DoE-based development of celecoxib loaded PLGA nanoparticles: In ovo assessment of its antiangiogenic effect

Abstract

Abnormal angiogenesis plays a main role in the pathogenesis of many diseases such as cancer, and inflammatory autoimmune disorders among others, and its inhibition represents a potential strategy for their management. Celecoxib (CXB) that is one of the most prescribed selective COX-2 inhibitors and is currently approved for the treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis inhibits angiogenesis. The objective of this manuscript was to design, develop, and characterize polymeric nanoparticles for the parenteral administration of CXB which the aim of facilitating its administration and improving its antiangiogenic activity while decreasing its adverse effects. A Plackett-Burman design was used to optimize the formulation. The PVA concentration, the sonication time, the sonicator amplitude and the CXB:PLGA ratio were selected as independent variables and particle size, polydispersity index, drug loading, and entrapment efficiency as responses. Optimized nanoparticles (formulations F2, F6 and F9) showed a particle size around 280 nm, a low polydispersion (PDI ≤ 0.2), a negative zeta potential around -25 mV, a high entrapment efficiency (above 88 %) and a controlled drug release for at least 10 days. Moreover, they were physically and chemically stable for at least 3 months when stored at 4 °C. Interestingly, CXB-loaded nanoparticles showed a higher angiogenesis inhibition than CXB in solution administered at the same concentration. F9 nanoparticles that were prepared using PVA at 0.5 %, a sonication time of 7 min, a sonicator amplitude of 80 % and a CXB:PLGA ratio of 20:100 were selected as the most suitable CXB-formulation. It represents a promising strategy to administer CXB and improve its efficacy in disorders with pathological angiogenesis such as cancer and arthritic diseases.

Keywords: Angiogenesis; COX-2 inhibitors; Inflammation; Nanomedicine; Plackett-Burman design; Polymeric nanoparticles; Yolk sac model (YSM).