Non-invasive transferrin targeted nanovesicles sensitize resistant glioblastoma multiforme tumors and improve survival in orthotopic mouse models

Dec 13, 2021Nanoscale

Targeted nanovesicles that increase sensitivity of resistant brain tumors and improve survival in mouse models

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Targeted lipid nanovesicles increased brain concentration of chemotherapy agents by 500- and 280-fold after 18 hours of treatment.

The intranasal delivery method may enhance chemotherapeutic bioavailability in glioma treatment.
Lipid nanovesicles co-encapsulating temozolomide and miltefosine demonstrated a 6.4-fold increase in cytotoxicity against resistant cancer cells compared to the individual drugs.
Targeted lipid nanovesicles showed controlled and significantly different release kinetics in simulated nasal and cerebrospinal fluids.
The optimized formulation exhibited mucoadhesiveness, suggesting improved retention in the nasal cavity.
Survival of tumor-bearing mice improved by 1.8-fold with the targeted delivery system compared to free drugs.

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The blood-brain barrier (BBB) and tumor heterogeneity have resulted in abysmally poor clinical outcomes in glioblastoma (GBM) with the standard therapeutic regimen. Despite several anti-glioma drug delivery strategies, the lack of adequate chemotherapeutic bioavailability in gliomas has led to a suboptimal therapeutic gain in terms of improvement in survival and increased systemic toxicities. This has paved the way for designing highly specific and non-invasive drug delivery approaches for treating GBM. The intranasal (IN) route is one such delivery strategy that has the potential to reach the brain parenchyma by circumventing the BBB. We recently showed thathydrogel embedded with miltefosine (HePc, proapoptotic anti-tumor agent) and temozolomide (TMZ, DNA methylating agent) loaded targeted nanovesicles prevented tumor relapses in orthotopic GBM mouse models. In this study, we specifically investigated the potential of a non-invasive IN route of TMZ delivered from lipid nanovesicles (LNs) decorated with surface transferrin (Tf) and co-encapsulated with HePc to reach the brain by circumventing the BBB in glioma bearing mice. The targeted nanovesicles (228.3 ± 10 nm, -41.7 ± 4 mV) exhibited mucoadhesiveness with 2% w/v mucin suggesting their potential to increase brain drug bioavailability after IN administration. The optimized TLNs had controlled, tunable and significantly different release kinetics in simulated cerebrospinal fluid and simulated nasal fluid demonstrating efficient release of the payload upon reaching the brain. Drug synergy (combination index, 0.7) showed a 6.4-fold enhanced cytotoxicity against resistant U87MG cells compared to free drugs.gamma scintigraphy ofTc labeled LNs showed 500- and 280-fold increased brain concentration post 18 h of treatment. The efficacy of the TLNs increased by 1.8-fold in terms of survival of tumor-bearing mice compared to free drugs. These findings suggested that targeted drug synergy has the potential to intranasally deliver a high therapeutic dose of the chemotherapy agent (TMZ) and could serve as a platform for future clinical application. in situ In vivo99m

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Non-invasive transferrin targeted nanovesicles sensitize resistant glioblastoma multiforme tumors and improve survival in orthotopic mouse models

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