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

  • Neeraj VijEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 2118)


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.

Key words

Cystic fibrosis COPD Asthma Emphysema Cystamine Cysteamine CFTR Autophagy Dendrimers Aging Lung Theranostics 



The author was supported by the NIH (CTSA RRO25005 and RHL096931), Flight Attendant Medical Research Institute’s (FAMRI), Young Clinical Scientist Award (YCSA_082131), and CFF (CFF, R025-CR07 and VIJ07IO) grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Declaration of Interests: The author is the lead inventor on a patent targeting proteostasis mechanisms for rescuing CFTR protein-processing defect and CF lung disease. The author is also the lead inventor of nano-based selective drug delivery and therapeutic targeting for obstructive lung diseases. The author is a founder of VIJ BIOTECH & PRECISION THERANOSTICS INC that focuses on bench-side translation of novel CF and COPD therapeutics and declares that he has no other competing interests.


  1. 1.
    Min T, Bodas M, Mazur S, Vij N (2011) Critical role of proteostasis-imbalance in pathogenesis of COPD and severe emphysema. J Mol Med 89:577–593CrossRefGoogle Scholar
  2. 2.
    Bodas M, Min T, Mazur S, Vij N (2011) Critical modifier role of membrane cystic fibrosis transmembrane conductance regulator-dependent ceramide signaling in lung injury and emphysema. J Immunol 186:602–613CrossRefGoogle Scholar
  3. 3.
    Bodas M, Min T, Vij N (2011) Critical role of CFTR-dependent lipid-rafts in cigarette smoke-induced lung epithelial injury. Am J Physiol Lung Cell Mol Physiol 300:L811–L820CrossRefGoogle Scholar
  4. 4.
    Bodas M, Min T, Vij N (2010) Early-age-related changes in proteostasis augment immunopathogenesis of sepsis and lung injury. PLoS One 5:e15480CrossRefGoogle Scholar
  5. 5.
    Vij N (2017) Nano-based rescue of dysfunctional autophagy in chronic obstructive lung diseases. Expert Opin Drug Deliv 14:483–489CrossRefGoogle Scholar
  6. 6.
    Vij N, Min T, Bodas M, Gorde A, Roy I (2016) Neutrophil targeted nano-drug delivery system for chronic obstructive lung diseases. Nanomedicine 12:2415–2427CrossRefGoogle Scholar
  7. 7.
    Brockman SM, Bodas M, Silverberg D, Sharma A, Vij N (2017) Dendrimer-based selective autophagy-induction rescues ΔF508-CFTR and inhibits Pseudomonas aeruginosa infection in cystic fibrosis. PLoS One 12:e0184793CrossRefGoogle Scholar
  8. 8.
    Walworth K, Bodas M, Campbell RJ, Swanson D, Sharma A, Vij N (2016) Dendrimer-based selective proteostasis-inhibition strategy to control NSCLC growth and progression. PLoS One 11:e0158507CrossRefGoogle Scholar
  9. 9.
    Faraj J, Bodas M, Pehote G, Swanson D, Sharma A, Vij N (2019) Novel cystamine-core dendrimer-formulation rescues ΔF508-CFTR and inhibits Pseudomonas aeruginosa infection by augmenting autophagy. Expert Opin Drug Deliv 16:177–186CrossRefGoogle Scholar
  10. 10.
    Kannan RM, Nance E, Kannan S, Tomalia DA (2014) Emerging concepts in dendrimer-based nanomedicine: from design principles to clinical applications. J Intern Med 276:579–617CrossRefGoogle Scholar
  11. 11.
    Tomalia DA, Christensen JB, Boas U (2012) Dendrimers, dendrons and dendritic polymers: discovery, applications and the future. Cambridge University Press, New YorkCrossRefGoogle Scholar
  12. 12.
    Freschet JM, Tomalia DA (2002) Dendrimers and other dendritic polymers. Wiley series on polymer science. John Wiley and Sons Ltd, ChichesterGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of Pediatrics and Pulmonary MedicineThe Johns Hopkins University School of MedicineBaltimoreUSA
  2. 2.4Dx LimitedLos AngelesUSA

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