Targeting hepatic cancer cells with pegylated dendrimers displaying N-Acetylgalactosamine and SP94 peptide ligands
Advanced Healthcare Materials, cilt.2, sa.10, ss.1337-1350, 2013 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 2 Sayı: 10
- Basım Tarihi: 2013
- Doi Numarası: 10.1002/adhm.201200406
- Dergi Adı: Advanced Healthcare Materials
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
- Sayfa Sayıları: ss.1337-1350
- Anahtar Kelimeler: Kupffer cells, N-acetylgalactosamine sugar ligands, PAMAM dendrimers, Particle opsonization, Targeting hepatic cancer cells
- İstanbul Medipol Üniversitesi Adresli: Evet
Özet
Poly(amidoamine) (PAMAM) dendrimers are branched water-soluble polymers defined by consecutive generation numbers (Gn) indicating a parallel increase in size, molecular weight, and number of surface groups available for conjugation of bioactive agents. In this article, we compare the biodistribution of N-acetylgalactosamine (NAcGal)-targeted [14C]1-G5-(NH2)5-(Ac)108-(NAcGal)14 particles to non-targeted [14C]1-G5-(NH2)127 and PEGylated [14C]1-G5-(NH2)44-(Ac)73-(PEG)10 particles in a mouse hepatic cancer model. Results show that both NAcGal-targeted and non-targeted particles are rapidly cleared from the systemic circulation with high distribution to the liver. However, NAcGal-targeted particles exhibited 2.5-fold higher accumulation in tumor tissue compared to non-targeted ones. In comparison, PEGylated particles showed a 16-fold increase in plasma residence time and a 5-fold reduction in liver accumulation. These results motivated us to engineer new PEGylated G5 particles with PEG chains anchored to the G5 surface via acid-labile cis-aconityl linkages where the free PEG tips are functionalized with NAcGal or SP94 peptide to investigate their potential as targeting ligands for hepatic cancer cells as a function of sugar conformation (α versus β), ligand concentration (100-4000 nM), and incubation time (2 and 24 hours) compared to fluorescently (Fl)-labeled and non-targeted G5-(Fl)6-(NH2)122 and G5-(Fl)6-(Ac)107-(cPEG)15 particles. Results show G5-(Fl)6-(Ac)107-(cPEG[NAcGalβ])14 particles achieve faster uptake and higher intracellular concentrations in HepG2 cancer cells compared to other G5 particles while escaping the non-specific adsorption of serum protein and phagocytosis by Kupffer cells, which make these particles the ideal carrier for selective drug delivery into hepatic cancer cells. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.