Optimizing Kartogenin Delivery By Modifying PLGA-Peg Nanoparticle Size and Surface Charge

Osteoarthritis is a degenerative joint disease affecting over 500 million people worldwide, resulting in irreversible degradation of articular cartilage, further leading to pain, inflammation, and loss of mobility¹. Kartogenin (KGN) is a synthetic molecule known to enhance chondrogenesis and chondroprotection, resulting in cartilage regeneration². However, its small size and hydrophobicity present limitations for delivery within aqueous cellular and tissue environments. We propose to improve the delivery of KGN through encapsulation in poly(lactic-co-glycolide)-poly(ethylene-glycol) (PLGA-PEG) nanoparticles (NPs). Previous work has demonstrated the efficacy of KGN-loaded PLGA-PEG NPs against free drug and placebo controls, yet optimization of KGN loading and release is still required³. Nanoparticle properties, such as size, composition, are known to affect the release profiles of encapsulated drugs³. Thus, we seek to investigate the effects of NP size, composition, and surface charge in order to optimize KGN delivery by changing PLGA molecular weight (15 kDa vs 45 kDa), PEG molecular weight (2 kDa vs 10 kDa), and Molar ratio between the PLGA and PEG (1:1 vs 1:5 vs 1:10). Briefly, a dicyclohexylcarbodiimide catalyzed conjugation reaction of PLGA with a terminal carboxylic acid group and PEG-bis-amine in dichloromethane is used to synthesize the PLGA-PEG copolymer, which is analyzed using proton nuclear magnetic resonance (¹H NMR). Following copolymer synthesis, KGN and PLGA-PEG are dissolved within acetonitrile to form nanoparticles using nanoprecipitation into aqueous polyvinyl alcohol. We have successfully fabricated and characterized KGN-loaded PLGA-PEG NPs using 15 kDa PLGA, 10 kDa PEG, and a Molar ratio of 1:7 PLGA to PEG (NP1), as well as NPs using 15 kDa PLGA, 2 kDa PEG, and a Molar ratio of 1:15 PLGA to PEG (NP2). NP1 resulted in a mean hydrodynamic diameter of 214 ± 7.20 nm and a mean surface charge of -7.0 ± 2.1 mV whereas NP2 resulted in a mean hydrodynamic diameter of 142 ± 30 nm and a mean surface charge of -0.50 ± 0.20. Current and future work is focused on continuing to characterize the remaining NP combinations as well as investigating the effects of size and surface charge on KGN encapsulation and release using high-performance liquid chromatography.

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2. Johnson, K., 2012. Science, 336(6082):717-721
3. Almeida, B, 2020. Ann Biomed Eng, 48(7):2090-2102