Synthesis, characterisation and antitumour activity of platinum(II) complexes of novel functionalised poly(amido amine)s

Abstract

SUMMARY: Polyamidoamine polymers were prepared by hydrogen-transfer polyaddition of 2-methylpiperazine to 2,29-bis(acrylamido)acetic acid sodium salt to yield PAA-1, polyaddition of amino-b-cyclodextrin and 2-methylpiperazine to 2,29-bis(acrylamido)acetic acid to give PAA-2 and polyaddition of the same amino-bcyclodextrin and 2-methylpiperazine to 1,4-bis(acryloyl)piperazine to produce PAA-3. These polymers were reacted with cisplatin to give products containing between 8 -70 wt.-% platinum. The amount of platinum released from the conjugates during incubation at pH 5.5 and pH 7.4 varied between 0 -20%/72 h. PAA-3-Pt showed pH-dependent platinum release. The PAA-platinates were generally less toxic towards lung tumour cell lines in vitro. The IC 50 for cisplatin being 2 -5 lg/mL and for the PAA-platinates 1 -130 lg/mL, this was only to be expected due to their very different cellular pharmacokinetics. In vivo experiments showed that the PAA-1-Pt and PAA-2-Pt were equi-active compared with cisplatin against an i.p. L1210 leukaemia model, confirming their ability to liberate biologically active platinum species. Whereas PAA-1-Pt was significantly less toxic than cisplatin, PAA-2-Pt did show toxicity on repeated dosing, suggesting further investigations are needed to establish the biocompatibility of PAAs containing pendant b-cyclodextrin. PAA-1-Pt is suitable for further in vivo preclinical study in a range of solid tumour models.

Anionic linear-globular dendrimer-cis-platinum (II) conjugates promote cytotoxicity in vitro against different cancer cell lines

“…24 The ultimate cytotoxic actions of many types of these conjugates are met when they are used in vivo as an example the polymer-drug conjugates are very stable and not able to release the specified drug when they are inside the tumor cell environment for their final action. 25 In this study we have shown the synergistic toxic effect of the anionic linear-globular dendrimers (with terminal citric acid groups) conjugated to the surface of cisplatin.…”

Synthesis and Endosomolytic Properties of Poly(amidoamine) Block Copolymers

“…2-Methylpiperazine (2-MePip) was also obtained from Fluka but was recrystallised from hexane, its purity was determined titrimetrically before use. 2,2-Bis(acrylamido)acetic acid (BAC) and bisacryloylpiperazine (PB) were synthesised as previously described, [18,19] and their purity was determined titrimetrically (BAC) or by NMR (BP) just before use.…”

Polyamidoamine Nanoparticles as Nanocarriers for the Drug Delivery to Malaria Parasite Stages in the Mosquito Vector

“…administration in mice, with different grades of toxicity and activity, although none of them were active against the primary tumour [49]. More recently, PAAs have been adopted as carriers for anticancer drugs such as mytomycin C [50], platinates [51] and doxorubicin. Conjugation of doxorubicin to polymers improves drug solubility, increases its blood half-life, decreases its toxicity, and mediates more efficient tumour targeting [52].…”

“…It is a rather weak polymeric base with, on average, 0.55 positive charges per unit at pH 7.4. All these polymers had been reported as vectors for the intracellular delivery of nucleic acids [56,61,71], whereas ISA1 and ISA23 had been also studied for protein delivery [45,62,71] and as anticancer drug carriers [51,53]. ISA23 in particular has been proven to be endowed with stealth-like properties without selectively concentrating in the liver [44], while a significant portion of AGMA1 did show hepatic localization after intravenous injection in mice [42].…”