In-vitro stability and cytostatic activity of liposomal formulations of 5-fluoro-2′-deoxyuridine and its diacylated derivatives

Waalkes, Mv; Vangalen, M; Morselt, Hwm; Sternberg, Brigitte; Scherphof, Gl

doi:10.1016/0005-2736(93)90174-x

Cited by 21 publications

(12 citation statements)

References 21 publications

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“…Van Borssum Waalkes et al (1993) showed that little or no hydrolysis of FUdR-dP occurs in serum. Extensive hydrolysis of FUdR-dP, leading to the virtually complete availability of the active drug in 48 to 72 h, can only occur after uptake of the prodrug and subsequent intracellular hydrolytic removal of the esterified palmitic acid chains (Van Borssum Waalkes et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

“…We showed that FUdR-dP remains firmly associated with the liposomes and does not exchange with serum components such as albumin or lipoproteins or with liposomal bilayers (Van Borssum Waalkes et al, 1993).…”

mentioning

confidence: 87%

“…FUdR-dP was synthesized as described earlier (Van Borssum Waalkes et al, 1993). Briefly, 0.4 mmol of FUdR was dissolved in 1 ml of dimethylacetamide to which 0.8 mmol of palmitoylchloride was added.…”

Section: Synthesis Of Fudr-dpmentioning

confidence: 99%

“…Since FUdR is not efficiently retained in liposomes under in vivo conditions we synthesized a lipophilic dipalmitoyl ester of FUdR, FUdR-dP (Nishizawa et al, 1965), to anchor the drug in the liposomal bilayer (Schwendener et al, 1985;Van Borssum Waalkes et al, 1993). We showed that FUdR-dP remains firmly associated with the liposomes and does not exchange with serum components such as albumin or lipoproteins or with liposomal bilayers (Van Borssum Waalkes et al, 1993).…”

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confidence: 99%

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Antiproliferative effect of immunoliposomes containing 5-fluorodeoxyuridine-dipalmitate on colon cancer cells

et al. 1999

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SummaryWe have investigated the antiproliferative action towards CC531 colon adenocarcinoma cells of target cell-specific immunoliposomes containing the amphiphilic dipalmitoyl derivative of 5-fluorodeoxyuridine (FUdR-dP). FUdR-dP incorporated in immunoliposomes caused a 13-fold stronger inhibition of CC531 cell growth in vitro, during a 72-h treatment, than FUdR-dP in liposomes without antibody, demonstrating that the prodrug is efficiently hydrolysed to yield the active drug, FUdR, intracellularly. The intracellular release of active FUdR was confirmed by determining the fate of 3 H-labelled immunoliposomal FUdR-dP. Treatments shorter than 72 h with FUdR-dP in immunoliposomes resulted in anti-tumour activities comparable to, or even higher than, that of free FUdR. The shorter treatments reflect more closely the in vivo situation and illustrate the potential advantage of the use of immunoliposomes over non-targeted liposomal FUdR-dP or free FUdR. Association of tumour cell-specific immunoliposomes with CC531 cells was up to tenfold higher than that of liposomes without antibody or with irrelevant IgG coupled, demonstrating a specific interaction between liposomes and target cells which causes an efficient intracellular delivery of the drug. Since biochemical evidence indicates a lack of internalization or degradation of the liposomes as such, we postulate that entry of the drug most likely involves the direct transfer of the prodrug from the immunoliposome to the cell membrane during its antigen-specific interaction with the cells, followed by hydrolysis of FUdR-dP leading to relatively high intracellular FUdR-levels. In conclusion, we describe a targeted liposomal formulation for the anticancer drug FUdR, which is able to deliver the active drug to colon carcinoma cells with high efficiency, without the need for the cells to internalize the liposomes as such.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 87%

Section: Synthesis Of Fudr-dpmentioning

confidence: 99%

mentioning

confidence: 99%

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Antiproliferative effect of immunoliposomes containing 5-fluorodeoxyuridine-dipalmitate on colon cancer cells

et al. 1999

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“…A sustained drug delivery system to circumvent them is desirable. There has been increasing interest in the use o f liposomes and microspheres as vehicles for the delivery o f drugs [28][29][30][31][32][33][34][35][36][37][38], We evaluated the pharmacokinetic behavior of intra vitreally injected liposome-encapsulated 5-fluorouridinc (5-FUR) in the rabbit eye. Additionally we determined tht ocular toxicity o f various doses o f this liposome-encapsu lated agent.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Retinal Toxicity of Intravitreal Liposome-Encapsulated 5-Fluorouridine

García‐Arumí¹,

Pascual²,

Fonseca³

et al. 1997

Ophthalmologica

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Background: Fluoropyrimidines may be effective in preventing proliferative vitreoretinopathy after repair of complicated retinal detachments. Liposome encapsulation of these antiproliferative drugs may extend the intravitreal half-life and increase their efficacy. Methods: The current study evaluated the pharma-cokinetic behavior of intravitreally injected 5-fluorouridine (5-FUR), free and encapsulated in liposomes, either conventionally or coated with collagen into 25 New Zealand rabbits. Additionally, we investigated the retinal toxicity of intravitreal injections of 100, 250 and 500 µg as well as 1 mg 5-FUR as free drug or encapsulated in liposomes in the rabbit eye. Results: The half-life of free 5-FUR after liposome injection into the vitreous cavity was 18.17+2.43 h, considerably longer than the half-life of free 5-FUR (0.82 h). Electrophysiologic tests did not show any changes in latency and a-wave amplitude and minimal changes in the b-wave amplitude. Histopathologic studies revealed integrity of the inner limiting membrane, and mild vacuolization in the outer retina. Conclusion: Encapsulation of 5-FUR within liposomes markedly increases its intravitreal half-life. Our study suggests that liposome-encapsulated 5-FUR is not toxic to the retina even at doses of 1 mg.

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Liposomal gemcitabine (GemLip)—efficient drug against hormone‐refractory Du145 and PC‐3 prostate cancer xenografts

Jantscheff¹,

Esser²,

Graeser³

et al. 2009

The Prostate

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In-vitro stability and cytostatic activity of liposomal formulations of 5-fluoro-2′-deoxyuridine and its diacylated derivatives

Cited by 21 publications

References 21 publications

Antiproliferative effect of immunoliposomes containing 5-fluorodeoxyuridine-dipalmitate on colon cancer cells

Antiproliferative effect of immunoliposomes containing 5-fluorodeoxyuridine-dipalmitate on colon cancer cells

Pharmacokinetics and Retinal Toxicity of Intravitreal Liposome-Encapsulated 5-Fluorouridine

Liposomal gemcitabine (GemLip)—efficient drug against hormone‐refractory Du145 and PC‐3 prostate cancer xenografts

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