(16d) Drug Release Kinetics from Dendritic Nanodevices for Sustained Delivery

Recent research has shown that Polyamidoamine (PAMAM) dendrimers have great prospect as targeted drug delivery nanodevices. PAMAM dendrimers are highly hyper-branched synthetic polymers with well defined spherical structure and size. The surface of the spherical structure consists of functional groups (cationic, anionic or neutral) that make them very hydrophilic and highly water soluble, thus offer enhancements in solubility for hydrophobic drugs upon attachment. In addition, PAMAM dendrimers were shown to enhance cell entry on drug resistant cells by changing cellular uptake pathway. It was previously demonstrated that PAMAM dendrimers can accumulate in the tumor tissue via enhanced permeation retention effect (EPR) and receptor mediated tumor targeting. One key challenge success of such systems hang on is to design systems that release the drug payload form dendritic nanodevice in a predetermined fashion in the targeted site while staying intact elsewhere in the body. The goal of this work was to engineer a model PAMAM dendrimer based nanodevice for sustained drug delivery applications. This model device is used to evaluate the applicability of ester and amide linkages in preparation, determine the corresponding drug release rates, and to understand the nanoscale structural effects on drug release mechanism.

Ibuprofen, a poorly water-soluble anti-inflammatory drug, was used as a model drug to study the release kinetics and mechanism of -NH2 and -OH terminated G4-PAMAM dendrimers (M.W ~14kDa) containing amide and ester linkages respectively. mPEG (Mw=5000) was also conjugated to Ibuprofen via an ester linkage for comparison with dendrimer conjugates. The payloads of G4-OH and G4-NH2 and mPEG conjugates were 8.9, 5.34 and 3 percent by weight respectively. The hydrolytic and enzymatic stability of the ester and amide linked conjugates were analyzed in various pH buffers and in diluted human plasma. Amide conjugates were stable in all buffers for 10 days and did not release significant amount of the drug. Ester linked G4-OH-Ibu conjugate showed pH dependent hydrolytic cleavage and sustained drug release for more than 10 days. Neither amide nor ester bonded PAMAM conjugates showed enzymatic hydrolysis in diluted human plasma within 12 hours. On the other hand, ester bonded mPEG conjugate was cleaved enzymatically within the same amount of time. The stability of G4-OH-Ibu against enzymatic hydrolysis suggests that the conjugate structure blocks esterase enzyme activity to cleave the ester linkage and release the drug. Nanometer scale spherical structure of G4 PAMAM dendrimer conjugate provided a unique way to protect the ester linkage from enzymatic cleavage in plasma. In this work a dendritic nanodevice that can provide sustained Ibuprofen release intracellularly while maintaining stability in plasma is described.