The data generated here demonstrates significant growth delay with the doxil and two ltsl treatment groups on the primary tumour side. Jul 10, 2018 a lysolipid thermally sensitive liposome encapsulating the chemotherapy agent, doxorubicin, thermodox is designed to release targeted levels of doxorubicin into and around liver tumors with heat activation. The liposomes comprise phospholipids and a surface active agent, such as a lysolipid, that increases the amount of active agent released by the liposome at the phase transition temperature of the liposome. Thermosensitive liposomes for localized delivery and triggered. In slt, strands of the polymers are attached to drug molecules, or to a system that can improve the safety and efficacy of the therapeutic agents. Jun 19, 2017 key findings of our work showed that, unlike regular thermally sensitive liposomes, there was a second peak of dox accumulation in the presence of irgd. Celsion stock blown apart on thermodox phase iii data. Development of lysolipidbased thermosensitive liposomes. In general, pegylation is attained by the incubation of a reactive derivative of peg with the target moiety. Ranjan a, jacobs gc, woods dl, negussie ah, partanen a, yarmolenko ps, et al. Sep 16, 2014 thermosensitive liposomes and their historical development. The second generation, lysolipid thermally sensitive liposomes ltsl technology, has been developed with incorporation of lysolipids that form stabilized defects at phase transition temperature. In summary, our results have demonstrated that lysolipid based thermally sensitive liposomes are able to release high mw hydrophilic protein molecules upon temperature rise.
A new temperaturesensitive liposome for use with mild. Use of these lipids enables researchers to obtain highly efficient ph sensitive carriers for efficient cytoplasmic delivery of bioactive molecules. The membranes of these liposomes are composed of either cholesterol hemisuccinate chems, phosphatidyl ethanolamine pe, oleic acid oa or dioleoylphosphatidyl ethanolamine dope. Dsc plots of low temperature sensitive liposomes containing dppc, mspc and dspepeg2000. Ultrasound responsive nanoparticles in cancer imaging and therapy. Except for the pure dppc bilayer, for all experiments dspcpeg2000 1. Motion compensated ultrasound imaging allows thermometry and.
Currently carrying out phase 3 clinical trials heat study for its lead candidate. Systemic antitumour effects of local thermally sensitive. Targteted drug delivery technologies and applications. We observed that the tumor accumulation for the irgdtsldox had a first peak at 1 hour that decreased at 2 hours. Thermal sensitive liposomes, which encapsulated the protein were prepared using a passive encapsulation methodology involving freezethawing cycles followed by extrusion. Ltsl, which stands for lysolipid thermally sensitive liposomes, is a unique liposomal technology used in celsions lead product, thermodox. Materials characterization of the low temperature sensitive liposome ltsl. The traditional thermal sensitive liposomes ttsl have utilized dppc and dspc as a combination.
Since then, liposomes have made their way to the market. Formation of protein corona in vivo affects drug release from. Celsion announces publication of thermodox study results in. Thermodoxs active ingredient is actually a commonly used chemotherapeutic agent called doxorubicin, which is encapsulated in lysolipid thermally sensitive liposomes ltsls to make a. We have paid close attention to advanced technologies and built lysolipid thermally sensitive liposomes platform to allow for sitespecific and fast drug release at. Currently, lysolipidcontaining thermal sensitive liposome ltsl is a standard formulation due to its rapid release behaviour. Pharmaceutics free fulltext liposomal formulations in. In addition, studies in cats with spontaneous vaccineassociated soft tissue sarcomas demonstrated a 216fold increase in liposomal delivery to tumours with the use of hyperthermia 25.
Liposomes have also been used for ultrasound imaging by enclosing air within the phospholipid bilayer. Delay in tumour growth is known to occur with local ht in combination with nonthermally sensitive liposomes doxil and thermally sensitive liposomes 11,25,26. Designing efficient vectors antibodies, protein carriers, viruses, nanoparticles to deliver therapeutics, especially to the diseaseaffected brain tissue, in a controlled and noninvasive manner remains one of the key goals of drug development. Tumorpenetrating peptideintegrated thermally sensitive liposomal doxorubicin enhances efficacy of radiofrequency ablation in liver tumors. Novel temperaturesensitive liposomes with prolonged circulation.
With nearly one hundred years of intensive study, lipids have proven to be a vital and evermorepromising area of cell biological research. Development of lysolipidbased thermosensitive liposomes for. Apr 10, 2012 combining lysolipid containing liposomes with superparamagnetic iron oxide nanoparticles or a targeting ligand might be required to efficiently localize drug delivery to a disease affected tissue and to avoid endothelial disruption over the entire body. Temperaturesensitive liposomal formulation duke university. Thermosensitive vesicles in controlled drug delivery for. Systemic antitumour effects of local thermally sensitive liposome therapy.
Moreover, neutral liposomes do not interact sig nificantly with cells, and in such cases, the drug may mainly enter cells after being released from liposomes extracellularly sharma et al. The appropriate reference solutions were hbs or fbs. When ultrasound was applied the liposomes, structure was fragmented and the. Yan f, duan w, li y, wu h, zhou y, pan m, liu h, liu x, zheng h. Today, they are a very useful reproduction, reagent, and tool in various scientific disciplines, including mathematics and theoretical physics, biophysics, chemistry, colloid science, biochemistry, and biology. Details for lysolipid thermally sensitive liposomes in 45. This is the basis for the temperaturetriggered nanotechnology for drug release. Dec 09, 20 thermally responsive liposomes, lysolipid thermally sensitive liposomes ltsl celsion corporation, nj, usa a patented liposomal tumor targeting delivery system delivers high concentrations of drug to target site tumors on exposure to local hypothermia. However, concerns have been raised regarding the negative effect of lysolipid on ltsl stability that results in undesirable leakage of encapsulated drug in vivo at physiological temperature. Only tsls containing lysolipids demonstrate a faster release with a.
Such lipids, when mixed with normal phospholipids can lower the phase transition temperature of the lipid bilayer to the mild hyperthermia range. Lysolipid thermally sensitive liposomes production. Several formulations have been developed since 1978, with lysolipidcontaining, low temperaturesensitive liposomes currently under clinical. Hyperthermia and temperaturesensitive vesicles tsv.
Details for lysolipid thermally sensitive liposomes in 451 ramsey road, shirley, ny 11967, usa, shirley, usa, 11967. Liposomes were diluted in hbs or 90% fetal bovine serum fbs and transferred into aluminum pans t zero hermetic aluminum pans and sealed with lids. We have shown previously that lysolipids readily desorb from liquidphase lipid bilayers once the vesicle is washed with lysolipidfree buffer 19, 20. Full text thermosensitive liposomal drug delivery systems. Synthesis and in vitro evaluation of cyclic ngr peptide. Transcytosis holds a great potential for drug delivery across different endothelial barriers.
An optical and micropet assessment of thermally sensitive liposome biodistribution in the met1 tumor model. Thermally sensitive liposomes deliver drugs to the targeted region and release them when local hyperthermia is applied. Therefore, it is a promising tool for sitespecific chemotherapy. International journal of pharmaceutical studies and research eissn 22294619 ijpsrvol. Liposomes are spherical vesicles formed by a membrane bilayer usually composed by phospholipids figure 1. Ltsl allows for the triggered release of a drug payload through low temperature just above body temperature heat activation.
Mar, 2001 temperature sensitive liposomes containing active agents are described. Samples were thermally scanned from 35 c to 45 c at 0. Methods and protocols, leading experts in the related fields explore cuttingedge experimental methods involving all aspects of lipids as essential components of the cell membrane. Thermally triggered drug release from temperature sensitive liposomes tsl holds great promise for cancer therapy.
Depofoamtm technology and lysolipid thermally sensitive technology ltst 4. These liposomes fuse with cells when the ph is low, thus. An optical and micropet assessment of thermallysensitive. Imageguided drug delivery with magnetic resonance guided high. Temperaturesensitive liposomes encapsulating doxorubicin thermodox, celsion, md are under evaluation for the treatment of liver and breast cancer, generally. Lysolipid thermally sensitive liposomes, a heat sensitive liposomal based dosage form that targets disease with known therapeutics.
Nirlasercontrolled drug release from doxir780loaded temperature sensitive liposomes for chemophotothermal synergistic tumor therapy. In the near future, optimization of the formulation will be carried out to accelerate its release rate in a mildhyperthermia temperature range. Our first platform is lysolipid thermally sensitive liposomes, a heat sensitive liposomal based dosage form that targets disease with known therapeutics in the presence of mild heat. Nahum goldberg, hao wu, wanlu duan, zhiting deng, haibo han, hairong zheng. They call them lysolipid thermally sensitive liposomes ltsl, and theyre being billed by celsion as the first in. Lysolipid containing liposomes for transendothelial drug.
Ltsl released much more rapidly seconds than prior formulations 16. Lysolipid thermally sensitive liposomes production creative. The promising preclinical results of ngrtargeted non thermally sensitive liposomes in metastatic models suggests that the ngrtargeted thermally sensitive formulation reported herein may be able to provide excellent localregional control with tumor targeted hyperthermia as well as improved therapy through ngrtargeting of unheated metastatic. Pdf materials characterization of the low temperature. Different types of tsl have been designed recently for heat triggered drug release inside tumor blood vessels or after accumulation into the tumor interstitium. Rationale for and measurement of liposomal drug delivery with. Dec 15, 2011 read development of lysolipid based thermosensitive liposomes for delivery of high molecular weight proteins, international journal of pharmaceutics on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Fluorescein isothiocyanate conjugatealbumin was used as a model drug mw 66 kda. Temperaturetriggered nanotechnology for chemotherapy. Current developments in drug delivery with thermosensitive liposomes. The design of delivery vehicles that are stable in circulation but can be activated by exogenous energy sources is challenging.
Several formulations have been developed since 1978, with lysolipidcontaining, low temperaturesensitive liposomes currently under clinical investigation. Contents of these liposomes are most often destined for lysosomes new, 1990. Our goals are to validate new imaging methods for the assessment of particle stability, to engineer stable and activatable particles and to assess accumulation of a hydrophilic model drug in an orthotopic tumor. Materials characterization of the low temperature sensitive liposome. Lysolipid thermally sensitive liposome ltsl technology thermosensitive liposomes have been studied for drug release at sites of elevated temperature. The temperature dependence of liposomal extravasation clearly establishes a rationale for developing methods to quantify and image liposomal drug delivery, even if the liposome is not thermally sensitive itself. Temperaturesensitive liposomes encapsulating doxorubicin thermodox, celsion, md are under evaluation for the treatment of liver and breast cancer, generally using microwave radiation as a heat source.
Lysolipid containing liposomes for transendothelial drug delivery. Nirlasercontrolled drug release from doxir780loaded. Synthesis and in vitro evaluation of cyclic ngr peptide targeted thermally sensitive liposome article in journal of controlled release 1432. Tumorpenetrating peptideintegrated thermally sensitive. Pdf thermosensitive liposomal drug delivery systems. As the example of carriers, we have designed ph sensitive liposomes. Liposomes, sphereshaped vesicles consisting of one or more phospholipid bilayers, were first described in the mid60s. Temperaturesensitive liposomes are an especially attractive option. Development of thermal sensitive liposomes for targeted. Thus lysolipid incorporated thermal sensitive liposomes ltsl are the most widely studied and applied formulation among various types of thermally sensitive liposomes.
Sunbright dspepg8 series designs for ph sensitive liposomal drug. Celsion corporation clsn view as pdf united states. Lysolipid appears to not desorb from the liposomes during heating, but remains in the membranes stabilizing long lasting pores through which small molecules and drugs can freely diffuse. We offer production services for thermally sensitive liposomes to facilitate precise treatment both in intravascular.
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