Suppression of inflammation in a mouse model of rheumatoid arthritis using targeted lipase-labile fumagillin prodrug nanoparticles

Abstract

Nanoparticle-based therapeutics are emerging technologies that have the potential to greatly impact the treatment of many human diseases. However, drug instability and premature release from the nanoparticles during circulation currently preclude clinical translation. Herein, we use a lipase-labile (Sn 2) fumagillin prodrug platform coupled with a unique lipid surface-to-surface targeted delivery mechanism, termed contact-facilitated drug delivery, to counter the premature drug release and overcome the inherent photo-instability of fumagillin, an established anti-angiogenic agent. We show that αvβ3-integrin targeted fumagillin prodrug nanoparticles, administered at 0.3 mg of fumagillin prodrug/kg of body weight suppress the clinical disease indices of KRN serum-mediated arthritis in a dose-dependent manner when compared to treatment with the control nanoparticles with no drug. This study demonstrates the effectiveness of this lipase-labile prodrug nanocarrier in a relevant preclinical model that approximates human rheumatoid arthritis. The lipase-labile prodrug paradigm offers a translatable approach that is broadly applicable to many targeted nanosystems and increases the translational potential of this platform for many diseases.

Nanomedicine Delivers Promising Treatments for Rheumatoid Arthritis

“…The passive targeting of nanomedicines to inflamed tissues based on enhanced permeability has been supported by various in vivo biodistribution studies [51,56,59,63,70]. Ishihara et al showed that PEGylated polymersomes encapsulated with the glucocorticoid betamethasone preferentially accumulated in inflamed joints in a mouse model of antibody-induced arthritis.…”

“…This increased localization was interesting, as the conjugated liposomes were cleared significantly faster from circulation than the nonconjugated liposomes, showing how effective the targeted liposomes were, even with a shorter circulation time [59]. The same receptor was also targeted for the delivery of an angiogenesis inhibitor, fumagillin and the targeted fumagillin showed a higher affinity to inflamed tissues, decreased leukocytes recruited into the tissues, and suppressed inflammation [70]. In addition, the effective dose of the optimized targeted fumagillin nanoparticle formulation was decreased by eightfold [70].…”

“…The same receptor was also targeted for the delivery of an angiogenesis inhibitor, fumagillin and the targeted fumagillin showed a higher affinity to inflamed tissues, decreased leukocytes recruited into the tissues, and suppressed inflammation [70]. In addition, the effective dose of the optimized targeted fumagillin nanoparticle formulation was decreased by eightfold [70]. …”

Molecular targets in arthritis and recent trends in nanotherapy

“…In another study, delivery of lipase-labile fumagillin prodrug (Fum-PD) was achieved using perfluorocarbon targeted with αvβ3-integrin peptidomimetic antagonists. 93,94 Fum-PD nanotherapy induces the production of endothelial nitric oxide by which it indirectly suppresses inflammation in experimental RA. Tocilizumab-loaded hyaluronate-gold nanoparticles targeted with a monoclonal antibody against IL-6 have also been tested in CIA mice.…”

Small Molecule MYC Inhibitor Conjugated to Integrin-Targeted Nanoparticles Extends Survival in a Mouse Model of Disseminated Multiple Myeloma

“…22), that transfers nanoparticle (NP) lipid surfactant components to the targeted cell membrane through a hemifusion complexation process (23). Moreover, we have advanced this technology through the recent development of phospholipid Sn 2 prodrugs that stabilize and sequester the drug in the hydrophobic aspect of the outer lipid membrane of nanocolloids and prevent premature drug escape or metabolism during circulation to target cells (24, 25). Following transfer of the lipid monolayer components to the target cell membrane, cytosolic lipases enzymatically cleave the Sn 2 ester and liberate the drug into the cytosol (25, 26).…”