The Phospholipid System with the Targeted Peptide Angiopep-2 for Delivery of Chlorine e6 an in vitro Study
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Abstract
The previously obtained phospholipid nanosystem for the delivery of the photosensitizer chlorine e6 was modified with a targeting ligand, the oligopeptide angiopep-2, exhibiting a high ability to transcytose through the blood-brain barrier. This feature of angiopep-2 is especially relevant for the targeted delivery of therapeutic and diagnostic agents to pathological area (tumor) of the brain. According to the analysis of the physico-chemical parameters of the developed composition, the particle size was 31.98±1.98 nm (PdI 0.453±0.03), the ζ-potential corresponded to -27.43±1.14 mV, while the substance was almost completely (98.6±0.43%) incorporated into nanoparticles. An in vitro experiment on the human glioblastoma cell line U-87 MG showed an increase in the total accumulation and internalization of chlorine e6 in the variant with the phospholipid form containing the targeted peptide compared with the free substance by 33% and 40%, respectively. The study of the cytotoxic action without irradiation showed no differences between the samples in the concentration range from 0.125 μg/ml to 2.5 μg/ml (in terms of to chlorine e6); the percentage of living cells was about 100%. The study of the photoinduced activity (with a dose 1,5 J/cm2 irradiation) showed that the IC50 value for the obtained composition was 1,33 times lower than that for the free substance and amounted to 2.85±0.1 μg/ml. The results of the experiments suggest the prospects of the developed composition and the clear need for further studies in vitro and in vivo.
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References
- Cramer S.W., Chen C.C. (2020) Photodynamic therapy for the treatment of glioblastoma. Frontiers in Surgery, 6(81). DOI
- Vermandel M., Dupont C., Lecomte F., Leroy H. A., Tuleasca C., Mordon S., Hadjipanayis C. G., Reyns, N. (2021) Standardized intraoperative 5-ALA photodynamic therapy for newly diagnosed glioblastoma patients: a preliminary analysis of the INDYGO clinical trial. Journal of Neuro-Oncology, 152(3), 501-514. DOI
- Dupont C., Vermandel M., Leroy H. A., Quidet M., Lecomte F., Delhem N., Mordon S., Reyns, N. (2019) INtraoperative photoDYnamic therapy for GliOblastomas (INDYGO): study protocol for a phase I clinical trial. Neurosurgery, 84(6), 414-419. DOI
- Mahmoudi K., Garvey K.L., Bouras A., Cramer G., Stepp H., Jesu Raj J.G., Bozec D., Busch T.M., Hadjipanayis C.G. (2019) 5-aminolevulinic acid photodynamic therapy for the treatment of high-grade gliomas. Journal of Neuro-Oncology, 141(3), 595-607. DOI
- Kim H.S., Lee D.Y. (2022) Nanomedicine in clinical photodynamic therapy for the treatment of brain tumors. Biomedicines, 10(1), 96. DOI
- Eljamel M.S., Goodman C., Moseley H. (2008) ALA and Photofrin fluorescence-guided resection and repetitive PDT in glioblastoma multiforme: a single centre Phase III randomised controlled trial. Lasers in Medical Science, 23(4), 361-367. DOI
- Li Y., Yu Y., Kang L., Lu Y. (2014) Effects of chlorin e6-mediated photodynamic therapy on human colon cancer SW480 cells. International Journal of Clinical and Experimental Medicine, 7(12), 4867-4876. DOI
- Mikaelyan K.A., Krylov K.Y., Petrova M.V., Shestopalov A.E. (2021) Izmenenie morfologii i mikrobiotsenoza kishechnika u neirokhirurgicheskikh patsientov v kriticheskom sostoyanii [Intestine morphology and microbiocenosis changes in critically ill patients in neurosurgery]. Zhurnal Voprosy Neirokhirurgii Imeni N. N. Burdenko, 85(1), 104–110. DOI
- Rynda A.Y., Olyushin V.E., Rostovtsev D.M., Zabrodskaya Y.M., Papayan G.V. (2022) Sravnitel'nyi analiz fluorestsentnoi navigatsii v khirurgii zlokachestvennykh gliom s ispol'zovaniem 5-ALA i khlorina E6 [Comparative analysis of 5-ALA and chlorin E6 fluorescence-guided navigation in malignant glioma surgery]. Khirurgiia, (1), 5-14. DOI
- Kozlikina E.I., Trifonov I.S., Sinkin M.V., Krylov V.V., Loschenov V.B. (2022) The combined use of 5-ALA and chlorin e6 photosensitizers for fluorescence-guided resection and photodynamic therapy under neurophysiological control for recurrent glioblastoma in the functional motor area after ineffective use of 5-ALA: preliminary results. Bioengineering (Basel, Switzerland), 9(3), 104. DOI
- Hak A., Ali M.S., Sankaranarayanan S.A., Shinde V.R., Rengan A.K. (2023) Chlorin e6: a promising photosensitizer in photo-based cancer nanomedicine. ACS Applied Bio Materials, 6(2), 349-364. DOI
- Kim T.E., Chang J.E. (2023) Recent studies in photodynamic therapy for cancer treatment: from basic research to clinical trials. Pharmaceutics, 15(9), 2257. DOI
- Gilyadova A., Ishchenko A., Shiryaev A., Alekseeva P., Efendiev K., Karpova R., Loshchenov M., Loschenov V., Reshetov I. (2022) Phototheranostics of cervical neoplasms with chlorin e6 photosensitizer. Cancers, 14(1), 211. DOI
- Pardridge W. M. (2005). The blood-brain barrier: bottleneck in brain drug development. NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics, 2(1), 3-14. DOI
- Novell A., Kamimura H.A.S., Cafarelli A., Gerstenmayer M., Flament J., Valette J., Agou P., Conti A., Selingue E., Aron Badin R., Hantraye P., Larrat B. (2020). A new safety index based on intrapulse monitoring of ultra-harmonic cavitation during ultrasound-induced blood-brain barrier opening procedures. Scientific reports, 10(1), 10088. DOI
- Bhunia S., Kolishetti N., Vashist A., Yndart Arias A., Brooks D., Nair M. (2023). Drug delivery to the brain: recent advances and unmet challenges. Pharmaceutics, 15(12), 2658. DOI
- Sharma G., Sharma A.R., Lee S.S., Bhattacharya M., Nam J.S., Chakraborty C. (2019). Advances in nanocarriers enabled brain targeted drug delivery across blood brain barrier. International Journal of Pharmaceutics, 559, 360-372. DOI
- Liu J., Sun Y., Zeng X., Liu Y., Liu C., Zhou Y., Liu Y., Sun G., Guo M. (2023) Engineering and characterization of an artificial drug-carrying vesicles nanoplatform for enhanced specifically targeted therapy of glioblastoma. Advanced materials (Deerfield beach, Fla.), 35(41), e2303660. DOI
- Miranda A., Blanco-Prieto M. J., Sousa J., Pais A., Vitorino C. (2017) Breaching barriers in glioblastoma. Part II: Targeted drug delivery and lipid nanoparticles. International Journal of Pharmaceutics, 531(1), 389-410. DOI
- Zhao Y., Li D., Zhao J., Song J., & Zhao Y. (2016) The role of the low-density lipoprotein receptor-related protein 1 (LRP-1) in regulating blood-brain barrier integrity. Reviews in the Neurosciences, 27(6), 623-634. DOI
- Xin H., Jiang X., Gu J., Sha X., Chen L., Law K., Chen Y., Wang X., Jiang Y., Fang X. (2011) Angiopep-conjugated poly(ethylene glycol)-co-poly(ε-caprolactone) nanoparticles as dual-targeting drug delivery system for brain glioma. Biomaterials, 32(18), 4293-4305. DOI
- Demeule M., Régina A., Ché C., Poirier J., Nguyen T., Gabathuler R., Castaigne J.P., Béliveau R. (2008) Identification and design of peptides as a new drug delivery system for the brain. The Journal of Pharmacology and Experimental Therapeutics, 324(3), 1064-1072. DOI
- Habib S., Singh M. (2022). Angiopep-2-modified nanoparticles for brain-directed delivery of therapeutics: a review. Polymers, 14(4), 712. DOI
- Kumthekar P., Tang S.C., Brenner A.J., Kesari S., Piccioni D.E., Anders C., Carrillo J., Chalasani P., Kabos P., Puhalla S., Tkaczuk K., Garcia A.A., Ahluwalia M.S., Wefel J.S., Lakhani N., Ibrahim N. (2020) ANG1005, a brain-penetrating peptide-drug conjugate, shows activity in patients with breast cancer with leptomeningeal carcinomatosis and recurrent brain metastases. Clinical cancer research: an official journal of the American association for cancer research, 26(12), 2789-2799. DOI
- Kostryukova L. V., Prozorovskiy V. N., Medvedeva N. V., Ipatova O. M. (2018) Comparison of a new nanoform of the photosensitizer chlorin e6, based on plant phospholipids, with its free form. FEBS Open Bio, 8(2), 201-210. DOI
- Torkhovskaya T.I., Kostryukova L.V., Tereshkina Y.A., Tikhonova E.G., Morozevich G.E., Plutinskaya A.D., Lupatov A.Y., Pankratov A.A. (2021) Chlorin e6 embedded in phospholipid nanoparticles equipped with specific peptides: Interaction with tumor cells with different aminopeptidase N expression. Biomedicine & pharmacotherapy = Biomedecine & Pharmacotherapie, 134, 111154. DOI
- Chen C., Duan Z., Yuan Y., Li R., Pang L., Liang J., Xu X., Wang J. (2017) Peptide-22 and cyclic RGD functionalized liposomes for glioma targeting drug delivery overcoming BBB and BBTB. ACS Applied Materials & Interfaces, 9(7), 5864-5873. DOI
- Kostryukova L.V., Tereshkina Y.A., Korotkevich E.I., Prozorovsky V.N., Torkhovskaya T.I., Morozevich G.E., Toropygin I.Y., Konstantinov M.A., Tikhonova E.G. (2020) Targeted drug delivery system for doxorubicin based on a specific peptide and phospholipid nanoparticles. Biomeditsinskaya Khimiya, 66(6), 464-468. DOI
- Tikhonova E.G., Sanzhakov M.A., Tereshkina Y.A., Kostryukova L.V., Khudoklinova Y.Y., Orlova N.A., Bobrova D.V., Ipatova O.M. (2022) Drug transport system based on phospholipid nanoparticles: production technology and characteristics. Pharmaceutics, 14(11), 2522. DOI
- Sheldon K., Liu D., Ferguson J., Gariepy J. (1995) Loligomers: Design of de novo peptide-based intracellular vehicles. Proceedings of the National Academy of Sciences of the United States of America, 92(6), 2056-2060. DOI
- IC50 Calculator https://www.aatbio.com
- Cramer S.W., Chen C.C. (2020) Photodynamic therapy for the treatment of glioblastoma. Frontiers in surgery, 6, 81. DOI
- Patel V.R., Agrawal Y.K. (2011) Nanosuspension: an approach to enhance solubility of drugs. Journal of Advanced Pharmaceutical Technology & Research, 2(2), 81-87. DOI
- Seo J.W., Ang J., Mahakian L.M., Tam S., Fite B., Ingham E.S., Beyer J., Forsayeth J., Bankiewicz K.S., Xu T., Ferrara K.W. (2015) Self-assembled 20-nm (64)Cu-micelles enhance accumulation in rat glioblastoma. Journal of controlled release : official journal of the Controlled Release Society, 220(Pt A), 51–60. DOI
- Mohanty I., Parija S.C., Suklabaidya S., Rattan S. (2018) Acidosis potentiates endothelium-dependent vasorelaxation and gap junction communication in the superior mesenteric artery. European Journal of Pharmacology, 827, 22–31. DOI
- Shruthi N.R, Behera M.M., Naik S.K., Das S.K., Gopan S., Ghosh A., Sahu R.N., Patra S., Purkait S. (2022) Elevated expression of cholesterol transporter LRP-1 is crucially implicated in the pathobiology of glioblastoma. Frontiers in Neurology, 13, 1003730. DOI