Development of Potential Orphan Drug Therapy of Intravesical Liposomal Tacrolimus for Hemorrhagic Cystitis Due to Increased Local Drug Exposure

Nirmal, Jayabalan; Tyagi, Pradeep; Chancellor, Michael B.; Kaufman, Jonathan; Anthony, Michele; Chancellor, David D.; Chen, Yen-Ta; Chuang, Yao‐Chi

doi:10.1016/j.juro.2012.10.123

Cited by 21 publications

(23 citation statements)

References 16 publications

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“…Bladder cancer patients are among the longest cancer survivors [18] and face difficulties due to the adverse effect of treatments including cyclophosphamide and radiation therapy. Hemorrhagic cystitis occurs mainly due to acrolein formation after cyclophosphamide or radiation treatment [2]. Therefore, acrolein induction of cellular (UT) damage is a clinically relevant model for studying mechanisms of underlying bladder urothelial damage and repair.…”

Section: Discussionmentioning

confidence: 99%

“…Hence there is interest in developing an agent that can repair and restore the UT barrier against various damaging conditions. The urinary bladder can be exposed to acrolein and its metabolites due to dietary, endogenous, drug induced and environmental sources [1,2]. Acrolein has been shown to cause severe inflammation and damage to the bladder.…”

Section: Introductionmentioning

confidence: 99%

“…CYP is converted to acrolein, which activates urothelial transient receptor potential cation channel (TRPV1 and TRPA1) receptors, causing calcium influx and cytokine gene transcription via the calcineurin dependent nuclear factor of activated T cells (NF-AT) pathway. Radiation can have a similar effect by causing membrane lipid peroxidation, leading to acrolein formation and activating inflammatory pathways [2]. …”

Section: Introductionmentioning

confidence: 99%

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Liposomal inhibition of acrolein-induced injury in rat cultured urothelial cells

Nirmal

Tyagi

et al. 2014

Int Urol Nephrol

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Purpose To study the protection offered by empty liposomes alone against acrolein-induced changes in urothelial cell viability and explored uptake of liposomes by primary (rat) urothelial cells. Methods Acrolein was used as a means to induce cellular damage and reduce urothelial cellular viability. The effect of acrolein or liposomal treatment on cellular proliferation was studied using BrdU assay. Cytokine release was measured after urothelial cells were exposed to acrolein. Temperature dependent uptake study was carried out for fluorescent labeled liposomes using confocal microscopy. Results Liposome pretreatment protected against acrolein-induced decrease in urothelial cell proliferation. Liposomes also significantly affected the acrolein induced cytokine (IFNγ) release offering protection to the urothelial cells against acrolein damage. We also observed a temperature-dependent urothelial uptake of fluorescent-labeled liposomes occurred at 37 °C (but not at 4 °C). Conclusions Empty liposomes alone provide a therapeutic efficacy against acrolein induced changes in urothelial cell viability and may be a promising local therapy for bladder diseases. Hence our preliminary evidence provides support for liposome-therapy for urothelial protection and possible repair.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Liposomal inhibition of acrolein-induced injury in rat cultured urothelial cells

Nirmal

Tyagi

et al. 2014

Int Urol Nephrol

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“…Today, many liposomal compositions are available, or can be produced, that mimic the natural composition of the eukaryotic cell membranes (68). Even though it is well known that urothelial cells exhibit low endocytotic activity, many studies suggest that empty liposomes may help to restore urothelial barrier function (69). Recent clinical trials demonstrate that the intavesical injection of liposomes in IC patients, instilled once a week for 4 weeks 80mg in distilled water, is a safe and reliable method to regenerate the bladder epithelial barrier as well as to reduce the inflammation and pain symptoms (68) (Table 1).…”

Section: Liposomesmentioning

confidence: 99%

Reviewing Interstitial Cystitis Models and Treatments: A Focus on the Urothelium

F¹

2017

Razavi Int J Med

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Context: Interstitial cystitis is a multifactorial chronic and debilitating disease which is commonly associated with pain localized in the bladder region, increased urinary frequency, urgency and nocturia. Due to the high prevalence of pain in the population affected more recently the condition is often referred to as interstitial cystitis / bladder pain syndrome (IC/BPS). Evidence Acquisition: Although IC presents with many different symptoms, researchers have formulated three different theories, which are not mutually exclusive, to explain IC pathology: the first is related to the alteration of the proteoglycan and protein junction composition, structure and presence in the urothelium. The second is an immune induced IC resulting from an increased number of activated mast cells in the bladder internal layers, such as detrusor muscle (DM), and mucosa/submucosa. The third type, which is closely related to the second one, is due to a sensory nerve sensitization as an effect of neurotrophic factors molecule release. Results: Previous classification has been mirrored in the development of various in vitro and in vivo disease models created to mimic IC, as well as in the available therapies used to treat the condition to date. Conclusions: This review will summarize the most recent advances in the field, related to the different causative factors contributing to the development of the condition, the in vivo models used as well as the evidence they provide in advancing our knowledge and their limitations. The focus will be on works reporting on IC in the domain related to alterations in proteoglycans and cellular junction, specifically their composition, structure and appearance in the urothelium, and also discuss present and future therapies. Conclusions: This review will summarize the most recent advances in the field, related to the different causative factors contributing to the development of the condition, the in vivo models used as well as the evidence they provide in advancing our knowledge and their limitations. The focus will be on works reporting on IC in the domain related to alterations in proteoglycans and cellular junction, specifically their composition, structure and appearance in the urothelium, and also discuss present and future therapies.

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“…In recent years, studies regarding the intravesical delivery of several drugs (chemo drugs, toxins, nucleic acids, genes) by liposomes have been reported. [2][3][4][5][6][7][8] We also reported that Bacille Calmette-Guerin cell wall skeleton (BCG-CWS) loaded liposomes have potential for use as an immunotherapeutic drug against bladder cancer. 9) However, the effect of the nature of liposomes on the features of bladder or intravesical delivery have not been extensively examined.…”

mentioning

confidence: 99%

Modifying Cationic Liposomes with Cholesteryl-PEG Prevents Their Aggregation in Human Urine and Enhances Cellular Uptake by Bladder Cancer Cells

Nakamura

Noma

Sakurai

et al. 2017

Biological & Pharmaceutical Bulletin

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Intravesical drug delivery by cationic liposomes (Cat-LPs) represents a potent nanotechnology for enhancing therapeutic effects against bladder disorders. However, preventing the aggregation of Cat-LPs in urine poses a significant barrier. We report on an examination of the effect of modifying liposomes with polyethylene glycol (PEG) lipids to prevent Cat-LPs from aggregating in human urine. Although Cat-LPs underwent significant aggregation in human urine, introducing 5 mol% of PEG2k lipid or 2 mol% of PEG5k lipid completely inhibited the aggregation of the Cat-LPs. When 2 mol% of PEG2k lipids were introduced, the lipid structures of 1,2-distearoly-sn-glycero-3-phosphoethanolamine (DSPE) and 1,2-distearoyl-snglycerol (DSG) greatly prevented aggregation compared with cholesterol. By contrast, when Cat-LPs, after incubation in urine, were exposed to bladder cancer cells, only introducing cholesteryl-PEG into the CatLPs showed a significant enhancement in cellular uptake. These results offer the potential for incorporating cholesteryl-PEG into Cat-LPs for achieving both stability in urine and effective cellular uptake.

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Development of Potential Orphan Drug Therapy of Intravesical Liposomal Tacrolimus for Hemorrhagic Cystitis Due to Increased Local Drug Exposure

Cited by 21 publications

References 16 publications

Liposomal inhibition of acrolein-induced injury in rat cultured urothelial cells

Liposomal inhibition of acrolein-induced injury in rat cultured urothelial cells

Reviewing Interstitial Cystitis Models and Treatments: A Focus on the Urothelium

Modifying Cationic Liposomes with Cholesteryl-PEG Prevents Their Aggregation in Human Urine and Enhances Cellular Uptake by Bladder Cancer Cells

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