Surface-Functionalized PAMAM Dendrimers as Synthetic Chaperones for Prevention of Bovine γ-Crystallin Aggregation

We present a fundamental study that supports the feasibility of delaying the onset of presbyopia and age-related cataracts via the utilization of surface-functionalized poly(amidoamine) (PAMAM) dendrimers. These PAMAM derivatives are known to have the added benefit of permeating the human cornea with possible absorption/distribution into the crystalline lens, indicating the potential for use in a topically applied eye solution. Mature onset cataract formation occurs because of γ-crystallin and β-crystallin aggregation in the human lens over time. As the molecular chaperone α-crystallin becomes saturated with unfolded γ-crystallins, the ability to prevent aggregation becomes limited. PAMAM dendrimers containing either sodium carboxylate- or succinamic acid-surface functionality are employed as synthetic chaperones to evaluate the effect of structure and local concentration on γ-crystallin aggregation. The chaperone/γ-crystallin blends are examined via DLS, zeta potential measurements, and fluorescence spectroscopy. DLS studies show a reduction in hydrodynamic size for γ-crystallin in the presence of PAMAM dendrimers and their small molecule counterparts compared to the control. Structural identity and local concentration of functionality are found to impact solution behavior. Zeta potential measurements and fluorescence studies indicate that synthetic chaperones can have multiple modes of non-covalent interactions and are the most effective in preventing or reducing γ-crystallin aggregation.