Interaction of PLGA nanoparticles with human blood constituents

https://doi.org/10.1016/j.colsurfb.2004.05.007Get rights and content

Abstract

When nanoparticles are injected into the blood for drug delivery or drug detoxification, detrimental interaction of these particles with blood constituents must be avoided. In previous studies, the adsorption of albumin immunoglobulin G, and fibrinogen from blood plasma to a model hydrophobic polymer like polystyrene was investigated as was decreasing surface hydrophobicity, which quantitatively leads to decreasing amounts of adsorbed proteins on latex particles. However, the uptake of other blood constituents, such as inorganic blood electrolytes, by particles and the dispersion/coagulation characteristics of these particles in the blood stream have not been fully studied. Most importantly, the effect s of these particles on blood coagulation and hemolysis are not well known.

In the present study, the poly(lactide-co-glycolide) acid(PLGA) nanoparticles were synthesized by using nanoprecipitation. The uptake of blood electrolytes from simulated blood fluid (SBF) and the stability (dispersion/aggregation) of nanoparticles in SBF was examined by using different loading amounts of PLGA and different contact time between PLGA nanoparticles and SBF. The interaction of particles with the organic components of blood was also studied by using the measurement of red blood cell hemolysis and blood clotting with raw PLGA, surfactant modified PLGA, and PEGylated PLGA.

Introduction

In treating patients suffering from drug overdose, it is imperative to remove the toxicants from the drugs in the patient’s system as quickly and completely as possible. This process, known as drug detoxification, may be accomplished by using engineered nanoparticles. This is advantageous because particles’ sizes are key in preventing further damage to the patient’s organs. Nanoparticles are too large to allow transmission of the drug to target tissues through systemic circulation or across the mucosal membrane [1].1 At the same time, though, nanoparticles allow intravenous injection and also provide intramuscular and subcutaneous administration by reducing irritant reactions that may occur in bodies. Another important benefit of nanoparticles is they can avoid take-ins by microphages [2], [3], [4].

To develop nanoparticles for drug detoxification, it is critical for the physicochemical properties of poly(lactide-co-glycolide) acid (PLGA) to be closely studied. PLGA is a strong candidate as drug carrier for a drug delivery system because of its biocompatibility and biodegradability [5], [6].

Currently, there are many investigations on the possibility of using PLGA as a drug carrier. Yoon [7] introduced an attachment of specific cells like galactose onto PLGA surface via ligand-receptor interactions. In another investigation [8], lysozyme as a model protein was encapsulated into a PLGA polymer by a double emulsion-solvent extraction/evaporation method. Nano-sized PLGA particles were also used as drug carriers of estrogen [9]. Finally, it has been found that biodegradable polyethylene glycol (PEG)-coated PLGA increases blood circulation time with increasing molecular weight (Mw) of the PEG blocks in diblock PEG-PLGA copolymer [10].

Due to its biocompatibility and biodegradability, PLGA could be a good candidate to use in engineered particles for the purpose of drug detoxification. However, when nanoparticles of PLGA are injected into the blood for drug delivery and drug detoxification, detrimental interaction of these particles with blood constituents must be avoided. In previous studies, the adsorption of albumin, IgG, and fibrinogen from blood plasma to a model hydrophobic polymer like polystyrene was investigated [11]. The decreasing surface hydrophobicity of particles quantitatively leads to decreasing amounts of adsorbed proteins on latex particles [12]. However, the uptake of other blood constituents, such as inorganic blood electrolytes, by particles and the dispersion/coagulation characteristics of the particles in the blood stream have not been fully studied. Most importantly, the effect of these particles on blood coagulation and blood damage is not well known. Therefore, the goal of this study was to investigate the interaction of particles with blood and determine the optimum conditions for using synthesized, engineered particles in drug detoxification.

In this study, the PLGA nanoparticles were synthesized by using nanoprecipitation [13]. The uptake of blood electrolytes from simulated blood fluid (SBF) by these nanoparticles and their stability (dispersion/aggregation) in SBF were examined by using different loading amounts of PLGA and different contact times between PLGA nanoparticles and SBF. The interaction of particles with blood organic components was also studied by using the measurement of red blood cell damage and blood clotting with surfactant modified PLGA and PEGylated PLGA.

Section snippets

Materials

In this study, three different poly(lactide-co-glycolide) acids were used: PLGA 50:50, PLGA 65:35, and PLGA 85:15. They were purchased from Birmingham Polymers Inc. The numbers indicate the monomer ratio (mol%) between lactide versus glycolide in the copolymer. These polymers randomly consisted of lactide and glycolide in the main chain.

Other chemicals such as NaCl, CaCl·2H2O, KH2PO4, pyruvic acid (sodium salt), MgSO4·7H2O, Na2HPO4·12H2O, sodium bicarbonate, monomethoxy poly(ethylene glycol)

Interaction of particles with SBF

After synthesizing PLGA 50:50 particles by nanoprecipitation, the particles were characterized by measuring particle size distribution and zeta potential. The mean particle size of PLGA 50:50 is 106 ± 18 nm and it has a zeta potential value of 34 ± 1 mV (in DI water at pH 7.4). The resulting negative charge was caused by the dissociation of hydrogen ion from the carboxyl (–COOH) end group in the polymer chain.

Particle size distributions can be characterized by the mean size and the spread

Summary and concluding remarks

To study the interaction of particles with human blood electrolytes, particle size and ion uptake were investigated at different conditions. Particle size data indicate that PLGA particle size is increased due to aggregation. This is attributed to the adsorption of cations from SBF onto the particles, resulting in a decrease of electrostatic repulsive forces. In addition, statistical design analysis is used to determine the interaction effect of the loading and contact time on particles. The

Acknowledgements

The authors acknowledge the financial support of the Particle Engineering Research Center (PERC) at the University of Florida and the National Science Foundation (NSF Grant EEC-94-02989).

References (21)

  • L. Brannon-Peppas

    Int. J. Pharm.

    (1995)
  • R.S. Langer et al.

    Biomaterials

    (1981)
  • H.-Y. Kwon et al.

    Colloids Surf. A: Physicochem. Eng. Aspects

    (2001)
  • R.J. Green et al.

    Biomaterials

    (1999)
  • A. Gessner et al.

    Int. J. Pharm.

    (2000)
  • H. Fessi et al.

    Int. J. Pharm.

    (1989)
  • Y.-P. Li et al.

    J. Control. Release

    (2001)
  • M. Jumaa et al.

    Eur. J. Pharm. Sci.

    (1999)
  • H.-P. Zobel et al.

    Eur. J. Pharm. Biopharm.

    (1999)
  • R. Gref et al.

    Adv. Drug Deliv. Rev.

    (1995)
There are more references available in the full text version of this article.

Cited by (134)

  • Nanotechnological strategies for drug delivery and treatment of COVID-19

    2023, Nanotechnology Principles in Drug Targeting and Diagnosis
  • Recent update of toxicity aspects of nanoparticulate systems for drug delivery

    2021, European Journal of Pharmaceutics and Biopharmaceutics
  • Effect of PEGylation on the biological properties of cationic carbosilane dendronized gold nanoparticles

    2020, International Journal of Pharmaceutics
    Citation Excerpt :

    This steric shield protects the charge surface from interaction with blood components and other carriers, increasing also circulation time (Veronese and Pasut, 2005; Yang and Lai, 2015). Particularly, PEGylation of NPs and dendrimers reduces haemolysis (Kim et al., 2005; Barrios-Gumiel et al., 2019; Thakur et al., 2015) and interaction with several blood proteins (Boulos et al., 2013; Xiao et al., 2018). Unfortunately, this widespread strategy has also its own problems such as making difficult cellular absorption or production of antibodies by the immune system that specifically recognize PEG.

View all citing articles on Scopus
View full text