<i>In vivo</i>distribution and antitumour activity of liposomal 3′,5′-<i>O</i>-dipalmitoyl-5-fluoro-2′-deoxyuridine

Waalkes, M. Van Borssum; Fichtner, Iduna; Dontje, Bert; Lemm, Margit; Becker, Markus; Arndt, Dieter; Scherphof, Gl

doi:10.3109/02652049209021248

Cited by 12 publications

(7 citation statements)

References 17 publications

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“…The AUC is generally higher for liposomes prepared with high phase transition lipids such as DSPC (T m = 55.1 °C [74]). Floxuridine-dipalmitate loaded into liquid crystalline EPC liposomes was cleared faster than when incorporated into more rigid DSPC vesicles [75].…”

Section: Impact Of the Liposomal Carrier On L-ldc Pksmentioning

confidence: 89%

“…For instance, the incorporation of a phospholipid-anchored LDC of 2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine was reported to reduce the blood circulation time of liposomes compared to unloaded vesicles [33]. Similarly, conventional liposomes loaded with 10 mol% floxuridine-dipalmitate were cleared faster than those containing 2 mol% of the drug [75].…”

Section: Impact Of the Liposomal Carrier On L-ldc Pksmentioning

confidence: 99%

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Pharmacokinetics of lipid-drug conjugates loaded into liposomes

Signorell

Luciani

Brambilla

et al. 2018

European Journal of Pharmaceutics and Biopharmaceutics

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Drugs that are neither lipophilic nor suitable for encapsulation via remote loading procedures are generally characterized by low entrapment efficiencies and poor retention in liposomes. One approach to circumvent this problem consists in covalently linking a lipid to the drug molecule in order to permit its insertion into the vesicle membrane. The nature of the conjugated lipid and linker, as well as the composition of the liposomal bilayer were found to have a profound impact on the pharmacokinetic properties and biodistribution of the encapsulated drugs as well as on their biological activity. This contribution reviews the past and recent developments on liposomal lipid-drug conjugates, and discusses important issues related to their stability and in vivo performance. It also provides an overview of the data that were generated during the clinical assessment of these formulations. The marketing authorization of the immunomodulating compound mifamurtide in several countries as well as the promising results obtained with the lipid prodrug of mitomycin C suggest that carefully designed liposomal formulations of lipid-drug conjugates is a valid strategy to improve a drug's pharmacokinetic profile and with that its therapeutic index and/or efficacy.

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Section: Impact Of the Liposomal Carrier On L-ldc Pksmentioning

confidence: 89%

Section: Impact Of the Liposomal Carrier On L-ldc Pksmentioning

confidence: 99%

Pharmacokinetics of lipid-drug conjugates loaded into liposomes

Signorell

Luciani

Brambilla

et al. 2018

European Journal of Pharmaceutics and Biopharmaceutics

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“…In a previous study high in vivo toxicity was observed for a similar prodrug, 3′,5′-dipalmitoyl-FUdR. 19,21 In our model and at the dosage used (100 µg), compound 6 showed evident signs of toxicity and no antitumor activity. In contrast, both the liposomes and the immunoliposomes bearing drug 6 eradicated the tumor nodules progressively in a time-dependent manner, reaching maximum effect on day 27 postgraft.…”

Section: Discussionmentioning

confidence: 73%

“…For this reason, FUdR has usually been incorporated into the lipid vesicle as lipophilic prodrug. [19][20][21][22] To increase delivery efficiency, liposomes have been conjugated with monoclonal antibodies; the resulting immunoliposomes have been studied to establish their potential as a tool to achieve more site-specific drug delivery. 23 We are particularly interested in using a model of intraabdominal-disseminated human colorectal cancer, intraperitoneally grafted in athymic mice, as a means to prove the efficacy of new drug delivery systems.…”

Section: Introductionmentioning

confidence: 99%

Antitumoral Activity of Liposomes and Immunoliposomes Containing 5-Fluorouridine Prodrugs

Crosasso¹,

Brusa²,

Dosio³

et al. 1997

Journal of Pharmaceutical Sciences

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Liposomes and immunoliposomes containing cytotoxic agents may be highly efficacious in intracavity therapy of malignancies confined principally to the peritoneal cavity. To assess the feasibility of this locoregional treatment, we prepared two derivatives of 5-fluorouridine (5-FUR), a highly cytotoxic metabolite of 5-fluorouracile, and incorporated them into REV liposomes, prepared with the reverse phase evaporation method. Encapsulation efficiency, drug leakage, and stability were determined, and size analysis and differential scanning calorimetry were carried out to evaluate the drug delivery potential of liposomes containing 5'-palmitoyl-5-FUR, 5'-succinyl-5-FUR, or the parent drug 5-FUR. The most suitable drug for encapsulation, in terms of minimum leakage and encapsulation efficiency, was 5'-palmitoyl-5-FUR, which differential scanning calorimetry indicated as being firmly anchored to the lipid bilayer. Thus, 5'-palmitoyl-5-FUR was chosen to prepare a chemotherapeutic liposome-monoclonal antibody conjugate (immunoliposome). The covalent linkage between antibody and liposome was realized by coupling the thiolated monoclonal antibody AR-3 with REV liposomes, containing N-[4-(p-maleimidophenyl)butyryl]phosphatidylethanolamine. The cytotoxic activity of drug-bearing liposomes and immunoliposomes was evaluated on the HT-29 human colon adenocarcinoma cell line; the immunoliposomes had higher cytotoxicity than liposomes or 5-FUR. To explore the potential of these drug formulations in anticancer therapy, we ip injected liposomes or immunoliposomes into athymic mice ip grafted with human HT-29 cell line. In this mouse model, the immunoliposome containing 5'-palmitoyl-5-FUR displayed the best antitumoral activity, since on day 27 postgraft only 5% of residual tumor mass was present, compared to control mice; there was a close relationship between exposure time of tumor tissue to the drug and antitumor potency.

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“…For non-targeted, non-long-circulating (conventional) liposomes containing FUdR-dP, increased toxicity compared to free FUdR has been described (Supersaxo et al, 1988;Van Borssum Waalkes et al, 1992). This was attributed to the sustained release of FUdR from Kupffer cells after uptake of the FUdR-dP-liposomes .…”

Section: Discussionmentioning

confidence: 98%

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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In vivodistribution and antitumour activity of liposomal 3′,5′-O-dipalmitoyl-5-fluoro-2′-deoxyuridine

Cited by 12 publications

References 17 publications

Pharmacokinetics of lipid-drug conjugates loaded into liposomes

Pharmacokinetics of lipid-drug conjugates loaded into liposomes

Antitumoral Activity of Liposomes and Immunoliposomes Containing 5-Fluorouridine Prodrugs

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

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