Encapsulation of a nitric oxide donor into a liposome to boost the enhanced permeation and retention (EPR) effect

Abstract

We propose a method to improve the enhanced permeability and retention (EPR) effect of nanomedicines based on tumor-specific vasodilation using a nitric oxide (NO) donor-containing liposome. NONOate, a typical NO donor, was incorporated into a PEGylated liposome to retard the protonation-induced release of NO from NONOate by the protecting lipid bilayer membrane. The NONOate-containing liposome (NONOate-LP) showed similar blood retention to an empty PEGylated liposome but almost twice the amount accumulated within the tumor. This improvement in the EPR effect is thought to have been caused by specific vasodilation in the tumor tissue by NO released from the NONOate-LP accumulated in the tumor. The improved EPR effect by NONOate-LP will be useful for the accumulation of co-administered nanomedicines.

Augmentation of EPR Effect and Efficacy of Anticancer Nanomedicine by Carbon Monoxide Generating Agents

“…Based on this knowledge, we have developed a method counteracting against the problems by using a vascular dilator, nitric oxide (NO) donor such as nitroglycerin (NG), and an angiotensin-I converting enzyme (ACE) inhibitor such as enarapril [5,6,12,13]. We and other groups have further described additional strategies to enhance the EPR, and thus the therapeutic effect of anticancer nanodrugs using nano-designed NO donors [14,15]. More recently, we further elaborated various NO generating agents, all of which are clinically used drugs, and obtained a significantly increased antitumor effect when combined with the proto type nanodrugs (e.g., polymer conjugated pirarubicin—P-THP), in five different tumor models, including carcinogen-induced autochthonous advanced tumors of the colon and breast [8].…”

Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity

“…Second, imaging-based clinical methods (e.g., magnetic resonance imaging imaging of iron oxide nanoparticles to identify patients exhibiting nanoparticle accumulation in tumors prior to nanoparticle therapy), are beginning to be employed clinically 40 , 41 , which pave the way for rational selection of patients for EPR-dependent therapies. Lastly, a variety of clinically-relevant strategies to increase the EPR effect in tumors are beginning to be defined, such as radiation therapy 42 , 43 , photodynamic therapy 44 , and use of vasodilators 45 , to name just a few. We hypothesize that this approach is better suited to immunostimulatory agents that act at low doses rather than drugs that block inhibitory receptors (e.g., anti-PD-1, anti-CTLA-4), which may require high doses to fully block target receptors on tumor-infiltrating immune cells.…”

Recent progress of magnetic nanoparticles in biomedical applications: A review

“…MPI imaging of these two groups showed clear accumulation of the particles in the xenografted tumor region, [ 255 ] which is explained by enhanced permeation and retention (EPR) theory. [ 256 ] According to EPR, vasculatures near tumor region are defective and leaky, allowing increased concentration of the circulating particles in the tumor sites. [ 257 ] The advantage of MPI method utilizes high signal to background ratio, which can be as high as 50 at 6 hours post injection in case of A group (high SPIONs conc.).…”