Potential Role of Liposomes for the Delivery of Phosphodiesterase Inhibitors to Erythrocytes for the Treatment of Type 2 Diabetes

Human erythrocytes participate in the regulation of vascular diameter in the microcirculation through the controlled release of the vasodilator adenosine triphosphate (ATP) in response to physiological stimuli, including exposure to low oxygen tension as occurs in the microcirculation of skeletal muscle. The localized release of this vasodilator has been suggested to be an important mechanism for matching perfusion (oxygen delivery) with need in this tissue. However, in certain diseases, such as type 2 diabetes (DM2), the ability of erythrocytes to release ATP in response to this stimulus is severely compromised. This defect in erythrocyte physiology could contribute to impairment of vasodilation in the peripheral circulation leading to vascular insufficiency and delayed wound healing. It has been shown that inhibitors of specific phosphodiesterases (PDEs) can augment low oxygen-induced ATP release from erythrocytes of humans with DM2. However, these drugs are associated with serious side effects that limit their use in clinical medicine.

Here we summarize the evidence in support of the hypothesis that delivery of PDE3 inhibitors encapsulated in liposomes to erythrocytes could provide a new approach for the treatment of DM2. In addition we report that inhibitors of PDE5 can also rescue low oxygen-induced ATP release from DM2 erythrocytes making this class of drugs another that could be targeted to erythrocytes.