Osteoarthritis is a debilitating joint disease that degrades a patient’s articular cartilage until a large lesion forms in the otherwise smooth surface. Currently, there are no disease modifying osteoarthritis drugs that are capable of slowing the progression of the disease. This is mainly due to the avascular nature of the articular cartilage which prevents therapeutic drug doses from reaching their target site after systemic delivery. In addition, locally injected therapies are quickly eliminated from the joint space by synovial fluid turnover without efficiently interacting with the dense, negatively-charged matrix. As a result, a number of drug delivery formulations have been explored for the sustained delivery of osteoarthritic therapies. Previously, positively-charged, multivalent carriers of size less than 15 nm have shown to utilize electrostatic interactions to bind to and penetrate through articular cartilage faster than they can be cleared from the joint space. Among those studied are poly(amidoamine) dendrimers (PAMAM) which consist of a hierarchically branched polymer with a high surface density of cationic primary amines. The cytotoxicity of the polymer’s high charge density can be mitigated by covalently conjugating poly(ethylene glycol) (PEG) to its surface. When locally introduced into the joint of a rat model, these PAMAM-PEG conjugates have shown to improve the retention time of a bound therapy ten-fold versus the free drug. Though literature shows that surface-bound PEG is able to enhance tissue penetration while reducing uptake and cytotoxicity, the role that the PEG corona plays in these interactions has not been explored. Here, using a novel charge-based method to characterize the PEG corona, we found that the dendrimer-cartilage interactions are solely dependent on the conjugate’s solvent-accessible charge, or the amount of primary amines accessible on the surface of the conjugate: tissue uptake and cytotoxicity both increase with increasing solvent-accessible charge, whereas cartilage penetration depth decreases. In addition, we show that covalently-bound PEG chains do not directly contribute to these ex vivo interactions between carrier and cartilage, instead they contribute to only the accessibility of PAMAM’s primary amines by hydrogen bonding to them and shielding them from cartilage. Further investigation will assess translation in vivo to optimize the conjugate for the sustained delivery of osteoarthritic therapies.

Understanding the role of dendrimer surface modifications for osteoarthritis drug delivery

ACS Spring Meeting 2021

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