PLGA-Based Nanoparticles: a Safe and Suitable Delivery Platform for Osteoarticular Pathologies

Abstract

Purpose

Despite the promising applications of PLGA based particles, studies examining the fate and consequences of these particles after intra-articular administration in the joint are scanty. This study was carried out to evaluate the neutrality of the unloaded delivery system on different articular cell types. To facilitate tracking, we have thus developed a fluorescent core of particles, combined to a hyaluronate shell for cell recognition.

Methods

Fluorescence pictures were taken at time intervals to assess the internalization and the corresponding inflammatory response was monitored by RT-qPCR and biochemical measurements. After NPs pre-treatment, mesenchymal stem cells (MSCs) were cultured into chondrogenic, adipogenic or osteogenic differentiation media, to investigate if NPs exposure interferes with differentiation ability. Finally, intra-articular injections were performed in healthy rat knees and joint’s structure analysed by histological studies.

Results

Particles were detected in cytoplasm 8 h after exposure. Internalization led to a slight and reversible increase of inflammatory markers, but lower than in inflammatory conditions. We have confirmed particles exposure minimal neutrality on MSCs pluripotency. Histological exams of joint after intra-articular injections do not demonstrate any side effects of NPs.

Conclusions

Our findings suggest that such a delivery platform is well tolerated locally and could be used to deliver active molecules to the joint.

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Abbreviations

BSA:

Bovine seric albumin

Cy3:

Cyanine 3

DAPI:

4′,6-diamidino-2-phenylindole

DM:

Differentiation medium

FITC:

Fluorescein isothiocyanate

HA:

Hyaluronic acid

HES:

Haematoxylin Eosin Saffron

IA:

Intra-articular

LDH:

Lactate deshydrogenase

LPS:

Lipopolysaccharide

MbT :

Mycobacterium tuberculosis

MSCs:

Mesenchymal stem cells

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NO:

Nitric oxide

NPs:

Nanoparticles

NSAIDs:

Non steroidal anti-inflammatory drugs

OA:

Osteoarthritis

PBS:

Phosphate Buffer Saline

PFA:

Paraformaldehyde

PGE2 :

Prostaglandins E2

PLGA:

Poly (lactic-co-glycolic) acid

rAAV:

Recombinant adeno-associated virus

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Acknowledgments and Disclosures

We thank David Moulin and Jean-Baptiste Vincourt for their critical reading of the manuscript, Michel Thiery for his good care of the animals and Naranayan Venkatesan for English editing.

The authors declare they have no conflict of interest.

Funding

This work was supported by grants from Agence Nationale de la Recherche – programme ANR Blanc 2007: Nanostructured polymers as drug carriers for cartilage repair and engineering (PARTICART, ANR-07-1_1831-56) and grants from the Région Lorraine Communauté Urbaine du Grand Nancy, and Conseil Général de Meurthe et Moselle.

The funding agency had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Ethical Approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Correspondence to Pierre Gillet.

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Riffault, M., Six, JL., Netter, P. et al. PLGA-Based Nanoparticles: a Safe and Suitable Delivery Platform for Osteoarticular Pathologies. Pharm Res 32, 3886–3898 (2015). https://doi.org/10.1007/s11095-015-1748-5

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KEY WORDS

  • hyaluronate
  • nanoparticles
  • osteoarticular
  • PLGA
  • vectorization