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Targeted Fluoxetine Delivery Using Folic Acid-Modified PLGA Nanoparticles for Selective Uptake by Glioblastoma Cells.

Maria João Ramalho1,2, Carina Nóbrega1,2, Stéphanie Andrade1,2

  • 1LEPABE-Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, 4200-465 Porto, Portugal.

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Summary

Researchers developed folic acid-functionalized nanoparticles to deliver fluoxetine for glioblastoma treatment. These nanoparticles enhance drug delivery to brain tumors and show potential as a standalone therapy or chemosensitizer.

Keywords:
MGMT-mediated resistancebrain deliverybrain tumordrug resistancefolate receptornon-alkylating drug

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Area of Science:

  • Nanotechnology
  • Neuro-oncology
  • Drug Delivery

Background:

  • Conventional glioblastoma (GBM) treatments using alkylating agents are limited by the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT).
  • The antidepressant fluoxetine (FL) shows anti-cancer properties but faces challenges with oral administration, including first-pass metabolism and poor brain targeting.
  • Developing novel drug delivery systems is crucial for effective GBM therapy.

Purpose of the Study:

  • To develop poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) functionalized with folic acid (FA) for targeted delivery of fluoxetine (FL) to glioblastoma (GBM) cells.
  • To optimize NP formulation using a Central Composite Design (CCD).
  • To evaluate the physicochemical properties, stability, drug release, cellular uptake, and cytotoxicity of the developed NPs.

Main Methods:

  • Optimization of FA-functionalized PLGA NPs using Central Composite Design (CCD).
  • Characterization of NPs for size, polydispersity index (PdI), and zeta potential.
  • Assessment of encapsulation efficiency (EE) and loading capacity (LC).
  • In vitro evaluation of NP stability, drug release kinetics, cellular uptake, and cytotoxicity.

Main Results:

  • Optimized FA-functionalized PLGA NPs showed suitable physicochemical properties for brain delivery (167 nm diameter, 0.23 PdI, -22.2 mV zeta potential).
  • High encapsulation efficiency (44.4%) and loading capacity (3.1%) were achieved, with sustained FL release over 17 days.
  • FA conjugation significantly enhanced NP uptake in GBM cells via folate receptor-mediated endocytosis.
  • Encapsulated FL maintained efficacy and increased GBM cell sensitivity to alkylating agents.

Conclusions:

  • The developed FA-functionalized PLGA NPs are effective nanocarriers for targeted glioblastoma drug delivery.
  • These NPs demonstrate potential as a standalone therapy for GBM.
  • The NPs can also act as a chemosensitizer, enhancing the efficacy of standard GBM treatments.