Ion-Responsive Drug Delivery Systems.

BACKGROUND: Some kinds of cations and anions are contained in body fluids such as blood, interstitial fluid, gastrointestinal juice, and tears at relatively high concentration. Ionresponsive drug delivery is available to design the unique dosage formulations which provide optimized drug therapy with effective, safe and convenient dosing of drugs. OBJECTIVE: The objective of the present review was to collect, summarize, and categorize recent research findings on ion-responsive drug delivery systems. RESULTS: Ions in body fluid/formulations caused structural changes of polymers/molecules contained in the formulations, allow formulations exhibit functions. The polymers/molecules responding to ions were ion-exchange resins/fibers, anionic or cationic polymers, polymers exhibiting transition at lower critical solution temperature, self-assemble supramolecular systems, peptides, and metalorganic frameworks. The functions of ion-responsive drug delivery systems were categorized to controlled drug release, site-specific drug release, in situ gelation, prolonged retention at the target sites, and enhancement of drug permeation. Administration of the formulations via oral, ophthalmic, transdermal, and nasal routes has showed significant advantages in the recent literatures. CONCLUSION: Many kinds of drug delivery systems responding to ions have been reported recently for several administration routes. Improvement and advancement of these systems can maximize drugs potential and contribute to patients in the world.

Formulation design and evaluation of liposomal sepantronium bromide (YM155), a small-molecule survivin suppressant, based on pharmacokinetic modeling and simulation.

PURPOSE: Sepantronium bromide (YM155) is administered by 168-hour continuous infusions in clinical studies due to its time-dependent pharmacological efficacy and rapid elimination from plasma. To enable more convenient administration, i.e., bolus injections with low frequency, we prepared liposomal formulations of YM155 and evaluated their antitumor activities. METHODS: A kinetic simulation model of liposomal YM155 to predict the free drug concentration in both tumor and plasma was developed. A liposomal formulation with the target drug release rate was prepared based on the simulation. Antitumor activities of the formulation were examined in various tumor xenograft mouse models. In addition, antitumor activities of liposomal formulations with different drug release rates were compared in order to confirm the validity of the simulation-based prediction. RESULTS: Liposomal YM155 with the release half-life of 48 h was prepared as a promising formulation. This formulation showed significantly potent antitumor activities in tumor xenograft models by weekly bolus injections. Further studies demonstrated that this release rate was optimal for YM155 in terms of both efficacy and safety. CONCLUSIONS: We successfully developed a liposomal formulation of YM155 that could substitute for long-term continuous infusion of the drug solution in clinical settings by being given as weekly bolus injections.

Antitumor efficacy and biodistribution of liposomal sepantronium bromide (YM155), a novel small-molecule survivin suppressant.

Sepantronium bromide (YM155) exhibits time-dependent antitumor activity, although the plasma half-life of YM155 after a bolus intravenous (i.v.) administration is very short. Therefore, greater antitumor efficacy is obtained by continuous infusion than by bolus i.v. administration. In the present study, we attempted to liposomalize YM155 to obtain a longer circulation time than that achieved by bolus i.v. administration and yet retain sufficient antitumor activity. Encapsulation of YM155 in polyethylene glycol-coated liposomes extended the half-life of the drug, and high tumor accumulation of the drug was observed. Bolus i.v. administration of liposomal YM155 by a weekly administration regimen showed antitumor activity comparable to that obtained by the continuous infusion without severe toxicity in a murine xenograft model. Therefore, this liposomal formulation can be a new dosage form of YM155 that achieves sufficient efficacy and safety and is a more convenient administration regimen for users. It should be noted that liposomal YM155 showed unexpectedly high accumulation in the kidneys. This is a specific finding for liposomal YM155, offering important information for the consideration of the potential toxicity of liposomal YM155.

Induction of cytotoxic T lymphocytes following immunization with cationized soluble antigen.

Antigen presentation on major histocompatibility complex (MHC) class I and subsequent priming of antigen-specific cytotoxic T lymphocytes (CTLs) are essential steps for vaccination but exogenous soluble proteins are conventionally taken up by endosomes and presented on MHC class II rather than class I. In this study, we demonstrated, for the first time, that ovalbumin (OVA) chemically cationized with hexamethylenediamine (HMD) can induce OVA-specific CTLs without any adjuvants. Cationization of OVA greatly enhances cellular uptake by antigen-presenting cells (APCs) through adsorptive endocytosis. Two kinds of Cat-OVAs with different cationic charges were evaluated to elicit a CTL response through enhanced uptake by APCs and concomitant participation in the class I pathway. Cat(20)-OVA, a cationized OVA derivative with more cationic charges, showed pronounced induction of the OVA-specific CTL response after subcutaneous immunization. The CTL response was comparable with that induced by OVA with CFA. In contrast to the CFA formulation that actually produced local tissue damage in this study, local damage at the injection sites was not observed with Cat-OVAs. Cat(20)-OVA also showed a significant protective effect on the growth of OVA-expressing E.G7 tumor cells. In conclusion, cationization of soluble antigen is a useful and safe vaccination strategy.

Efficient scavenger receptor-mediated uptake and cross-presentation of negatively charged soluble antigens by dendritic cells.

Exogenous antigens endocytosed in large amounts by antigen-presenting cells (APC) are presented on major histocompatibility complex (MHC) class I molecules as well as on class II molecules, a process called cross-presentation. Among APC, dendritic cells (DC) play a key role in cross-presentation by transporting internalized antigen to the cytosol. The present study shows that ovalbumin (OVA) introduced with negative charges by succinylation (Suc-OVA), maleylation (Mal-OVA) or cis-aconitylation (Aco-OVA) was efficiently taken up by DC via scavenger receptors (SR). Mal-OVA and Aco-OVA were efficiently cross-presented by DC, while cross-presentation of Suc-OVA was hardly observed. MHC class I presentation of acylated OVA introduced directly into the cytosol was inefficient and presentation of exogenous native OVA but not of Aco-OVA was markedly augmented by chloroquine, an inhibitor of endosomal acidification, suggesting that deacylation in endosomes or lysosomes is necessary for cross-presentation of acylated OVA. MHC class I presentation of exogenous native OVA and Aco-OVA by DC was blocked by lactacystin and brefeldin A, demonstrating that exogenous antigens taken up by DC are cross-presented through the conventional cytosolic pathway. Therefore, SR-mediated delivery of antigen to DC leads to efficient cross-presentation, although the pathway of chemical modification should be considered.