Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intranasal (i.n.) immunization with ricin toxoid (RT) vaccine encapsulated in poly (lactide-co-glycolide) microspheres (RT-PLG-Ms) and poly (L-lactide) microspheres (RT-PLA-Ms) stimulated systemic and mucosal immune responses and protected mice from aerosolized ricin intoxication. High titers of anti-ricin IgG2a were stimulated in the serum of mice with one or two doses of RT-Ms 6 weeks postimmunization. However, in the lungs, no IgG2a or total IgG was elicited either with RT-Ms or with aqueous RT. At 6 weeks postimmunization, a single dose of the RT-Ms stimulated secretory IgA (sIgA) in the lungs of four of six mice, but a second immunizing dose did not enhance the stimulation. A single dose of aqueous RT vaccine failed to stimulate sIgA in the lungs, while, a second dose induced sIgA in 50% of the mice. One or two i.n. doses of RT-Ms protected most of the mice against lethal aerosol-delivered ricin toxin 6 weeks postimmunization. In contrast, protection was absent or marginal after one or two doses of aqueous RT vaccine. In both studies, the protection against lethal aerosol challenge was significantly better with one dose of RT-Ms than with two doses of aqueous vaccine, which may be attributed to the induction of sIgA in the lungs and the serum. Duration of the IgG2a and IgA in the serum, particularly that of IgG2a was much longer after the administration of RT-Ms than after the aqueous vaccine. The geometric mean IgG2a titers stimulated with two doses of RT-Ms remained high during 40 weeks postimmunization and were up to 25 times higher than the titers induced with aqueous RT vaccine. After 6 weeks, the IgG2a induced by two doses of aqueous vaccine was no longer detectable. Persistence of antibody response was predictive of efficacy. At 1 year postimmunization with two doses of RT-Ms, 100% of mice were protected against lethal ricin challenge. However, at the same time no protection was afforded by two doses of aqueous RT. The results of the present study consistently demonstrated the advantages of microencapsulated RT vaccine to stimulate effective and long-lasting protection by i.n. administration.
 ...
PMID:Intranasal stimulation of long-lasting immunity against aerosol ricin challenge with ricin toxoid vaccine encapsulated in polymeric microspheres. 887 98

Aiming at successful targeted drug delivery - a system that possesses both targeting and prodrug features that can be activated once the system reaches the target site upon systemic administration - would be desired to reduce systemic toxicity. Previously we proposed a heparin/protamine-based system for delivery of protease drugs such as tissue-specific plasminogen activator (t-PA). This approach, termed 'antibody targeted, triggered, electrically modified prodrug-type strategy' (ATTEMPTS), would permit antibody-directed administration of inactive t-PA and allow a subsequent triggered release of the active t-PA at the target site. This system can be adapted to target tumor tissues when protein transduction domain (PTD) peptide such as TAT is incorporated in the ATTEMPTS construct. Both in vitro and preliminary in vivo studies using TAT-gelonin (TAT-Gel) and TAT-asparaginase (TAT-ASNase) conjugates have demonstrated that the on/off regulation of the membrane translocation activity of PTD at tumor target, followed by intracellular delivery of cytotoxic macromolecular drug, can be accomplished. Hence, the PTD-mediated delivery system derived from our previous ATTEMPTS approach is a system that incorporates all of the targeting function, prodrug feature, release mechanism and cell entry mechanism and could become a generic system for delivery of macromolecular drugs.
 ...
PMID:The ATTEMPTS delivery systems for macromolecular drugs. 1897 35

In order to reduce systemic toxicity and effectively deliver macromolecular drug into tumor cells, a system termed "ATTEMPTS" (antibody targeted, [protamine] triggered, electrically modified prodrug-type strategy) was developed in our laboratory. This approach was adapted from our previously reported heparin/protamine-based system for controlled delivery of protease drugs such as tissue- specific plasminogen activator (tPA). In this "ATTEMPTS" system, the cell-permeable protein drugs are synthesized by conjugating proteins to cell-penetrating peptides (CPPs). Cell penetration ability of such CPP-protein conjugates would initially be disabled, acting as a "prodrug", by forming polyelectrolyte complexes with a functionalized heparin-antibody moiety. The complexes would accumulate in tumor sites by the antibody targeting function, and then the local release of CPP-protein conjugates would be triggered by protamine. We applied this system to the macromolecular anticancer agents, such as the protein drugs (gelonin and asparaginase) as well as the polymerdrugs (polyrotaxane-doxorubicin and polyrotaxane-camptothecin). Both in vitro and preliminary in vivo studies demonstrated the regulable cell penetration behavior based on the competitive ionic interactions between CPP/heparin and heparin/protamine. Thus, this ATTEMPTS approach provides a multi-functionalized system incorporating the features of targeting, prodrug-like, triggerable release, and cell penetration ability for the delivery of macromolecular anticancer agents. A summary of our work on "ATTEMPTS" is presented in this review.
 ...
PMID:ATTEMPTS system: a macromolecular prodrug strategy for cancer drug delivery. 2061 57

Ricin is a protein toxin classified as a bioterror agent, for which there are no known treatment options available after intoxication. It is composed of an enzymatically active A-chain connected by a disulfide bond to a cell binding B-chain. After internalization by endocytosis, ricin is transported retrogradely to the Golgi and ER, from where the ricin A-chain is translocated to the cytosol where it inhibits protein synthesis and thus induces cell death. We have identified cytoplasmic phospholipase A(2) (PLA(2)) as an important factor in ricin retrograde transport. Inhibition of PLA(2) protects against ricin challenge, however the toxin can still be endocytosed and transported to the Golgi. Interestingly, ricin transport from the Golgi to the ER is strongly impaired in response to PLA(2) inhibition. Confocal microscopy analysis shows that ricin is still colocalized with the trans-Golgi marker TGN46 in the presence of PLA(2) inhibitor, but less is colocalized with the cis-Golgi marker GM130. We propose that PLA(2) inhibition results in impaired ricin transport through the Golgi stack, thus preventing it from reaching the ER. Consequently, ricin cannot be translocated to the cytosol to exert its toxic action.
 ...
PMID:Role of phospholipase A(2) in retrograde transport of ricin. 2206 63