The efflux pump inhibitory properties of (thiolated) polyallylamines

In Vitro and In Vivo Anticancer Activity of a Novel Nano-sized Formulation Based on Self-assembling Polymers Against Pancreatic Cancer

“…The cross-linked polyallylamine (PAA) has been used clinically as an oral phosphate binder (23); however, hydrophobically modified PAA as a delivery system for hydrophobic drugs has not been reported before. Furthermore, the use of modified PAA for biomedical application includes attachment of hydrophilic moiety (methyl glycolate) (24) or histidine to PAA for gene delivery (25), and the use of thiolated PAA as an intestinal permeation enhancer (26). None of the work thus far has attempted to attach a cholesteryl pendant group to PAA for hydrophobic drug delivery.…”

Synthesis, characterisation and in vitro evaluation of novel thiolated derivatives of polyallylamine and quaternised polyallylamine

“…This contributed to the relatively low levels of thiolation observed in Paa/QPaa-NAC conjugates as can be seen from Table 1. The relatively low coupling efficiency of the EDAC-mediated thiolation process has previously been reported by other research groups [25,27] working on the thiolation of similar polycations using EDAC concentrations ranging between 25-200mM and has been attributed to a side reaction of EDAC with the nucleophilic thiolate anion that results in the formation of an adduct that is subsequently hydrolysed to one of the reaction by-products, urea [32]. In contrast, the reaction of Paa/QPaa with 2-iminothiolane was observed to proceed with greater efficiency considering the relatively high levels of sulphydryl groups substitution obtained for TBA conjugates (table 1) .…”

“…Each thiomer (10mg) was dissolved in 1ml of deionised water acidified with a drop of 2M HCl. 1% starch indicator (300µl) was added into the polymer solution before titrating the solution with a 1mM iodine solution until a permanent blue colour characteristic of the iodine-starch complex was observed [27]. The amount of thiol groups (in mols) per gram polymer was estimated from a calibration plot prepared from titrating iodine against increasing concentrations (2-100mgml -1 ) of an N-acetylcysteine reference standard (R 2 = 0.99).…”

“…[27]. A 1ml solution (1mgml -1 ) of each thiomer in tris buffer pH 7.4 was prepared in a glass vial and mixed with 4% sodium borohydride solution (2ml) and the reaction incubated at 37°C for 1hour in a shaking water bath.…”

“…The reaction was also carried out under nitrogen and at pH 4.5 to limit air or pH-induced oxidation of thiol groups to the reactive thiolate anion S -resulting in the formation of intramolecular disulphide bond formation [31]. An N-acylated amino acid was used during the reaction to prevent the occurrence of unwanted side reactions resulting in the formation of oligo/poly cysteine conjugates [27]. After lyophilisation, all polymer conjugates appeared as white, powders of fibrous structure which were readily soluble over a wide pH range (3)(4)(5)(6)(7)(8).…”