Drug release characteristics of PAMAM dendrimer-drug conjugates with different linkers

Drug release from polymer-drug conjugates plays a crucial role on the efficacy. This is especially true for dendrimers where there is a steric crowding at the surface. The drug release characteristics of G4-polyamidoamine (PAMAM) dendrimer-ibuprofen conjugates with ester, amide, and peptide linkers were investigated, in addition to a linear PEG-ibuprofen conjugate to understand the effect of architecture and linker on drug release. Ibuprofen was directly conjugated to NH₂-terminated dendrimer by an amide bond and OH-terminated dendrimer by an ester bond. A tetra-peptide-linked dendrimer conjugate and a linear mPEG-ibuprofen conjugate were also studied for comparison to direct linked dendrimer conjugates. Amide-linked conjugates were relatively stable against hydrolysis, whereas the ester-linked conjugates showed pH-dependent release and the extent of release varied with pH from 3% (pH 5) to 38% (pH 8.5) for the 10-day period studied. Direct amide- and ester-linked conjugates did not release ibuprofen enzymatically in cathepsin B buffer and diluted human plasma. In contrast, mPEG conjugate released 65% of its payload within 12 h in diluted plasma by esterase activity, and the peptide-linked dendrimer conjugate released 40% of its payload within 48 h by cathepsin B activity. It is demonstrated that the steric crowding at the surface of PAMAM dendrimer-drug conjugates, along with linking chemistry govern the drug release mechanisms as well as kinetics. Understanding these structural and steric effects on their drug release characteristics is crucial for the design of dendrimer conjugates with high efficacy.