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Release rates of liposomal contents are controlled by kosmotropes and chaotropes.

ABSTRACT: Contents release from redox-responsive liposomes is anion-specific. Liposomal contents release is initiated by the contact of apposed liposome bilayers having in their outer leaflet 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), whose presence is due to the redox-stimulated removal of a quinone propionic acid protecting group (Q) from Q-DOPE lipids. Contents release occurs upon the phase transition of DOPE from its lamellar liquid-crystalline phase (L?) to its hexagonal-II inverted micelle (HII) phase. Contents release is slower in the presence of weakly hydrated chaotropic anions versus highly hydrated kosmotropic anions and is attributed to ion accumulation near the zwitterionic DOPE headgroups, in turn altering the headgroup hydration, as indicated by the L? ? HII phase transition temperature, TH, for DOPE. The results are significant, not only for mechanistic aspects of liposome contents release in DOPE-based systems but also for drug delivery applications wherein exist at drug targeting sites variations in the type and concentration of ions and neutral species.

SUBMITTER: McCarley RL

PROVIDER: S-EPMC3932753 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Release rates of liposomal contents are controlled by kosmotropes and chaotropes.

McCarley Robin L RL Forsythe Jerimiah C JC Loew Martin M Mendoza Maria F MF Hollabaugh Nicole M NM Winter James E JE

Langmuir : the ACS journal of surfaces and colloids 20131105 46

Contents release from redox-responsive liposomes is anion-specific. Liposomal contents release is initiated by the contact of apposed liposome bilayers having in their outer leaflet 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), whose presence is due to the redox-stimulated removal of a quinone propionic acid protecting group (Q) from Q-DOPE lipids. Contents release occurs upon the phase transition of DOPE from its lamellar liquid-crystalline phase (Lα) to its hexagonal-II inverted micell ...[more]

PMID: 24160736

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Project description:AimsAcute myeloblastic leukemia (AML) is the most common type of acute leukemia in adults. Despite numerous treatment strategies including chemotherapy and radiotherapy, a large number of patients do not respond to treatment and experience relapse. The main problem of these patients is the development of resistance to anti-cancer drugs. Therefore, any endeavor to reduce drug resistance in these patients is of high priority. In general, several mechanisms such as changes in drug metabolic pathways, drug inactivation, drug target alterations and reduced drug accumulation in the cells contribute to drug resistance of cancer cells. In this context, evidence suggests that exosomes could reduce drug resistance by removing drugs from their parent cells. In the present study, we aimed to investigate the effects of exosome release inhibition on the resistance of U937 cells to PEGylated liposomal doxorubicin (PLD).Main methodsIn order to find a suitable ABCG2 (ATP-binding cassette sub-family G member 2) transporter substrate, virtual screening was performed among a list of drugs used in leukemia and PLD was selected. U937 cells were treated with PLD with/without co-treatment with the exosome release inhibitor, GW4869. Released exosomes within different study groups were isolated and characterized to determine the differences between groups. Doxorubicin presence in the isolated exosomes was also measured by high performance liquid chromatography (HPLC) to confirm drug export through the exosomes. Finally, the effect of exosome inhibition on the cytotoxicity of PLD on U937 cells was determined using different cytotoxicity assays including the standard lactate dehydrogenase (LDH) release assay and the flow cytometric analysis of apoptotic and non-apoptotic cell death.Key findingsGW4869 treatment caused a significant decrease in the exosome release of U937 cells compared to the untreated cells, as evidenced by the reduction of the protein content of the isolated exosomes (P<0.05). Co-treatment with GW4869 significantly increased cytotoxic cell death in the groups treated with 0.5 and 1 µM PLD, compared to the same groups without GW4869 co-treatment (P<0.05). Interestingly, co-treatment with GW4896 and 0.5 µM PLD was enough to induce the same cytotoxic effect as that of the sole 1 µM PLD group.SignificanceOur findings showed that U937 cells increase their resistance against the cytotoxic effects of PLD through the exosome-mediated expelling of the drug. Inhibition of exosome release could prevent PLD efflux and consequently increase the vulnerability of the U937 cells to the cytotoxic effects of PLD. Our results along with prior studies indicate that the integration of exosome release inhibitors into the common PLD-containing chemotherapy regimens could significantly lower the required concentrations of the drug and consequently reduce its associated side effects. Further studies are warranted to identify clinically safe inhibitors and investigate their clinical efficacy.

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Release rates of liposomal contents are controlled by kosmotropes and chaotropes.

Publications

Release rates of liposomal contents are controlled by kosmotropes and chaotropes.

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