Protease-Sensitive, Polymer-Caged Liposomes: A Method for Making Highly Targeted Liposomes Using Triggered Release

Abstract

Liposomes have become useful and well-known drug delivery vehicles because of their ability to entrap drugs without chemically modifying them and to deliver them somewhat selectively to tumorous tissue via the enhanced permeation and retention (EPR) effect. Although useful, liposome preparations are still less than ideal because of imperfect specificity, slow release kinetics in the tumor, and leakiness prior to reaching the tumor site. Cancer-associated proteases (CAPs), which are differentially expressed in tumors, have also gained traction recently as a method for tumor targeting and drug delivery. By combining the EPR effect with CAPs sensitivity, a much more specific liposome can be produced. The method described here creates an improved liposome system that can target more specifically, with faster release kinetics and lower general leaking, by deliberately producing a very unstable liposome (loaded with hyperosmotic vehicle) that is subsequently stabilized by a cross-linked polymer shell containing consensus sequences for cancer-associated proteases (protease-triggered, caged liposomes). A cholesterol-anchored, graft copolymer, composed of a short peptide sequence for urokinase plasminogen activator (uPA) and poly(acrylic acid), was synthesized and incorporated into liposomes prepared at high osmolarities. Upon cross-linking of the polymers, the protease-triggered, caged liposomes showed significant resistance to osmotic swelling and leaking of contents. Protease-triggered, caged liposomes also showed significant and substantial differential release of contents in the presence of uPA, while bare liposomes showed no differential effect in the presence of uPA. Thus a protease-sensitive liposome system with fast release kinetics was developed that could be used for more specific targeting to tumors.

Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery

“…Cancer-associated proteases are another set of enzymes that are upregulated in tumours and can be used to develop enzyme-sensitive NDDSs. For instance, conjugates composed of cholesterol, peptide and poly-acrylic acid were cleaved by a cancer-associated protease (urokinase) and induced rapid drug release in an in vitro model 93 .…”

The Smart Targeting of Nanoparticles

“…Hariri and coworkers investigated the use of radiation to guide FePt nanoparticles to tumor sites using a short peptide that targets TIP-1 receptor, a receptor upregulated on endothelial cells in response to radiation-induced injury [94]. Basel and coworkers demonstrated that targeting ligands may not always be necessary for effective nanoparticle targeting via the exploitation of high concentrations of cancer-associated protease (CAP), such as urokinase plasminogen activator (uPA), matrix metalloproteases (MMPs), and some cathepsins, in dysplastic tissues [95]. In a radical shift of nanoparticle targeting strategy, Choi and Kennedy demonstrated that macrophages and human T cells could be loaded with gold nanoparticles (AuNPs) and used to deliver those AuNPs to tumor sites [96, 97].…”

siRNA Delivery by Stimuli-Sensitive Nanocarriers

“…The altered levels of certain local enzymes in cancer tissues, such as matrix metallo proteinases (MMPs), human leukocyte elastase (HLE) and cancer-associated proteases (CAPs), have been the rationale to develop enzyme-triggered NPs for drug delivery [43]. Over-expressed levels of MMP2 and HLE are found in the tumor microenvironment, where they promote invasion, progression and metastasis of most human tumors by degrading the intercellular collagen matrix and extracellular matrix barrier, respectively [44-47].…”