TY - JOUR
T1 - Intracellular delivery of dendrimer triamcinolone acetonide conjugates into microglial and human retinal pigment epithelial cells
AU - Kambhampati, Siva P.
AU - Mishra, Manoj K.
AU - Mastorakos, Panagiotis
AU - Oh, Yumin
AU - Lutty, Gerard A.
AU - Kannan, Rangaramanujam M.
N1 - Funding Information:
This study was supported by funds from Wilmer Pooled Professor grant, NIH NIBIB RO1EB018306-01-(RMK) and Research to prevent blindness (RPB). We also acknowledge Wilmer core facility and imaging center (core grant: P30EY001765) for flow cytometry and confocal microscopy facilities.
Publisher Copyright:
© 2015 Elsevier B.V. All rights reserved.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - 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.
AB - 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.
KW - Anti-VEGF
KW - Anti-inflammatory
KW - Dendrimer
KW - Human retinal pigment epithelium
KW - Microglial cells
KW - Ocular drug delivery
KW - Triamcinolone acetonide
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U2 - 10.1016/j.ejpb.2015.02.013
DO - 10.1016/j.ejpb.2015.02.013
M3 - Article
C2 - 25701805
AN - SCOPUS:84943658467
SN - 0939-6411
VL - 95
SP - 239
EP - 249
JO - European Journal of Pharmaceutics and Biopharmaceutics
JF - European Journal of Pharmaceutics and Biopharmaceutics
ER -