and its substituents can strongly affect the lability and stability of the hydrazone bond formed. Recent progress have been made to accelerate the formation of hydrazone bonds notably by improving the rate and the versatility of the condensation. This aimed to propose more efficient bioconjugation of molecules (that should possess either a carbonyl moiety or an alphanucleophile group) such as reducing sugars, peptides or proteins. In the context of the "grafting to" approach, the main strategy to introduce hydrazone linkers into prodrugs is based on the conjugation between a drug, containing a ketone or an aldehyde group, and a polymer functionalized with hydrazine moieties via hydrazinolysis of ester groups or acylhydrazine formation. If no functional group is available on the drug molecule, a ketone or an aldehyde group can be grafted onto the polymer via hydrazone linkage prior to drug conjugation, such as a diamino-ketone ligand in the case of platinum (Pt). Direct grafting of Dox to a polymer scaffold to produce pH-sensitive polymer prodrug nanoparticles can be achieved from poly(2-methacryloyloxyethyl phosphorylcholine)-co-2-tertbutoxy-2-oxoethyl methacrylate) (P(MPC-co-TBOEMA)) random copolymers obtained by ATRP (Figure ). After ester-to-acyl hydrazine conversion, using hydrazine hydrate, Dox conjugation was carried out to achieve the corresponding pH-sensitive PMPC-b-TBOEMAhyd-Dox polymer prodrug with 15-45 wt % drug loading and 7-15 nm in diameter depending on the Dox content. The Dox release was pH-dependent, with half-life time ranging from 2 to 40 h at pH 5, and cell internalization experiments showed that the higher the drug loading, the higher the intracellular internalization and the cytotoxicity. In addition, the polymer prodrug with 30 wt % drug loading exhibited maximum tolerated doses in the range of 30-50 mg.kg -1 Dox equiv in mice. A very similar post-polymerization approach was carried out via the synthesis of poly (2-(methacryloyloxy)ethyl choline phosphate)-block-poly(2-methoxy-2-oxoethyl methacrylate) (PMCP-b-PMEMA) by ATRP (Figure ). 69 Subsequent hydrazinolysis of MEMA moieties in the presence of hydrazine hydrate, enabled conjugation of Dox under acidic conditions, resulting in PMCP-b-PMEMA-hyd-Dox polymer prodrug aggregates of 180 nm in diameter and 10 wt % drug loading. Dox release was shown to be pH-dependent as only ~6 % of Dox was released at pH 7.4 whereas ~60 % was released at pH 5 after 65 h. This polymer prodrug was also efficiently internalized by MCF-7 breast cancer cells within 1 h and appeared to be cytotoxic on three different cancer cell lines (MCF-7, A549, HepG2) while the drug-free copolymer showed good cytocompatibility. Surprisingly, despite a small structural difference in monomer structure (MCP vs. MPC and MEMA vs. TBOEMA) between these two studies, significant differences in drug loadings (15-45 wt % vs. 10 wt %, respectively) were obtained. ethyl acrylamide) (POEGMA-b-P(MAH-co-Rh6GEAm)) amphiphilic diblock copolymer to which Dox was grafted through an acylhydrazone bond. The copolymer was able to self-assemble into micelles of 50 nm in diameter, with enhanced Dox release at pH 5 (73 %) and pH 6.5