Remote loading of preencapsulated drugs into stealth liposomes

Abstract

Loading drugs into carriers such as liposomes can increase the therapeutic ratio by reducing drug concentrations in normal tissues and raising their concentrations in tumors. Although this strategy has proven advantageous in certain circumstances, many drugs are highly hydrophobic and nonionizable and cannot be loaded into liposomes through conventional means. We hypothesized that such drugs could be actively loaded into liposomes by encapsulating them into specially designed cyclodextrins. To test this hypothesis, two hydrophobic drugs that had failed phase II clinical trials because of excess toxicity at deliverable doses were evaluated. In both cases, the drugs could be remotely loaded into liposomes after their encapsulation (preloading) into cyclodextrins and administered to mice at higher doses and with greater efficacy than possible with the free drugs.T here is currently wide interest in the development of nanoparticles for drug delivery (1-7). This area of research is particularly relevant to cancer drugs, wherein the therapeutic ratio (dose required for effectiveness to dose causing toxicity) is often low. Nanoparticles carrying drugs can increase this therapeutic ratio over that achieved with the free drug through several mechanisms. In particular, drugs delivered by nanoparticles are thought to selectively enhance the concentration of the drugs in tumors as a result of the enhanced permeability and retention (EPR) effect (8-18). The enhanced permeability results from a leaky tumor vascular system, whereas the enhanced retention results from the disorganized lymphatic system that is characteristic of malignant tumors.Much current work in this field is devoted to designing novel materials for nanoparticle generation. This new generation of nanoparticles can carry drugs-particularly those that are insoluble in aqueous medium-that are difficult to incorporate into conventional nanoparticles such as liposomes. However, the older generation of nanoparticles has a major practical advantage in that they have been extensively tested in humans and approved by regulatory agencies such as the Food and Drug Administration in the United States and the European Medicines Agency in Europe. Unfortunately, many drugs cannot be easily or effectively loaded into liposomes, thereby compromising their general use.In general, liposomal drug loading is achieved by either passive or active methods (9,(19)(20)(21)(22). Passive loading involves dissolution of dried lipid films in aqueous solutions containing the drug of interest. This approach can only be used for water-soluble drugs, and the efficiency of loading is often low. In contrast, active loading can be extremely efficient, resulting in high intraliposomal concentrations and minimal wastage of precious chemotherapeutic agents (9,23,24). In active loading, drug internalization into preformed liposomes is typically driven by a transmembrane pH gradient. The pH outside the liposome allows some of the drug to exist in an unionized form, able to migrate across the lipid bi...

Enhancing delivery and cytotoxicity of resveratrol through a dual nanoencapsulation approach

“…However, the contribution of this factor on liposomal instability is expected to be minimal or insignificant [43] proven by our in-vitro and cell toxicity tests. While our current method resulted in RES-CD being passively encapsulated within the aqueous core, it has been previously reported that functionalized CD molecules may also be remotely loaded into liposomes [44]. The strategy, which utilizes pH or ion gradients to drive molecular entrapment, can substantially enhance the total effective load of CD-drug complex into the formulation.…”

New Developments in Liposomal Drug Delivery

“…The heat increased the fluidity and thus permeability of the liposomes toward the cyclodextrin (remote loading technique). 334 The other method employed a dehydration− rehydration technique. 335 Liposome−quantum dots hybrids, 336 hybrid capsules of alginate plus guar gum encapsulated with liposomes, 337 and hydrogel-in liposomes 338 to encapsulate several drugs have been described in separate studies.…”

Selective Surface PEGylation of UiO-66 Nanoparticles for Enhanced Stability, Cell Uptake, and pH-Responsive Drug Delivery

“…Thus, drug-delivery systems have become one of the most promising applications for health care 4, 5, 6. A large number of strategies have been studied, but for application, drug-delivery systems must overcome issues surrounding bioavailability,7, 8 the uncontrollable release of drugs (usually due to carrier instability),9, 10, 11 loading capacities,11, 12, 13 particle size,14, 15, 16 nanoparticle cellular internalization routes,14, 17, 18 and toxicity 19, 20. The exceptional storage capacities of metal-organic frameworks (MOFs), together with their robustness and structural tailorability, have made them attractive for a wide variety of applications,21, 22 including several promising breakthroughs in biomedicine 9, 10, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33.…”