No abstract

Glycopolymers have been synthesised by post-functionalisation of well-defined alkynefunctional polymers with sugar azides to yield N-glycosyl 1,2,3-triazole functional polymers. The Cu(I)-catalysed Huisgen cycloaddition was used to attach a-mannoside, bgalactoside and b-lactoside derivatives via an azide functionality bound directly to the sugar anomeric carbon. Three different catalytic systems were investigated for the click reactions; [(PPh 3 ) 3 Cu(I)Br], TBTA/Cu(I)Br and bathophenanthrolinedisulphonic acid disodium salt/Cu(I)Br. The latter of these was found to be the most efficient for the attachment of the larger/more sterically hindered disaccharide lactose moiety. The interaction of the lactose-and galactose-bearing glycopolymers with Ricinus Communis Agglutinin (RCA I) lectin was investigated by affinity HPLC analysis. The rate of the interaction between mannose polymer and concanavalin A (Con A) lectin was assessed by turbidimetry. The results from the lectin conjugation studies indicate that the glycopolymers prepared in this work are able to function as multivalent ligands, further suggesting that the attachment of the triazole directly to the sugar anomeric carbon has no significant effect on the interaction of these glycopolymers with Con A and RCA I.

Recent advances in polymerization strategies have led to the development of novel polymer-(poly)peptide biohybrid materials with potential application in the field of macromolecular therapeutics. In this current work, comb-shaped a-aldehyde poly(monomethoxy polyethylene glycol)methacrylates (p(mPEG)MA) with molecular masses in the 6.5-109 kDa range were prepared and conjugated, via reductive amination, to the Cys1 N-terminus of salmon calcitonin (sCT), a calcitropic hormone currently administered for the treatment of a number of hypercalcaemia-related diseases. The conjugation site was determined by tryptic digestion of the sCT-p(mPEG 1100 )MA biohybrids in conjunction with LC-MS MALDI-TOF spectrometry. Preliminary in vitro biological tests show that the polymer conjugation does not interfere with the biological activity of the sCT.

Targeted delivery of potent cytotoxic drugs to cancer cells minimizes systemic toxicity and several side effects. NHC*−Au−Cl has already been proven to be a potent anticancer agent. In this study, we explore a strategy based on chemoselective cysteine conjugation of NHC*−Au−Cl to albumin and trastuzumab (Thiomab LC‐V205C) to potentiate drug‐ligand ratio, pharmacokinetics, as well as drug efficacy and safety. This strategy is a step forward towards the use of gold‐based anticancer agents as targeted therapies.

Salmon calcitonin (sCT) was conjugated via cysteine-1 to novel combed-shaped endfunctionalised poly(PEG) methyl ether methacrylate) (sCT-P) comb-shaped polymers, to yield conjugates of total molecular weights (MW) inclusive of sCT: 6.5, 9.5, 23 and 40 kDa. The conjugates were characterised by HPLC and their in vitro and in vivo bioactivity was measured by cAMP assay on human T47D cells and following intravenous (i.v.) injection to rats, respectively. Stability against endopeptidases, rat serum and liver homogenates was assessed. There were linear and exponential relationships between conjugate MW with potency and efficacy respectively, however the largest MW conjugate still retained 70% of E max and an EC 50 of 3.7 nM. In vivo, while free sCT and the conjugates reduced serum [calcium] to a maximum of 15-30 % over 240 min, the half life (T½) was increased and the area under the curve (AUC) was extended in proportion to conjugate MW. Likewise, the polymer conferred protection on sCT against attack by trypsin, chymotrypsin, elastase, rat serum and liver homogenates, with the best protection afforded by sCT-P (40 kDa). Mathematical modelling accurately predicted the MW relationships to in vitro efficacy, potency, in vivo PK and enzymatic stability. With a significant increase in T½ for sCT, the 40 kDa MW comb-shaped PEG conjugate of sCT may have potential as a long-acting injectable formulation.

No abstract