title: Intracellular delivery of dendrimer triamcinolone acetonide conjugates into microglial and human retinal pigment epithelial cells.
abstract: Triamcinolone acetonide (TA) is a potent, intermediate-acting, steroid that has anti-inflammatory and anti-angiogenic activity. Intravitreal administration of TA has been used for diabetic macular edema, proliferative diabetic retinopathy and exudative age-related macular degeneration (AMD). However, the hydrophobicity, lack of solubility, and the side effects limit its effectiveness in the treatment of retinal diseases. In this study, we explore a PAMAM dendrimer-TA conjugate (D-TA) as a potential strategy to improve intracellular delivery and efficacy of TA to target cells. The conjugates were prepared with a high drug payload (∼ 21%) and were readily soluble in saline. Compared to free TA, D-TA demonstrated a significantly improved toxicity profile in two important target [microglial and human retinal pigment epithelium (RPE)] cells. The D-TA was ∼ 100-fold more effective than free TA in its anti-inflammatory activity (measured in microglia), and in suppressing VEGF production (in hypoxic RPE cells). Dendrimer-based delivery may improve the efficacy of TA towards both its key targets of inflammation and VEGF production, with significant clinical implications.
authors.affiliation: Center for Nanomedicine, Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA.
authors.forename: Siva P
authors.initials: SP
authors.lastname: Kambhampati
authors.affiliation: Center for Nanomedicine, Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Mishra
authors.affiliation: Center for Nanomedicine, Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Mastorakos
authors.affiliation: Center for Nanomedicine, Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Oh
authors.affiliation: Center for Nanomedicine, Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Lutty
authors.affiliation: Center for Nanomedicine, Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA. Electronic address: krangar1@jhmi.edu.
authors.forename: Rangaramanujam M
authors.initials: RM
authors.lastname: Kannan
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D050091:Dendrimers / Q000737:chemistry*; D016503:Drug Delivery Systems; D006801:Humans; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism; D012995:Solubility; D014222:Triamcinolone Acetonide / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; D050091:Dendrimers; C104700:PAMAM Starburst; D042461:Vascular Endothelial Growth Factor A; D014222:Triamcinolone Acetonide
keywords: Anti-VEGF; Anti-inflammatory; Dendrimer; Human retinal pigment epithelium; Microglial cells; Ocular drug delivery; Triamcinolone acetonide