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Overcoming Glucocorticoid Resistances and Improving Antitumor Therapies: Lipid and Polymers Carriers

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Abstract

Purpose

To improve chemotherapy protocols of lymphoid malignancies, by using polymeric and lipid microparticles as controlled delivery systems of dexamethasone, part of all combined chemotherapy protocols for its strong-inducing effect on malignant lymphoblasts.

Methods

Polymeric microparticles were prepared by the oil-in-water-emulsion cosolvent evaporation method, andlipid microparticles by spray drying. Their cytotoxic effects on GC-sensitive PC12 cells and GC-resistant PC3 cells were characterized by cell proliferation and apoptosis assays.

Results

Both elaboration methods rendered optimal-sized microparticles for parenteral administration with high drug loading. In vitro assays showed sustained dexamethasone release from polymeric microparticles over a month, whereas 100% dexamethasone release from lipid microparticles was achieved within 24 h. Similar PC12 cell death to that obtained with dexamethasone solution administered every 48 h was achieved with dexamethasone polymeric microparticles in 26-days assays. Dexamethasone solution and loaded polymeric microparticles induced apoptosis around 15.8 and 19.9%, respectively, after 2 days of incubation. Lipid microparticles increased further apoptosis induction in PC12 cells and, unlike dexamethasone solution and polymeric microparticles, showed antiproliferative effects on PC3 cells.

Conclusions

Dexamethasone polymeric microparticles constitute an alternative to current dexamethasone administration systems in combined chemotherapy, whereas dexamethasone lipid microparticles represent a potential tool to revert glucocorticoid resistance.

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Abbreviations

ABC:

ATP-binding cassette

ALL:

Acute lymphoblastic leukemia

ATCC:

American type culture collection

DCM:

Dichloromethane

Dex:

Dexamethasone

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethylsulfoxidel

DSC:

Differential scanning calorimetry

FACS:

Fluorescence-activated cell sorting

GCs:

Glucocorticoids

GR:

Glucocorticoids receptor

HPLC:

High performance liquid chromatography

MM:

Multiple myeloma

mTOR:

Mammalian target of the rapamicin

MTT:

Bromide (3-[4, 5-dimethyltiazol-2- yl]-2, 5-diphenyl)

OD:

Optical density

PAO:

Phenylarsine oxide

PBS:

Phosphate buffer solution

PI:

Polydispersity index

PpI:

Propidium iodide

PLGA:

Poly(lactic and glycolic) acid

PVA:

Polyvinyl alcohol

RPMI:

Oswell park memorial institute medium

SDmean :

Standard deviation of the mean diameter values

SEM:

Scanning electron microscopy

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ACKNOWLEDGMENTS AND DISCLOSURES

We want to thank the Counseling of Education of the Community of Madrid and the European Social Fund through the Regional Plan of Scientific Research and Technological Innovation. This work was partially funded by the Research Group GR35/10 Santander-UCM, Group: Parenteral administration of drugs. We also thank the UCM Microscopy Research Support Centre for the valuable technical and professional assistance. AJMO is granted by Ministry of Economy and Competitiveness by the FPU Program (Ref. AP2009/0343).

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Authors and Affiliations

  1. Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid, 28040, Madrid, Spain

    C. Martín-Sabroso, J. Aparicio-Blanco, A. I. Fraguas-Sánchez & A. I. Torres-Suárez

  2. Institute of Industrial Pharmacy, Complutense University of Madrid, Madrid, Spain

    A. I. Torres-Suárez

  3. Departamento de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario La Princesa, Diego de León 62, 28006, Madrid, Spain

    A. J. Moreno-Ortega & M. F. Cano-Abad

  4. Teófilo Hernando Institute, Madrid, Spain

    A. J. Moreno-Ortega & M. F. Cano-Abad

  5. Department of Pharmacology and Therapeutics, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain

    A. J. Moreno-Ortega & M. F. Cano-Abad

Authors
  1. C. Martín-Sabroso
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  2. A. J. Moreno-Ortega
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  3. J. Aparicio-Blanco
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  4. A. I. Fraguas-Sánchez
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  5. M. F. Cano-Abad
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  6. A. I. Torres-Suárez
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Corresponding authors

Correspondence to M. F. Cano-Abad or A. I. Torres-Suárez.

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Martín-Sabroso, C., Moreno-Ortega, A.J., Aparicio-Blanco, J. et al. Overcoming Glucocorticoid Resistances and Improving Antitumor Therapies: Lipid and Polymers Carriers. Pharm Res 32, 968–985 (2015). https://doi.org/10.1007/s11095-014-1510-4

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  • DOI: https://doi.org/10.1007/s11095-014-1510-4

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