:86-98.
35. Greene C, Campbell M. Tight junction modulation of the blood brain barrier: CNS delivery of small molecules. Tissue Barriers 2016; 4:e1138017.
36. Almutairi MM, Gong C, Xu YG, Chang Y, Shi H. Factors controlling permeability of the blood-brain barrier. Cell Mol Life Sci 2016; 73:57-77.
37. Villaseñor R, Lampe J, Schwaninger M, Collin L. Intracellular transport and regulation of transcytosis across the blood-brain barrier. Cell Mol Life Sci 2019; 76:1081-1092.
38. Knowland D, Arac A, Sekiguchi KJ, Hsu M, Lutz SE, Perrino J, et al. Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke. Neuron 2014; 82:603-617.
39. Mathiesen Janiurek M, Soylu-Kucharz R, Christoffersen C, Kucharz K, Lauritzen M. Apolipoprotein M-bound sphingosine-1-phosphate regulates blood-brain barrier paracellular permeability and transcytosis. Elife 2019; 8.
40. Stukel JM, Caplan MR. Targeted drug delivery for treatment and imaging of glioblastoma multiforme. Expert Opin Drug Deliv 2009; 6:705-718.
41. Ayloo S, Gu C. Transcytosis at the blood-brain barrier. Curr Opin Neurobiol 2019; 57:32-38.
42. Zlokovic BV, Mackic JB, McComb JG, Weiss MH, Kaplowitz N, Kannan R. Evidence for transcapillary transport of reduced glutathione in vascular perfused guinea-pig brain. Biochem Biophys Res Commun 1994; 201:402-408.
43. Moghadas-Sharif N, Fazly Bazzaz BS, Khameneh B, Malaekeh-Nikouei B. The effect of nanoliposomal formulations on Staphylococcus epidermidis biofilm. Drug Dev Ind Pharm 2015; 41:445-450.
44.Aoyama K, Wang F, Matsumura N, Kiyonari H, Shioi G, Tanaka K, et al. Increased neuronal glutathione and neuroprotection in GTRAP3-18-deficient mice. Neurobiol Dis 2012; 45:973-982.
45.Lee KH, Cha M, Lee BH. Neuroprotective Effect of Antioxidants in the Brain. Int J Mol Sci 2020; 21.
46.Kannan R, Chakrabarti R, Tang D, Kim KJ, Kaplowitz N. GSH transport in human cerebrovascular endothelial cells and human astrocytes: evidence for luminal localization of Na+-dependent GSH transport in HCEC. Brain Res 2000; 852:374-382.
47.Kannan R, Kuhlenkamp JF, Jeandidier E, Trinh H, Ookhtens M, Kaplowitz N. Evidence for carrier-mediated transport of glutathione across the blood-brain barrier in the rat. J Clin Invest 1990; 85:2009-2013.
48.Kannan R, Mittur A, Bao Y, Tsuruo T, Kaplowitz N. GSH transport in immortalized mouse brain endothelial cells: evidence for apical localization of a sodium-dependent GSH transporter. J Neurochem 1999; 73:390-399.
49.An Open-label, Phase I/IIa, Dose Escalating Study of 2B3-101 in Patients With Solid Tumors and Brain Metastases or Recurrent Malignant Glioma. Available from: https://clinicaltrials.gov/ct2/show/NCT01386580.
50.Clinical and Pharmacological Study With 2B3-101 in Patients With Breast Cancer and Leptomeningeal Metastases. Available from: https://clinicaltrials.gov/ct2/show/NCT01818713.
51.2B3-101 (GSH-PEG liposomal doxorubicin, now 2X-111 at Oncology Venture A/S) for brain metastases and recurrent malignant glioma has completed a Phase I/IIa clinical trial. Available from: https://www.2-bbb.com/products/2b3-101/.
52.Gaillard PJ, Appeldoorn CC, Dorland R, van Kregten J, Manca F, Vugts DJ, et al. Pharmacokinetics, brain delivery, and efficacy in brain tumor-bearing mice of glutathione pegylated liposomal doxorubicin (2B3-101). PLoS One 2014; 9:e82331.
53.Birngruber T, Raml R, Gladdines W, Gatschelhofer C, Gander E, Ghosh A, et al. Enhanced doxorubicin delivery to the brain administered through glutathione PEGylated liposomal doxorubicin (2B3-101) as compared with generic Caelyx,(®)/Doxil(®)--a cerebral open flow microperfusion pilot study. J Pharm Sci 2014; 103:1945-1948.
54.Maussang D, Rip J, van Kregten J, van den Heuvel A, van der Pol S, van der Boom B, et al. Glutathione conjugation dose-dependently increases brain-specific liposomal drug delivery in vitro and in vivo. Drug Discov Today Technol 2016; 20:59-69.
55.Lee DH, Rötger C, Appeldoorn CC, Reijerkerk A, Gladdines W, Gaillard PJ, et al. Glutathione PEGylated liposomal methylprednisolone (2B3-201) attenuates CNS inflammation and degeneration in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis. J Neuroimmunol 2014; 274:96-101.
56.Zhang L, Cao H, Zhang J, Yang C, Hu T, Li H, et al. Comparative study of (Asp)7-CHOL-modified liposome prepared using pre-insertion and post-insertion methods for bone targeting in vivo. J Drug Target 2017; 25:149-155.
57.Nakamura K, Yamashita K, Itoh Y, Yoshino K, Nozawa S, Kasukawa H. Comparative studies of polyethylene glycol-modified liposomes prepared using different PEG-modification methods. Biochim Biophys Acta 2012; 1818:2801-2807.
58.Nojima Y, Iwata K. Viscosity heterogeneity inside lipid bilayers of single-component phosphatidylcholine liposomes observed with picosecond time-resolved fluorescence spectroscopy. J Phys Chem B 2014; 118:8631-8641.
59.Szleifer I, Gerasimov OV, Thompson DH. Spontaneous liposome formation induced by grafted poly(ethylene oxide) layers: theoretical prediction and experimental verification. Proc Natl Acad Sci U S A 1998; 95:1032-1037.
60.Awasthi VD, Garcia D, Klipper R, Goins BA, Phillips WT. Neutral and anionic liposome-encapsulated hemoglobin: effect of postinserted poly(ethylene glycol)-distearoylphosphatidylethanolamine on distribution and circulation kinetics. J Pharmacol Exp Ther 2004; 309:241-248.
61.Allen TM, Sapra P, Moase E. Use of the post-insertion method for the formation of ligand-coupled liposomes. Cell Mol Biol Lett 2002; 7:889-894.
62.Mare R, Paolino D, Celia C, Molinaro R, Fresta M, Cosco D. Post-insertion parameters of PEG-derivatives in phosphocholine-liposomes. Int J Pharm 2018; 552:414-421.
63.Nag OK, Awasthi V. Surface engineering of liposomes for stealth behavior. Pharmaceutics 2013; 5:542-569.
64.Moreira JN, Ishida T, Gaspar R, Allen TM. Use of the post-insertion technique to insert peptide ligands into pre-formed stealth liposomes with retention of binding activity and cytotoxicity. Pharm Res 2002; 19:265-269.
65.Amiri Darban S, Nikoofal-Sahlabadi S, Amiri N, Kiamanesh N, Mehrabian A, Zendehbad B, et al. Targeting the leptin receptor: To evaluate therapeutic efficacy and anti-tumor effects of Doxil, in vitro and in vivo in mice bearing C26 colon carcinoma tumor. Colloids Surf B Biointerfaces 2018; 164:107-115.
66.Moosavian SA, Abnous K, Akhtari J, Arabi L, Gholamzade Dewin A, Jafari M. 5TR1 aptamer-PEGylated liposomal doxorubicin enhances cellular uptake and suppresses tumour growth by targeting MUC1 on the surface of cancer cells. Artif Cells Nanomed Biotechnol 2018; 46:2054-2065.
67.Arabi L, Badiee A, Mosaffa F, Jaafari MR. Targeting CD44 expressing cancer cells with anti-CD44 monoclonal antibody improves cellular uptake and antitumor efficacy of liposomal doxorubicin. J Control Release 2015; 220:275-286.
68.Lindqvist A, Rip J, van Kregten J, Gaillard PJ, Hammarlund-Udenaes M. In vivo Functional Evaluation of Increased Brain Delivery of the Opioid Peptide DAMGO by Glutathione-PEGylated Liposomes. Pharm Res 2016; 33:177-185.
69.Gaillard PJ. Case study: to-BBB’s G-Technology, getting the best from drug-delivery research with industry-academia partnerships. Ther Deliv 2011; 2:1391-1394.
70.Zamani P, Navashenaq JG, Teymouri M, Karimi M, Mashreghi M, Jaafari MR. Combination therapy with liposomal doxorubicin and liposomal vaccine containing E75, an HER-2/neu-derived peptide, reduces myeloid-derived suppressor cells and improved tumor therapy. Life Sci 2020; 252:117646.
71.Schelté P, Boeckler C, Frisch B, Schuber F. Differential reactivity of maleimide and bromoacetyl functions with thiols: application to the preparation of liposomal diepitope constructs. Bioconjug Chem 2000; 11:118-123.
72.Kirpotin D, Park JW, Hong K, Zalipsky S, Li WL, Carter P, et al. Sterically stabilized anti-HER2 immunoliposomes: design and targeting to human breast cancer cells in vitro. Biochemistry 1997; 36:66-75.
73.Bartlett GR. Phosphorus assay in column chromatography. J Biol Chem 1959; 234:466-468.
74.Korani M, Nikoofal-Sahlabadi S, Nikpoor AR, Ghaffari S, Attar H, Mashreghi M, et al. The Effect of Phase Transition Temperature on Therapeutic Efficacy of Liposomal Bortezomib. Anticancer Agents Med Chem 2020; 20:700-708.
75.Yoshida T, Lai TC, Kwon GS, Sako K. pH- and ion-sensitive polymers for drug delivery. Expert Opin Drug Deliv 2013; 10:1497-1513.
76.Korani M, Ghaffari S, Attar H, Mashreghi M, Jaafari MR. Preparation and characterization of nanoliposomal bortezomib formulations and evaluation of their anti-cancer efficacy in mice bearing C26 colon carcinoma and B16F0 melanoma. Nanomedicine: Nanotechnology, Biology and Medicine 2019; 20:102013.
77.Swenson CE, Perkins WR, Roberts P, Janoff AS. Liposome technology and the development of Myocet™ (liposomal doxorubicin citrate). The Breast 2001; 10:1-7.
78. Shah NN, Merchant MS, Cole DE, Jayaprakash N, Bernstein D, Delbrook C, et al. Vincristine Sulfate Liposomes Injection (VSLI, Marqibo®): Results From a Phase I Study in Children, Adolescents, and Young Adults With Refractory Solid Tumors or Leukemias. Pediatr Blood Cancer 2016; 63:997-1005.
79. Batist G, Barton J, Chaikin P, Swenson C, Welles L. Myocet (liposome-encapsulated doxorubicin citrate): a new approach in breast cancer therapy. Expert Opin Pharmacother 2002; 3:1739-1751.
80. Uster PS, Allen TM, Daniel BE, Mendez CJ, Newman MS, Zhu GZ. Insertion of poly(ethylene glycol) derivatized phospholipid into pre-formed liposomes results in prolonged in vivo circulation time. FEBS Lett 1996; 386:243-246.
81. Amin M, Mansourian M, Koning GA, Badiee A, Jaafari MR, Ten Hagen TLM. Development of a novel cyclic RGD peptide for multiple targeting approaches of liposomes to tumor region. J Control Release 2015; 220:308-315.
82. Lopes de Menezes DE, Pilarski LM, Allen TM. In vitro and in vivo targeting of immunoliposomal doxorubicin to human B-cell lymphoma. Cancer Res 1998; 58:3320-3330.
83. Ishida T, Iden DL, Allen TM. A combinatorial approach to producing sterically stabilized (Stealth) immunoliposomal drugs. FEBS Lett 1999; 460:129-133.
84. Maruyama K, Mori A, Bhadra S, Subbiah MT, Huang L. Proteins and peptides bound to long-circulating liposomes. Biochim Biophys Acta 1991; 1070:246-252.
85. Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, et al. Impact of Particle Size and Polydispersity Index on the Clinical Applications of Lipidic Nanocarrier Systems. Pharmaceutics 2018; 10.
86. Torchilin VP, Rammohan R, Weissig V, Levchenko TS. TAT peptide on the surface of liposomes affords their efficient intracellular delivery even at low temperature and in the presence of metabolic inhibitors. Proc Natl Acad Sci U S A 2001; 98:8786-8791.
87. Su C, Xia Y, Sun J, Wang N, Zhu L, Chen T, et al. Liposomes physically coated with peptides: preparation and characterization. Langmuir 2014; 30:6219-6227.
88. Allen C, Dos Santos N, Gallagher R, Chiu GN, Shu Y, Li WM, et al. Controlling the physical behavior and biological performance of liposome formulations through use of surface grafted poly(ethylene glycol). Biosci Rep 2002; 22:225-250.
89. Lasic DD, Martin FJ, Gabizon A, Huang SK, Papahadjopoulos D. Sterically stabilized liposomes: a hypothesis on the molecular origin of the extended circulation times. Biochim Biophys Acta 1991; 1070:187-192.
90. Yingchoncharoen P, Kalinowski DS, Richardson DR. Lipid-Based Drug Delivery Systems in Cancer Therapy: What Is Available and What Is Yet to Come. Pharmacol Rev 2016; 68:701-787.
91. Sur S, Fries AC, Kinzler KW, Zhou S, Vogelstein B. Remote loading of preencapsulated drugs into stealth liposomes. Proc Natl Acad Sci U S A 2014; 111:2283-2288.
92. Roces CB, Port EC, Daskalakis NN, Watts JA, Aylott JW, Halbert GW, et al. Rapid scale-up and production of active-loaded PEGylated liposomes. Int J Pharm 2020; 586:119566.
93. Agency EM. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/myocet-liposomal-previously-myocet.
94. Silverman JA, Deitcher SR. Marqibo® (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine. Cancer Chemother Pharmacol 2013; 71:555-564.
95. Belykh E, Shaffer KV, Lin C, Byvaltsev VA, Preul MC, Chen L. Blood-Brain Barrier, Blood-Brain Tumor Barrier, and Fluorescence-Guided Neurosurgical Oncology: Delivering Optical Labels to Brain Tumors. Front Oncol 2020; 10:739.
96. Santos AO, da Silva LC, Bimbo LM, de Lima MC, Simões S, Moreira JN. Design of peptide-targeted liposomes containing nucleic acids. Biochim Biophys Acta 2010; 1798:433-441.
97. Mastrotto F, Brazzale C, Bellato F, De Martin S, Grange G, Mahmoudzadeh M, et al. In Vitro and in Vivo Behavior of Liposomes Decorated with PEGs with Different Chemical Features. Mol Pharm 2020; 17:1444.
98. Shaffer CL. Chapter 4 - Defining Neuropharmacokinetic Parameters in CNS Drug Discovery to Determine Cross-Species Pharmacologic Exposure–Response Relationships. In: Macor JE, editor. Annual Reports in Medicinal Chemistry. 45: Academic Press; 2010. p. 55-70.
99. Mehrabian A, Mashreghi M, Dadpour S, Badiee A, Arabi L, Hoda Alavizadeh S, et al. Nanocarriers Call the Last Shot in the Treatment of Brain Cancers. Technol Cancer Res Treat 2022; 21:15330338221080974.
100. Shargel L. Applied biopharmaceutics and pharmacokinetics. 7 ed.
101. Paolino D, Accolla ML, Cilurzo F, Cristiano MC, Cosco D, Castelli F, et al. Interaction between PEG lipid and DSPE/DSPC phospholipids: An insight of PEGylation degree and kinetics of de-PEGylation. Colloids Surf B Biointerfaces 2017; 155:266-275.
Iranian Journal of Basic Medical Sciences
Volume 25, Issue 3
March 2022
Pages 302-312

Files

Share

How to cite

Statistics