Native and Complexed IGF-1: Biodistribution and Pharmacokinetics in Infantile Neuronal Ceroid Lipofuscinosis

Tuulia Huhtala,Ale Närvänen,Anu Jalanko,Martti Kaasalainen,Jarno Salonen,Raili Riikonen,Jussi Rytkönen

doi:10.1155/2012/626417

Abstract

Infantile neuronal ceroid lipofuscinosis (INCL) is a severe neurodegenerative disorder of childhood characterized by selective death of cortical neurons. Insulin-like growth factor 1 (IGF-1) is important in embryonic development and is considered as a potential therapeutic agent for several disorders of peripheral and central nervous systems. In circulation IGF-1 is mainly bound to its carrier protein IGFBP-3. As a therapeutic agent IGF-1 has shown to be more active as free than complexed form. However, this may cause side effects during the prolonged treatment. In addition to IGFBP-3 the bioavailability of IGF-1 can be modulated by using mesoporous silicon nanoparticles (NPs) which are optimal carriers for sustained release of unstable peptide hormones like IGF-1. In this study we compared biodistribution, pharmacokinetics, and bioavailability of radiolabeled free IGF-1, IGF-1/IGFBP-3, and IGF-1/NP complexes in a Cln1-/- knockout mouse model. IGF-1/NP was mainly accumulated in liver and spleen in all studied time points, whereas minor and more constant amounts were measured in other organs compared to free IGF-1 or IGF-1/IGFBP-3. Also concentration of IGF-1/NP in blood was relatively high and stable during studied time points suggesting continuous release of IGF-1 from the particles.

Highlights

Infantile neuronal ceroid lipofuscinosis (INCL) is a severe neurodegenerative disorder of childhood characterized by selective death of cortical neurons [1]
The Cln1-/- knockout mouse model is analogous to INCL in humans, with severe phenotype, and the overall neurologic features are highly similar to the clinical symptoms of INCL [4]
We have studied the biodistribution of I-125 labeled free Insulin-like growth factor 1 (IGF-1), IGF-1/IGFBP-3, and IGF-1/NP complexes in Cln1-/mouse model which genotypically and phenotypically represents INCL

Summary

Introduction

Infantile neuronal ceroid lipofuscinosis (INCL) is a severe neurodegenerative disorder of childhood characterized by selective death of cortical neurons [1]. To consistently study pathogenesis and treatment of INCL and other types of neuronal ceroid lipofuscinoses (NCLs), different mouse models have been established (CLN1, CLN2, CLN3, CLN5) and naturally occurring NCL mouse models exist (CLN8/mnd; CLN6/nclf) [6]. The Cln1-/- knockout mouse model is analogous to INCL in humans, with severe phenotype, and the overall neurologic features are highly similar to the clinical symptoms of INCL [4]. The analyses of two different Cln1-/- mouse models have revealed new pathological characteristics for INCL, including early thalamocortical neuron loss accompanied by astrocytosis, defects in axonal growth, cholesterol biosynthesis, and calcium metabolism [7,8,9,10]

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