The Characteristics and Mechanisms of Uptake of PLGA Nanoparticles in Rabbit Conjunctival Epithelial Cell Layers

Qaddoumi, Mohamed G.; Ueda, Hideo; Yang, Johnny; Davda, Jasmine; Labhasetwar, Vinod; Lee, Vincent H.L.

doi:10.1023/b:pham.0000022411.47059.76

Cited by 220 publications

(144 citation statements)

References 25 publications

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“…Reports from Muro and others have verified that ICAM-1 mediates endocytosis along a novel pathway (34) and prior work by Labhasetwar and others demonstrated the endocytosis and exocytosis of PLGA nanoparticles in multiple cell lines (35,36). Incubating HUVEC at 4°C was utilized to minimize energy dependent endocytic pathways.…”

Section: Preparation Of Nanoparticlesmentioning

confidence: 92%

PLGA Nanoparticle−Peptide Conjugate Effectively Targets Intercellular Cell-Adhesion Molecule-1

et al. 2007

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Targeted delivery of therapeutics possesses the potential to localize therapeutic agents to a specific tissue as a mechanism to enhance treatment efficacy and abrogate side effects. Antibodies have been used clinically as therapeutic agents and are currently being explored for targeting drug-loaded nanoparticles. Peptides such as RGD peptides are also being developed as an inexpensive and stable alternative to antibodies. In this study, cyclo(1,12)PenITDGEATDSGC (cLABL) peptide was used to target nanoparticles to human umbilical cord vascular endothelial cells (HUVEC) monolayers that have upregulated intercellular cell-adhesion molecule-1 (ICAM-1) expression. The cLABL peptide has been previously demonstrated to possess high avidity for ICAM-1 receptors on the cell surface. Poly(DL-lactic-co-glycolic acid) nanoparticles conjugated with polyethylene glycol and cLABL demonstrated rapid binding to HUVEC with upregulated ICAM-1, which was induced by treating cells with the proinflammatory cytokine, interferon-γ. Binding of the nanoparticles could be efficiently blocked by pre-incubating cells with free peptide suggesting that the binding of the nanoparticles is specifically mediated by surface peptide binding to ICAM-1 on HUVEC. The targeted nanoparticles were rapidly endocytosed and trafficked to lysosomes to a greater extent than the untargeted PLGA-PEG nanoparticles. Verification of peptide-mediated nanoparticle targeting to ICAM-1 may ultimately lead to targeting therapeutic agents to inflammatory sites expressing upregulated ICAM-1.

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Section: Preparation Of Nanoparticlesmentioning

confidence: 92%

PLGA Nanoparticle−Peptide Conjugate Effectively Targets Intercellular Cell-Adhesion Molecule-1

et al. 2007

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“…51 The mechanism of cellular internalization is thought to occur predominantly by adsorptive endocytosis indicated by nonspecific interactions between nanoparticles and cell membranes in the first layers of the corneal epithelium. 52 …”

Section: Ex Vivo Study Clsmmentioning

confidence: 99%

Role of hydroxypropyl-β-cyclodextrin on freeze-dried and gamma-irradiated PLGA and PLGA–PEG diblock copolymer nanospheres for ophthalmic flurbiprofen delivery

Vega¹,

Egea²,

Calpena³

et al. 2012

IJN

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Poly(D,L-lactide-co-glycolide) and poly(D,L-lactide-co-glycolide) with poly(ethylene glycol) nanospheres (NSs) incorporating flurbiprofen (FB) were freeze-dried with several cryoprotective agents and sterilized by γ-irradiation. Only when 5.0% (w/v) hydroxypropyl-β-cyclodextrin (HPβCD) was used, a complete resuspension by manual shaking and almost identical particle size of the NSs was obtained after freeze-drying. In vitro drug release and ex vivo corneal permeation of NSs with and without HPβCD were evaluated. The presence of HPβCD resulted in a reduction of burst effect, providing a more sustained release of the drug. A significant decrease in the FB transcorneal permeation of NSs containing HPβCD was obtained, related to the slower diffusion of FB observed in the in vitro results. The uptake mechanism of the NSs was examined by confocal microscopy, suggesting that NSs penetrate corneal epithelium through a transcellular pathway. Ocular tolerance was assessed in vitro and in vivo by the Eytex™ and Draize test, respectively. Long-term stability studies revealed that γ-irradiated NSs stored as freeze-dried powders maintained their initial characteristics. Stability studies of the resuspended NSs after 3 months of storage in the aqueous form showed that NSs were stable at 4°C, while formulations stored at 25°C and 40°C increased their initial particle size.

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“…Intracellular uptake (passive or facilitated delivery) of quantum dots or other particles may occur via various endocytotic mechanisms, 9 passive permeation, and adsorptive endocytosis. 10 It is clear that accumulation of quantum dots in cells is a complicated issue because numerous intrinsic factors influence the uptake and intracellular transport of nanoparticles, including size, surface charge, and structure of a coating. 1,11,12 Analysis of results presented in the literature reveals a very wide range of values for quantum dot internalization parameters, in particular, uptake time and intracellular localization.…”

Section: Introductionmentioning

confidence: 99%

Intracellular distribution of nontargeted quantum dots after natural uptake and microinjection

Damalakiene¹,

Karabanovas²,

Bagdonas³

et al. 2013

IJN

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Background:The purpose of this study was to elucidate the mechanism of natural uptake of nonfunctionalized quantum dots in comparison with microinjected quantum dots by focusing on their time-dependent accumulation and intracellular localization in different cell lines. Methods:The accumulation dynamics of nontargeted CdSe/ZnS carboxyl-coated quantum dots (emission peak 625 nm) was analyzed in NIH3T3, MCF-7, and HepG2 cells by applying the methods of confocal and steady-state fluorescence spectroscopy. Intracellular colocalization of the quantum dots was investigated by staining with Lysotracker ® . Results:The uptake of quantum dots into cells was dramatically reduced at a low temperature (4°C), indicating that the process is energy-dependent. The uptake kinetics and imaging of intracellular localization of quantum dots revealed three accumulation stages of carboxyl-coated quantum dots at 37°C, ie, a plateau stage, growth stage, and a saturation stage, which comprised four morphological phases: adherence to the cell membrane; formation of granulated clusters spread throughout the cytoplasm; localization of granulated clusters in the perinuclear region; and formation of multivesicular body-like structures and their redistribution in the cytoplasm. Diverse quantum dots containing intracellular vesicles in the range of approximately 0.5-8 µm in diameter were observed in the cytoplasm, but none were found in the nucleus. Vesicles containing quantum dots formed multivesicular body-like structures in NIH3T3 cells after 24 hours of incubation, which were Lysotracker-negative in serum-free medium and Lysotracker-positive in complete medium. The microinjected quantum dots remained uniformly distributed in the cytosol for at least 24 hours. Conclusion: Natural uptake of quantum dots in cells occurs through three accumulation stages via a mechanism requiring energy. The sharp contrast of the intracellular distribution after microinjection of quantum dots in comparison with incubation as well as the limited transfer of quantum dots from vesicles into the cytosol and vice versa support the endocytotic origin of the natural uptake of quantum dots. Quantum dots with proteins adsorbed from the culture medium had a different fate in the final stage of accumulation from that of the protein-free quantum dots, implying different internalization pathways.

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The Characteristics and Mechanisms of Uptake of PLGA Nanoparticles in Rabbit Conjunctival Epithelial Cell Layers

Abstract: Our findings suggest that PLGA nanoparticle uptake in primary cultured rabbit conjunctival epithelial cells occurs most likely by adsorptive-type endocytosis.

Cited by 220 publications

References 25 publications

PLGA Nanoparticle−Peptide Conjugate Effectively Targets Intercellular Cell-Adhesion Molecule-1

PLGA Nanoparticle−Peptide Conjugate Effectively Targets Intercellular Cell-Adhesion Molecule-1

Role of hydroxypropyl-β-cyclodextrin on freeze-dried and gamma-irradiated PLGA and PLGA–PEG diblock copolymer nanospheres for ophthalmic flurbiprofen delivery

Intracellular distribution of nontargeted quantum dots after natural uptake and microinjection

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The Characteristics and Mechanisms of Uptake of PLGA Nanoparticles in Rabbit Conjunctival Epithelial Cell Layers

Abstract: Our findings suggest that PLGA nanoparticle uptake in primary cultured rabbit conjunctival epithelial cells occurs most likely by adsorptive-type endocytosis.

Cited by 220 publications

References 25 publications

PLGA Nanoparticle−Peptide Conjugate Effectively Targets Intercellular Cell-Adhesion Molecule-1

PLGA Nanoparticle−Peptide Conjugate Effectively Targets Intercellular Cell-Adhesion Molecule-1

Role of hydroxypropyl-&beta;-cyclodextrin on freeze-dried and gamma-irradiated PLGA and PLGA&ndash;PEG diblock copolymer nanospheres for ophthalmic flurbiprofen delivery

Intracellular distribution of nontargeted quantum dots after natural uptake and microinjection

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Role of hydroxypropyl-β-cyclodextrin on freeze-dried and gamma-irradiated PLGA and PLGA–PEG diblock copolymer nanospheres for ophthalmic flurbiprofen delivery