Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:88-96-0 (P-D)
 118 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

pH-responsive polymers have been synthesised by grafting l-valine (PV-75), l-leucine (PL-75) and l-phenylalanine (PP-75) onto the pendant carboxylic acid moieties of a pseudo-peptide, poly(l-lysine iso-phthalamide), at a stoichiometric degree of substitution of 75 mol%. The effect of such modification on the pH-, concentration- and time-dependent cell membrane-disruptive activity of the grafted polymers has been investigated using a haemolysis model. At 0.025 mg mL(-1), the grafted polymers were almost non-haemolytic at pH 7.4, but mediated considerable membrane lysis after 60 min in the pH range characteristic of early endosomes, which ranked in the order: PP-75 > PL-75 > PV-75 > poly(l-lysine iso-phthalamide). PP-75 was 35-fold more lytic on a molar basis than the membrane-lytic peptide melittin. With increasing concentration, the grafted polymers showed an increased ability to lyse cell membranes and caused noticeable membrane disruption at physiological pH. The mechanism of the polymer-mediated membrane destabilisation has been investigated. The in-vitro cytotoxicity of the grafted polymers has been assessed using a propidium iodide fluorescence assay. It has been demonstrated by confocal microscopy that the grafted polymers can induce a significant release of endocytosed materials into the cytoplasm of HeLa cells, which is a feature critical for drug delivery applications.
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PMID:The role of hydrophobic amino acid grafts in the enhancement of membrane-disruptive activity of pH-responsive pseudo-peptides. 1913 97

The endosomal membrane has proven to be a challenging barrier for the delivery of therapeutic biomacromolecules, including DNA, siRNA and proteins, which are taken up by endosomes but cannot freely diffuse across lipid bilayers. Anionic polymers that undergo conformational changes and become membrane disruptive in low-pH environments have the potential to assist in the delivery of these biomacromolecules across the endosomal membrane to the cytosol. Such endosomolytic polymers have been synthesized through the grafting of hydrophobic side-chains to a poly(L-lysine iso-phthalamide) backbone. The phenylalanine grafted form of poly(L-lysine iso-phthalamide) has a pH-sensitive membrane disruptive profile corresponding to the pH range of maturing endosomes and, thus, has a favourable endosomolytic profile. In order to understand the influence of hydrophobicity versus pi-pi interactions mediated by aromatic rings, a tyrosine grafted form of poly(L-lysine iso-phthalamide) was synthesized and its aqueous pH-sensitive properties, cytotoxicity and endosomal disruptive capacity were compared to phenylalanine-grafted poly(L-lysine iso-phthalamide). The similarity between these two polymers' properties, despite the large difference in hydrophobicity between their side-chains, supports the conclusion that the aromatic character of sidechains in poly(L-lysine iso-phthalamide) is an important property, as opposed to hydrophobicity alone, in determining the effectiveness of acidic pH triggered endosomolysis.
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PMID:The influence of aromatic side-chains on the aqueous properties of pH-sensitive poly(L-lysine iso-phthalamide) derivatives. 2053 42

The use of small interfering RNAs (siRNAs) to down-regulate the expression of disease-associated proteins carries significant promise for the treatment of a variety of clinical disorders. One of the main barriers to the widespread clinical use of siRNAs, however, is their entrapment and degradation within the endolysosomal pathway of target cells. Here we report the trafficking and function of PP75, a non-toxic, biodegradable, lipid membrane disruptive anionic polymer composed of phenylalanine derivatized poly(L-lysine iso-phthalamide). PP75 is readily endocytosed by cells, safely permeabilizes endolysosomes in a pH dependent manner and facilitates the transfer of co-endocytosed materials directly into the cytoplasm. The covalent attachment of siRNAs to PP75 using disulfide linkages generates conjugates that effectively traffic siRNAs to the cytoplasm of target cells both in vitro and in vivo. In a subcutaneous malignant glioma tumor model, a locally delivered PP75-stathmin siRNA conjugate decreases stathmin expression in tumor cells and, in combination with the nitrosourea chemotherapy carmustine, is highly effective at inhibiting tumor growth. PP75 may be clinically useful for the local delivery of siRNAs, in particular for the treatment of solid tumors.
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PMID:Endosomolytic anionic polymer for the cytoplasmic delivery of siRNAs in localized in vivo applications. 2427 80

Biopolymers have become important drug delivery systems for therapeutic molecules by enhancing their accessibility and efficacy intracellularly. However, the transport of these drugs across the cell membrane and their release into the cytosol remain a challenge. The trafficking of poly (l-lysine iso-phthalamide) grafted with phenylalanine (PP-50) was investigated using an osteosarcoma cell line (SAOS-2). Colocalisation of this amphipathic biopolymer with endocytosis tracers, such as transferrin and lactosylceramide, suggested that PP-50 is partially internalised by both clathrin and caveolin-mediated endocytosis. Macropinocytosis was also investigated, but a smaller correlation was found between this mechanism and PP-50 transport. A significant decrease in polymer-mediated calcein uptake was found when cells were pre-incubated with endocytosis inhibitors, suggesting also the use of a combination of mechanisms for cell internalisation. In addition, PP-50 colocalisation with endosome and lysosome pathway markers showed that the polymer was able to escape the endolysosomal compartment before maturation. This is a critical characteristic of a biopolymer towards use as drug delivery systems and biomedical applications.
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PMID:The intracellular fate of an amphipathic pH-responsive polymer: Key characteristics towards drug delivery. 2761 2