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Targeted nano-delivery of chemotherapy via intranasal route suppresses in vivo glioblastoma growth and prolongs survival in the intracranial mouse model

Abstract

Nanotechnology-based drug delivery platforms have shown great potential in overcoming the limitations of conventional therapy for glioblastoma (GBM). However, permeation across the blood–brain barrier (BBB), physiological complexity of the brain, and glioma targeting strategies cannot entirely meet the challenging requirements of distinctive therapeutic delivery stages. The objective of this research is to fabricate lipid nanoparticles (LNPs) for the co-delivery of paclitaxel (PTX) and miltefosine (HePc) a proapoptotic agent decorated with transferrin (Tf-PTX-LNPs) and investigate its anti-glioma activity both in vitro and in vivo orthotopic NOD/SCID GBM mouse model. The present study demonstrates the anti-glioma effect of the dual drug combination of PTX and proapoptotic HePc lipid-based transferrin receptor (TfR) targeted alternative delivery (direct nose to brain transportation) of the nanoparticulate system (Tf-PTX-LNPs, 364 ± 5 nm, −43 ± 9 mV) to overcome the O6-methylguanine-DNA methyltransferase induce drug-resistant for improving the effectiveness of GBM therapy. The resulting nasally targeted LNPs present good biocompatibility, stability, high BBB transcytosis through selective TfR-mediated uptake by tumor cells, and effective tumor penetration in the brain of GBM induced mice. We observed markedly enhanced anti-proliferative efficacy of the targeted LNPs in U87MG cells compared to free drug. Nasal targeted LNPs had shown significantly improved brain concentration (Cmax fivefold and AUC0-24 4.9 fold) with early tmax (0.5 h) than the free drug. In vivo intracranial GBM-bearing targeted LNPs treated mice exhibited significantly prolonged survival with improved anti-tumor efficacy accompanied by reduced toxicity compared to systemic Taxol® and nasal free drug. These findings indicate that the nasal delivery of targeted synergistic nanocarrier holds great promise as a non-invasive adjuvant chemotherapy therapy of GBM.

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Acknowledgements

The authors acknowledge Sophisticated Analytical Instrumental Facility (SAIF) and Industrial Research and Consultancy Center (IRCC) at the Indian Institute of Technology Bombay for instrumental infrastructures and facilities. The author would like to specially acknowledge Prof. Abhijeet De and Ms. Snehal Valvi (Advance Center for Cancer, Treatment, Research and Education in Cancer, Navi-mumbai, India) for the IVIS imaging facility. We would like to thanks Ms. Khushbu Gandhi, (Clinical Pharmacology Lab, Advance Center for Cancer, Treatment, Research and Education in Cancer, Navi-Mumbai, India) for her help in immunohistochemistry analysis. Puja Sandbhor also acknowledges Tata Memorial Trust, India for the research fellowship.

This article is devoted to late Prof. Rinti Banerjee who had ceded to a post-COVID complication on July 8, 2021. She pioneered this non-invasive drug delivery approach against highly malignant brain tumors with a prophecy to transform this technology into clinics to diminish the mortality and socio-economic stack of brain tumors across the world.

Funding

This work was supported by the Lady Tata Memorial Trust (LTMT) of Tata Memorial Center.

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Contributions

PS: conceptualization, methodology, formal analysis, investigation, and writing and reviewing the original draft. BM: investigations, reviewing the original draft, and formal analysis. JG: writing, reviewing, and editing. RB, JG, PC, and SD: supervision, resources, conceptualization, methodology, and funding acquisition. SY and GC: in vivo experiments. PG: histology and immunohistochemistry studies.

Corresponding author

Correspondence to Jayant Goda.

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Ethical statement for animal studies

Animals were maintained in the laboratory animal facility of ACTREC following the national guidelines mentioned by the Committee for the Purpose of Control and Supervision of the Experiments on Animals (CPCSEA), Ministry of Fisheries, animal Husbandry and Dairying department of animal Husbandry and Dairying, Government of India. The Institutional Animal Ethics Committee (IAEC) of the Advanced Center for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Center, India, Registration no. 65/GO/ReBiBt/S/99/CPCSEA approved the protocol (IAEC protocol no. 07/2017). The animal studies were performed only after taking prior consent and approval from the Institutional Animal Ethics Committee, ACTREC. All the experiments were conducted in strict accordance for the care and use of the laboratory animals. A controlled environment was provided to the animals with a temperature of 22 ± 2 °C and relative humidity maintained at 40–70%. A 12-h day night cycle was maintained (7:00 to 19:00 day and 19:00 to 7:00 night). The animals were given gamma irradiated balanced diet (Altromin 1314P) and sterile water. Individually ventilated Cage system (IVC, M/S Citizen, India) was used to house mice. These IVCs were provided with autoclaved corn cob as bedding for the mice. Animal euthanasia was done under the supervision of attending veterinarian using CPCSEA recommended euthanizing agent, carbon dioxide.

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Highlights

1. A novel transferrin receptor targeted dual drug paclitaxel and proapoptotic miltefosine lipid-based nano-carrier (Tf-PTX-LNPs) was developed to treat chemoresistant GBM via non-invasive nasal drug delivery platform.

2. Nasal targeted LNPs co-delivery of anti-tumor alkyl phospholipids and chemotherapeutic PTX demonstrated anti-glioma efficacy in vitro and in vivo.

3. This novel formulation with nasal route preferentially overcame the BBB barrier, which is a major obstacle in effective chemotherapeutic management GBM.

4. The non-invasive synergistic targeted delivery of PTX through non-neurological pathways demonstrated significant tumor regression and improved survival in orthotopic GBM model.

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Sandbhor, P., Goda, J., Mohanty, B. et al. Targeted nano-delivery of chemotherapy via intranasal route suppresses in vivo glioblastoma growth and prolongs survival in the intracranial mouse model. Drug Deliv. and Transl. Res. 13, 608–626 (2023). https://doi.org/10.1007/s13346-022-01220-8

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