Cyclodextrin polymers as carriers for the platinum-based anticancer agent LA-12

Abstract

Polymeric nanoparticles containing cyclodextrins are currently undergoing clinical trials as nanotherapeutics. In this context, we have synthesized high and low molecular weight β-cyclodextrin polymers and functionalized them with folate to improve their selectivity for cells overexpressing the folic acid receptor. Inclusion complexes of the unfunctionalized and FA-functionalized polymers with the antitumour complex cis-trans-cis-[PtCl2(CH3CO2)2(adamantyl-NH2)(NH3)] (LA-12) have been tested on tumour cells. In the presence of the high molecular weight polymers, LA-12 exhibited IC50 values significantly lower than that of LA-12 alone in MDA-MB-231 cells. The drug nanocarriers investigated do not appear to take significant advantage of the presence of folate residues, possibly because of the reduced accessibility of folate included in cyclodextrin moieties by the receptor or low degree of functionalization of the polymers. However the non-covalent approach, based on inclusion complexes with cyclodextrin polymers, looks very promising for improving the performance of LA-12

Aminocyclodextrin Oligomers as Protective Agents of Protein Aggregation

“…The poly-merization reaction was performed under basicc onditions using epichlorohydrin (ECH) as the crosslinking reagent. [38,39] The low ECH/monomer ratio (ECH/CyD = 5) ensured the reaction productsw ere oligomers. After Boc deprotection, the product was isolated.…”

“…[37] Recently, we have synthesized functionalized oligomers of b-CyD as drug carriers of the anionic drug diclofenac [38] ando ft he hydrophobic drug LA-12. [39] Inspired by the properties of multicavity systemsand the importanceo fa mino groups in am olecule to exhibit an antiaggregant action, [40] in this work we studied,f or the first time, oligomers of b-CyD as anti-Ab-aggregationa gents. In particular,w esynthesized and assayed the new co-oligomero f6 -(6aminohexyl)amino-6-deoxy-b-cyclodextrin and b-CyD (oCyDH-DA), and the oligomers of b-CyD (oCyD) [39] and 3-amino-3deoxy-b-CyD (oCyDNH 2 ) [38] as antiaggreganta gentst os tudy the effects of multicavity systemsa nd their amino functionalization ( Figure 1).…”

“…[39] Inspired by the properties of multicavity systemsand the importanceo fa mino groups in am olecule to exhibit an antiaggregant action, [40] in this work we studied,f or the first time, oligomers of b-CyD as anti-Ab-aggregationa gents. In particular,w esynthesized and assayed the new co-oligomero f6 -(6aminohexyl)amino-6-deoxy-b-cyclodextrin and b-CyD (oCyDH-DA), and the oligomers of b-CyD (oCyD) [39] and 3-amino-3deoxy-b-CyD (oCyDNH 2 ) [38] as antiaggreganta gentst os tudy the effects of multicavity systemsa nd their amino functionalization ( Figure 1). We comparedt heir activity to that of ac ommerciallya vailable b-CyD polymer (pCyD) and of per-6-amino-CyD (CyD(NH 2 ) 7 ).…”

Cyclodextrins as Protective Agents of Protein Aggregation: An Overview

“…[29] Upon adding bCyD to the peptide, the CD spectrum suggested random coil structure, which was maintained even if the sample was kept at room temperature for 1week. This fact indicatedt hat bCyD inhibited conformational changes in Ab (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) from random coil to b sheet in solution.T he role of bCyD was correlated to its ability to include the Phe19 and Phe20 side chains, which thusi nhibited aggregation.P he19 interactions have ak ey role in the formation of Ab oligomers and fibrils. [30] Twoy ears later,n ew studies on the interactions between Ab-peptide, full length as well as fragments of various sizes, and a-, b-, or gCyD were performed through NMR diffusion studies and 1 HNMR chemical shiftanalysis.…”

“…[6][7][8][9] In particular,C yDs have mainlyb een used in pharma as drug-deliverys ystems to improvet he solubility and bioavailability of drugs. [10][11][12][13] The properties of CyD can be modulated through their chemical modifications. In fact, covalent conjuga-tion of molecules with different properties provides an attractive approach to build multifunctional systemsa nd fascinating compounds, including enzyme mimics, sensors, and drug carriers.…”