Overcoming biological barriers BBB/BBTB by designing PUFA functionalised lipid-based nanocarriers for glioblastoma targeted therapy

Tamara Zwain, Jane Elizabeth Alder, Suha Zwayen, Andrew Shaw, Andrea J. Burrow, Kamalinder K. Singh

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
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Abstract

A major obstacle for chemotherapeutics in Glioblastoma (GB) is to reach the tumour cells due to the presence of the blood-brain barrier (BBB) and chemoresistance of anticancer drugs. The present study reports two polyunsaturated fatty acids, gamma-linolenic acid (GLA) and alpha-linolenic acid (ALA) appended nanostructured lipid carriers (NLCs) of a CNS negative chemotherapeutic drug docetaxel (DTX) for targeted delivery to GB. The ligand appended DTX-NLCs demonstrated particle size < 160 nm, PDI < 0.29 and a negative surface charge. The successful linkage of GLA (41 %) and ALA (30 %) ligand conjugation to DTX- NLCs was confirmed by diminished surface amino groups on the NLCs, lower surface charge and FTIR profiling. Fluorophore labelled GLA-DTX-NLCs and ALA-DTX-NLCs permeated the in-vitro 3D BBB model with Papp values of 1.8 × 10−3 and 1.9 × 10−3 cm/s respectively. Following permeation, both formulations showed enhanced uptake by GB immortalised cells while ALA-DTX-NLCs showed higher uptake in patient-derived GB cells as evidenced in an in-vitro 3D blood brain tumour barrier (BBTB) model. Both surface functionalised formulations showed higher internalisation in GB cells as compared to bare DTX-NLCs. ALA-DTX-NLCs and GLA-DTX-NLCs showed 13.9-fold and 6.8-fold higher DTX activity respectively at 24 h as indicated by IC50 values when tested in patient-derived GB cells. ALA-DTX-NLCs displayed better efficacy than GLA-DTX-NLCs when tested against 3D tumour spheroids and patient-derived cells. These novel formulations will contribute widely to overcoming biological barriers for treating glioblastoma.
Original languageEnglish
Article number213660
JournalBiomaterials Advances
Volume155
Early online date11 Oct 2023
DOIs
Publication statusPublished - Dec 2023

Keywords

  • Glioblastoma
  • Nanostructured lipid carrier
  • Polyunsaturated fatty acids (PUFA)
  • Gamma-linolenic acid (GLA)
  • Alpha-linolenic acid (ALA)
  • Surface functionalisation
  • Blood-brain barrier
  • Blood-brain tumour barrier
  • Targeted cancer therapy

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