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Immunocolloidal Targeting of the Endocytotic Siglec-7 Receptor Using Peripheral Attachment of Siglec-7 Antibodies to Poly(Lactide-co-Glycolide) Nanoparticles

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Abstract

Purpose

To prepare a nanoparticulate formulation expressing variable peripheral carboxyl density using non-endcapped and endcapped poly(lactide-co-glycolide), conjugated to antibodies recognising the siglec-7 receptor, which is expressed on most acute myeloid leukaemias. The aim is to exploit this receptor as a therapeutic target by constructing an internalising drug-loaded nanoparticle able to translocate into cytoplasm by siglec receptor-mediated internalisation.

Materials and Methods

Antibodies to the siglec-7 (CD33-like) receptor were conjugated to dye-loaded nanoparticles using carbodiimide chemistry, giving 32.6 μg protein per mg of nanoparticles using 100% of the non-endcapped PLGA. Binding studies using cognate antigen were used to verify preservation of antibody function following conjugation.

Results

Mouse embryonic fibroblasts expressing recombinant siglec-7 receptor and exposed to Nile-Red-loaded nanoparticles conjugated to antibody accumulated intracellular fluorescence, which was not observed if either antibody or siglec-7 receptor was absent. Confocal microscopy revealed internalised perinuclear cytoplasmic staining, with an Acridine Orange-based analysis showing red staining in localised foci, indicating localisation within acidic endocytic compartments.

Conclusions

Results show antibody-NP constructs are internalised via siglec-7 receptor-mediated internalisation. If loaded with a therapeutic agent, antibody-NP constructs can cross into cytoplasmic space and delivery drugs intracellularly to cells expressing CD33-like receptors, such as natural killer cells and monocytes.

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Authors and Affiliations

  1. School of Pharmacy, Queens University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK

    Christopher J. Scott, Waleed M. Marouf, Derek J. Quinn, Ryan F. Donnelly & Paul A. McCarron

  2. Fusion Antibodies Ltd., Springbank Industrial Estate, Pembroke Loop Road, Belfast, BT17 0QL, UK

    Richard J. Buick

  3. Centre for Cancer Research and Cell Biology, Queens University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK

    Selinda J. Orr

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  1. Christopher J. Scott
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  2. Waleed M. Marouf
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Correspondence to Paul A. McCarron.

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Scott, C.J., Marouf, W.M., Quinn, D.J. et al. Immunocolloidal Targeting of the Endocytotic Siglec-7 Receptor Using Peripheral Attachment of Siglec-7 Antibodies to Poly(Lactide-co-Glycolide) Nanoparticles. Pharm Res 25, 135–146 (2008). https://doi.org/10.1007/s11095-007-9400-7

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  • DOI: https://doi.org/10.1007/s11095-007-9400-7

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