Adenosine-Functionalized Biodegradable PLA-b-PEG Nanoparticles Ameliorate Osteoarthritis in Rats

Xiuling Liu, Carmen Corciulo, Stephanie Arabagian, Abraham Ulman, Bruce N. Cronstein

Research output: Contribution to journalArticle

Abstract

Short biologic half-lives limit the therapeutic utility of many small molecules. One approach to extending the half-life of pharmacologically active small molecules is conjugation to less degradable nanoparticles; here we report the synthesis and activity of six targeted polymeric (PEG-b-PLA) nanoparticles for use as adenosine receptor agonists. Using click chemistry, PLA-b-PEG400-N3 and PLA-b-PEG2000 block copolymers were bound to adenosine at the 3',4'-OH, 5'-OH, and 6-NH2 positions with an acetylene group. Activity of the conjugates as adenosine receptor ligands was tested by their capacity to stimulate cAMP increases in RAW264.7 murine macrophage cells. Only adenosine-conjugated nanoparticles (A-3',4'-OH-TPN2), in which PEG2000 was bound to adenosine on the 3',4' hydroxyl groups, stimulated cAMP increases and these increases were blocked by selective antagonists of both adenosine A2A and A2B receptors, consistent with ligation of these receptors. Adenosine nanoparticles were tested in vivo in a rat model of post-traumatic osteoarthritis; intra-articular injection of adenosine nanoparticles prevented the development of osteoarthritis in this model. These studies suggest that attachment of adenosine to biodegradable nanoparticles provides a novel approach to achieving prolonged therapeutic effects.

Original languageEnglish (US)
Number of pages1
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - May 15 2019

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Osteoarthritis
Adenosine
Nanoparticles
Adenosine A2 Receptor Antagonists
Purinergic P1 Receptor Agonists
Click Chemistry
Intra-Articular Injections
Acetylene
Purinergic P1 Receptors
Therapeutic Uses
Hydroxyl Radical
Ligation
Half-Life
poly(lactic acid-ethylene glycol)
Macrophages
Ligands

ASJC Scopus subject areas

  • General

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Adenosine-Functionalized Biodegradable PLA-b-PEG Nanoparticles Ameliorate Osteoarthritis in Rats. / Liu, Xiuling; Corciulo, Carmen; Arabagian, Stephanie; Ulman, Abraham; Cronstein, Bruce N.

In: Scientific reports, Vol. 9, No. 1, 15.05.2019.

Research output: Contribution to journalArticle

Liu, Xiuling ; Corciulo, Carmen ; Arabagian, Stephanie ; Ulman, Abraham ; Cronstein, Bruce N. / Adenosine-Functionalized Biodegradable PLA-b-PEG Nanoparticles Ameliorate Osteoarthritis in Rats. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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