Effects of a series of new synthetic high polymers on cancer metastases

Ferruti, Paolo; Danusso, F.; Franchi, G; Polentarutti, Nadia; Garattini, Silvio

doi:10.1021/jm00263a018

Cited by 41 publications

(13 citation statements)

References 4 publications

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“…This was expected as when the polymerisation is brought to high yields the copolymer composition reflects the stoichiometry of the monomer feed. [40] a) The M w , M n (g/mol) and M w =M n were calculated by GPC using PVP standards as described in the text. b) pI was calculated.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Endosomolytic Properties of Poly(amidoamine) Block Copolymers

Lavignac

Lazenby

Foka

et al. 2004

Macromolecular Bioscience

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Summary: The poly(amidoamine)s (PAAs) ISA 1 and ISA 23 display pH‐dependent conformational change and pH‐dependent membrane perturbation. These properties confer potential for use as endosomolytic polymers for intracytoplasmic delivery of toxins and genes. Both polymers are relatively non‐toxic, and moreover ISA 23 has the beneficial property in vivo, of being non hepatotropic when administered intravenously. Although ISA 23 and ISA 1 demonstrate ability to transfect cells, ISA 1 is also able to promote intracellular delivery of non‐permeant toxins. The aim of this study was to synthesise random and block copolymers of ISA 1 and ISA 23 and investigate whether these second generation hybrids would allow optimisation of PAA biological characteristics. Random and block copolymers of ISA 1 and ISA 23 were synthesised by hydrogen transfer polyaddition to generate a library of PAAs with an ISA 23:ISA 1 molar ratios of 2:1 to 4:1. The resultant polymers have a pI slightly below 7.4 and a $\overline M _{\rm w}$ of 19 900–49 000 g/mol and a $\overline M _{\rm n}$ of 13 100–24 100 g/mol. Whereas none of the random or block copolymers were haemolytic at pH 7.4 all demonstrated pH‐dependent membrane activity. At pH 5.5 they caused 50–60% haemoglobin (Hb) release over 1 h. This was slightly less than that seen for ISA 23 (80% Hb release). None of the copolymers were cytotoxic against B16F10 cells during a 72 h incubation (IC50 > 2 mg/ml; MTT assay). The ability of the random and block copolymer PAAs to deliver the toxin gelonin was also examined, but only ISA 1 and the block copolymer B2 (ISA 23:ISA 1 at a 2:1 molar ratio) were able to promote intracellular delivery, as measured by cytotoxic activity. It would be interesting to study the body distribution of B2 and determine whether this toxin‐delivering PAA is able to escape liver capture. magnified image

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Section: Resultsmentioning

confidence: 99%

Synthesis and Endosomolytic Properties of Poly(amidoamine) Block Copolymers

Lavignac

Lazenby

Foka

et al. 2004

Macromolecular Bioscience

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“…Although biologically active PAAs (Ferruti et al, 1973), PAA-based complexing agents (reviewed in Ferruti et al, 2002) and PAA drug conjugates have been described, relatively few PAA-peptide and PAA-protein conjugates have been synthesised. Ranucci et al (1995) described a PAA-albumin conjugate prepared using albumin as a macromonomer.…”

Section: Discussionmentioning

confidence: 99%

“…Synthesis of PAAs by hydrogen-transfer polyaddition of primary amines to bis-acrylamide has been well documented (Ferruti et al, 1973(Ferruti et al, , 2002Ferruti, 1996). The parent polymers ISA1 and ISA23 were synthesised and characterised by 1 H NMR as described previously (Richardson et al, 1999;Ferruti et al, 2000).…”

Section: Synthesis and Characterisation Of Paas And Paa-melittin Conjmentioning

confidence: 99%

Synthesis and preliminary evaluation of poly(amidoamine)–melittin conjugates as endosomolytic polymers and/or potential anticancer therapeutics

Lavignac

Lazenby

Franchini

et al. 2005

International Journal of Pharmaceutics

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The pH-responsive poly(amidoamine)s (PAAs) have been previously described. Whereas ISA23 enhances transfection in vitro and ISA1 promotes the cytosolic delivery of the non-permeant toxins this process shows poor efficiency. The aim of this study was to prepare and evaluate PAA conjugates containing the membrane disrupting peptide melittin (MLT). It was hypothesised that PAA conjugation would reduce the haemolytic activity of MLT at pH 7.4, however, upon delivery to tumours by the EPR effect, the polymer would uncoil in an acidic environment exposing MLT and allowing it to interact with membranes. PAA-MLT conjugates were prepared using MLT as a comonomer together with bis-acryloylpiperazine, 2-methylpiperazine and bis-hydroxyethylethylenediamine (ISA1-like), or bis-acrylamidoacetic acid and 2-methylpiperazine (ISA23-like). The melittin content of the conjugates was 6-19% (w/w). Although ISA1-MLT improved gelonin delivery compared to the parent polymer ISA1 (␣ 13-fold increase) and showed pH-dependent haemolytic activity at a polymer concentration of 0.05 mg/ml, this conjugate also displayed high haemolytic activity at pH 7.4. In contrast, ISA23-MLT like the parent compound ISA23 did not deliver gelonin. However, this conjugate could have potential as a novel polymeric anticancer conjugate due to its lack of haemolytic activity at pH 7.4 and retention of cytotoxicity.

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“…The use of polysoaps as matrix is reflected as well by functionalized polysoaps prepared for pharmaceutical applications [334], e.g. in form of copolymers with anticytostatica [335], or as polysoaps carrying targeting groups for drug delivery [336]. Other functional polysoaps are made for specific binding by bearing crown ethers [253-255] and saccharides.…”

Section: Functional Polysoapsmentioning

confidence: 99%

Molecular concepts, self-organisation and properties of polysoaps

Laschewsky

Polysoaps/Stabilizers/Nitrogen-15 NMR

223

126

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The article reviews water-soluble polymers characterized by surfactant side chains, and related amphiphilic polymers. Various synthetic approaches are presented, and rules for useful molecular architectures are given. Models for the self-organization of such polymers in water are presented comparing them with the micellization of low molecular weight surfactants. Highlighting key properties of aqueous polysoap solutions such as viscosity, surface tension and solubilization power, some structure-property relationships are established. Further, the formation of mesophases and of superstructures in bulk is addressed. Finally, the functionalization of polysoaps, and potential applications are discussed.

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Effects of a series of new synthetic high polymers on cancer metastases

Cited by 41 publications

References 4 publications

Synthesis and Endosomolytic Properties of Poly(amidoamine) Block Copolymers

Synthesis and Endosomolytic Properties of Poly(amidoamine) Block Copolymers

Synthesis and preliminary evaluation of poly(amidoamine)–melittin conjugates as endosomolytic polymers and/or potential anticancer therapeutics

Molecular concepts, self-organisation and properties of polysoaps

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