In Vivo Fates of Degradable Poly(β-Malic Acid) and of its Precursor,                Malic Acid

Domurado, Dominique; Fournié, Philippe; Braud, Christian; Vert, Michel; Guérin, Philippe; Simonnet, F

doi:10.1177/0883911503018001003

Cited by 20 publications

(16 citation statements)

References 6 publications

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“…Previous pharmacokinetic studies with synthetic radioactively labeled poly(β-D,Lmalic acid) indicated rapid urinary excretion of 70% of the injected radioactivity in 1 h and varying degrees of retention in the liver, spleen, kidney, muscle, heart, brain, lung, and intestine [39][40][41]. Time course of clearance indicated here by whole animal imaging is to some extent comparable to that of the neutral copolymer HPMA (M w 40,000-78,000) or immunoglobulin IgG (M w 150,000) [42,43].…”

Section: Discussionmentioning

confidence: 99%

Nanoconjugate based on polymalic acid for tumor targeting

Ljubimova

Fujita

Khazenzon

et al. 2008

Chemico-Biological Interactions

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A new prototype of polymer-derived drug delivery system, the nanoconjugate Polycefin, was tested for its ability to accumulate in tumors based on enhanced permeability and retention (EPR) effect and receptor mediated endocytosis. Polycefin was synthesized for targeted delivery of Morpholino antisense oligonucleotides into certain tumors. It consists of units that are covalently conjugated with poly(β-L-malic acid) (M w 50,000, M w /M n 1.3) highly purified from cultures of myxomycete Physarum polycephalum. The units are active in endosomal uptake, disruption of endosomal membranes, oligonucleotide release in the cytoplasm, and protection against enzymatic degradation in the vascular system. The polymer is biodegradable, non-immunogenic and non-toxic. Polycefin was also coupled with AlexaFluor 680 C2-maleimide dye for in vivo detection.Nude mice received subcutaneous injections of MDA-MB 468 human breast cancer cells into the left posterior mid-dorsum or intracranial injections of human glioma cell line U87MG. Polycefin at concentration of 2.5 mg/kg was injected via the tail vein. In vivo fluorescence tumor imaging was performed at different time points, 0-180 min up to 24 h after the drug injection. The custom-made macro-illumination imaging MISTI system was used to examine the in vivo drug accumulation in animals bearing human breast and brain tumors. In breast tumors the fluorescence signal in large blood vessels and in the tumor increased rapidly until 60 min and remained in the tumor at a level 6 times higher than in non-tumor tissue (180 min) (p < 0.003). In brain tumors drug accumulated selectively in 24 h without any detectable signal in non-tumor areas. The results of live imaging were corroborated histologically by fluorescence microscopic examination of various organs. In addition to tumors, only kidney and liver showed some fluorescent signal.

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Section: Discussionmentioning

confidence: 99%

Nanoconjugate based on polymalic acid for tumor targeting

Ljubimova

Fujita

Khazenzon

et al. 2008

Chemico-Biological Interactions

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“…Tumor vasculature can be targeted with a synthetic polymer, N-(2-hydroxypropyl)methacrylamide [8], conjugated with O-(chloracetyl-carbamoyl) fumagillol (TNP-470) [10]. Another promising drug carrier used here is β-poly(L-malic acid) (PMLA), a natural product of Physarum polycephalum [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of laminin-8 in vivo using a novel poly(malic acid)-based carrier reduces glioma angiogenesis

et al. 2006

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We have previously shown that laminin-8, a vascular basement membrane component, was overexpressed in human glioblastomas multiforme and their adjacent tissues compared to normal brain. Increased laminin-8 correlated with shorter glioblastoma recurrence time and poor patient survival making it a potential marker for glioblastoma diagnostics and prediction of disease outcome. However, laminin-8 therapeutic potential was unknown because the technology of blocking the expression of multi-chain complex proteins was not yet developed. To inhibit the expression of laminin-8 constituents in glioblastoma in vitro and in vivo, we used Polycefin, a bioconjugate drug delivery system based on slime-mold Physarum polycephalum-derived poly(malic acid). It carries an attached transferrin receptor antibody to target tumor cells and to deliver two conjugated morpholino antisense oligonucleotides against laminin-8 α4 and β1 chains. and area (p < 0.001) and increased animal survival (p < 0.0004). These data suggest that laminin-8 may be important for glioblastoma angiogenesis. Polycefin, a versatile nanoscale drug delivery system, was suitable for in vivo delivery of two antisense oligonucleotides to brain tumor cells causing a reduction of glioblastoma angiogenesis and an increase of animal survival. This system may hold promise for future clinical applications.

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“…[8] PMLA is perfectly biodegradable and biocompatible and it is metabolized in the mammalian tricarboxylic acid cycle. [9] Some PMLA derivatives are already used as components of crosslinked prodrugs, scaffolds for tissue regeneration, [10] and more recently, as a nanoconjugate prototype of drug delivery system for brain cancer chemotherapy. [11,12] Coupling of PMLA with cationic surfactants bearing long linear alkyl chains produces stable ionic complexes able to lodge hydrophobic drugs in the paraffinic subphase.…”

Section: Full Papermentioning

confidence: 99%

Biodegradable Nanoparticles of Partially Methylated Fungal Poly(β‐L‐malic acid) as a Novel Protein Delivery Carrier

Portilla-Arias

García‐Alvarez

Galbis

et al. 2008

Macromolecular Bioscience

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The preparation of nanoparticles from 75% methylated poly(beta-L-malic acid) is described. Their degradation in aqueous environments was examined and the influence of pH and lipase on the rate of hydrolysis was evaluated. Six proteins were used to estimate the loading efficiency of the nanoparticles. The amount of protein retained in the nanoparticles was found to depend on the acid/basic character of the protein. Protein release from the loaded nanoparticles upon incubation in water under physiological conditions encompassed polymer hydrolysis and happened steadily within 3-10 d. The activity loss of entrapped alpha-chymotrypsin caused by loading and releasing depended on the method used for loading.

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In Vivo Fates of Degradable Poly(β-Malic Acid) and of its Precursor, Malic Acid

Cited by 20 publications

References 6 publications

Nanoconjugate based on polymalic acid for tumor targeting

Nanoconjugate based on polymalic acid for tumor targeting

Inhibition of laminin-8 in vivo using a novel poly(malic acid)-based carrier reduces glioma angiogenesis

Biodegradable Nanoparticles of Partially Methylated Fungal Poly(β‐L‐malic acid) as a Novel Protein Delivery Carrier

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