Development of PEGylated carboxylic acid-modified polyamidoamine dendrimers as bone-targeting carriers for the treatment of bone diseases

• Published in: Journal of controlled release Vol. 262; pp. 10 - 17
• Main Authors: Yamashita, Shugo, Katsumi, Hidemasa, Hibino, Nozomi, Isobe, Yugo, Yagi, Yumiko, Kusamori, Kosuke, Sakane, Toshiyasu, Yamamoto, Akira
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 28-09-2017
• Subjects: Animals; Bone and Bones - metabolism; Bone Diseases - drug therapy; Bone targeting; Carboxylic acids; Carboxylic Acids - administration & dosage; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacokinetics; Carboxylic Acids - therapeutic use; Dendrimers - administration & dosage; Dendrimers - chemistry; Dendrimers - pharmacokinetics; Dendrimers - therapeutic use; Drug Carriers - administration & dosage; Drug Carriers - chemistry; Drug Carriers - pharmacokinetics; Drug Carriers - therapeutic use; Drug delivery; Male; Mice; Polyamidoamine (PAMAM) dendrimer; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacokinetics; Polyethylene Glycols - therapeutic use; Polyamidoamine (PAMAM) dendrimer; Drug delivery; Bone targeting; Carboxylic acids
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2017.07.018

In this study, we aimed to develop a polyethylene glycol (PEG)-conjugated third generation polyamidoamine (PAMAM) dendrimer with multiple carboxylic acids as a bone-targeting carrier for the treatment of bone diseases. We conjugated PAMAM backbones to various carboxylic acids [aspartic acid (Asp), glutamic acid (Glu), succinic acid (Suc), or aconitic acid (Aco)] to obtain four different types of carboxylic acid-modified PAMAMs. PEG was covalently bound to carboxylic acid-modified PAMAMs to obtain PEGylated carboxylic acid-modified PAMAMs. In a tissue distribution study, the amount of 111In-labeled unmodified PAMAM taken up by the bone after intravenous injection in mice was 11.3%. In contrast, the dose of 111In-labeled PEG(5)-Asp-PAMAM, PEG(5)-Glu-PAMAM, PEG(5)-Suc-PAMAM, or PEG(5)-Aco-PAMAM that accumulated in the bone after injection was approximately 46.0, 15.6, 22.6, and 24.5%, respectively. The bone clearance rates of 111In-labeled PEGylated carboxylic acid-modified PAMAMs were proportional to their affinities to hydroxyapatite and Ca2+. An intra-bone distribution study showed that fluorescein isothiocyanate-labeled PEG(5)-Asp-PAMAM predominantly accumulated on eroded and quiescent surfaces, a pattern associated with the pathogenesis of bone diseases, such as rheumatoid arthritis and osteoporosis. Our findings indicate that PEG(5)-Asp-PAMAM is a promising drug carrier for efficient drug targeting to the bones.
Efficient bone targeting by a polyamidoamine (PAMAM) dendrimer was successfully achieved by carboxylic acids. A combination of Asp and PEG modifications represented an optimal approach for effective bone targeting. [Display omitted]