Poly(amido-amine)s: Biomedical Applications

Ferruti, Paolo; Marchisio, Marina; Duncan, Ruth

doi:10.1002/1521-3927(20020401)23:5/6<332::aid-marc332>3.0.co;2-i

Cited by 205 publications

(250 citation statements)

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“…The two polymer classes chosen, both featuring linear polyamide-type main chains, were (1) polyaspartamides derived from polysuccinimide by nucleophilic ring-opening steps, and (2) polyamidoamines obtained by Michael addition polymerization of bisacrylamides with primary and/or secondary amine comonomers. The polyaspartamides were pioneered in the 'Seventies by Neri and Antoni [54,55] and others [56][57][58], whereas Ferruti's laboratory [59,60] initiated and promoted work on the polyamidoamines. Subsequently, the two carrier classes were further developed by our group [61,62].…”

Section: Resultsmentioning

confidence: 99%

Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum

Komane

Mukaya

Neuse

et al. 2007

J Inorg Organomet Polym

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Cancerous diseases, together with cardiac afflictions, account for the predominant causes of death among the adult population of the Western world. The classical platinum drugs, with cisplatin as their parent, have established themselves for years as leading components in the oncologist's arsenal of antitumor agents. As with most other antineoplastic drugs, however, incisive pharmacological deficiencies, notably excessive systemic toxicity and induction of drug resistance, have severely curtailed their overall efficaciousness. With the objective of overcoming these counterproductive deficiencies, the technique of polymer-drug conjugation, representing an advanced modality of drug delivery, has been developed in recent years to high standards worldwide. In a drug conjugate, water-soluble macromolecular carrier constructs designed in compliance with stringent pharmacological specifications are covalently, yet bioreversibly, interconnected with the bioactive agent. As a macromolecule following a pharmacokinetic pathway different from that of non-polymeric compounds, the conjugate acts as a pro-drug favorably transporting the agent through the various body compartments to, and into, the target cell, where the agent is enzymatically or hydrolytically separated from the carrier for its biological action. In the authors' laboratories the conjugation strategy has been adopted as the primary tool for drug efficacy enhancement. The present paper describes a special type of platinum complex carrier-bound via dicarboxymetal chelation, synthesized from carboxyl-functionalized polyamide-type carriers by platination with trans-1,2-diaminocyclohexanediaquaplatinum(II) dinitrate. In a series of in vitro tests antiproliferative activities have been determined against several human cancer cell lines. Whereas no improvements are observed in tests against a colorectal cancer, outstanding findings of the screening program include a 10-to 100-fold increase in cell-killing performance of the conjugates relative to the (non-polymeric) cisplatin standard against the HeLa adenocarcinoma, and distinctly reduced resistance factors (again, relative to cisplatin) in tests against the A2780 and A2780-cis pair of ovarian cell lines. These findings augur well for future developments of this class of platinum drugs. This article is dedicated to Professor Astruc.

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Section: Resultsmentioning

confidence: 99%

Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum

Komane

Mukaya

Neuse

et al. 2007

J Inorg Organomet Polym

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“…Furthermore, each PAAs repeating units can be considered as separate molecules and though will behave nearly independently towards protonation. [1][2][3] Hence, the complex molecular architecture of the copolymers should induce no or little variation of the aminic nitrogen pKa values relative to the parent polymer ISA1 and ISA23 (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…However, the relationship does not always hold true when an excess bisacrylamide is used. [3] This makes it difficult to predict the polymerisation degree of a vinyl-terminated pre-polymer. The a,o-bisamino terminated ISA 1 and ISA 23 pre-polymers were used for the subsequent chain-extension step without isolation, using the same bisacrylamides used for the preparation of ISA 1 and ISA 23.…”

Section: Resultsmentioning

confidence: 99%

“…Poly(amidoamine)s (PAAs) are synthetic tert-amino polymers, which are produced by hydrogen transfer polyaddition of primary or secondary mono(amine)s to bis(acrylamide)s. [1][2][3] They are water-soluble, biodegradable and are less toxic [4,5] than other cationic polymers such as poly(L-lysine), [6] polyethyleneimine (PEI) [7] or poly (amidoamine) (PAMAM) dendrimers [8] all of which have been widely proposed as non-viral vectors. In aqueous solution, amino and amido groups arranged along the PAA polymeric chain confer moderate basicity to the polymer.…”

Section: Introductionmentioning

confidence: 99%

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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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“…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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Poly(amido-amine)s: Biomedical Applications

Cited by 205 publications

References 0 publications

Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum

Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum

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

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