Synthesis and Evaluation of Dendrimers for Autophagy Augmentation and Alleviation of Obstructive Lung Diseases.

Abstract

Preservation of cellular homeostasis requires constant synthesis of fresh proteins and cellular organelles and efficient degradation or removal of damaged proteins and cellular components. This involves two cellular degradation processes or molecular mechanisms: the ubiquitin-proteasome and autophagy-lysosomal systems. Impairment of these catabolic processes has been linked to pathogenesis of a variety of chronic obstructive lung diseases such as COPD (chronic obstructive pulmonary disease) and CF (cystic fibrosis). Proteosomal and autophagic functions (proteostasis) are known to decline with advancing age leading to accumulation of cellular debris and proteins, initiating cellular senescence or death and accelerating lung aging. Obstructive lung diseases associated with airway hyperinflammation and mucus obstruction provide major challenges to the delivery and therapeutic efficacy of nanotherapeutics systems as they need to bypass the airway defense. Targeted autophagy augmentation has emerged, as a promising therapeutic utility for alleviating obstructive lung diseases, and promoting healthy aging. A targeted dendrimer-based approach has been designed to penetrate the airway obstruction and allow the selective correction of proteostasis/autophagy in the diseased cells while circumventing the side effects. This report describes methods for synthesis and therapeutic evaluation of autophagy augmenting dendrimers in the treatment of obstructive lung disease(s). The formulations and methods of autophagy augmentation described here are currently under clinical development in our laboratory for alleviating pathogenesis and progression of chronic obstructive lung diseases, and promoting healthy aging.