Controlled Synthesis of Camptothecin−Polylactide Conjugates and Nanoconjugates

Abstract

We report here a unique method of formulating camptothecin-polylactide (CPT-PLA) conjugate nanoparticles, termed nanoconjugates (NCs), through CPT/(BDI)ZnN(TMS) 2 [(BDI) = 2-((2,6-diisopropylphenyl)amido)-4-((2,6-bisalkyl)-imino)-2-pentene] mediated polymerization of lactide (LA) followed by nanoprecipitation. When CPT was used as the initiator to polymerize LA in the presence of (BDI)ZnN(TMS) 2 , the polymerization was complete within hours with nearly 100% CPT loading efficiency and 100% LA conversion. CPT loading as high as 19.5% can be achieved for the CPT-polylactide (CPT-PLA) conjugate prepared at a LA/CPT ratio of 10. The steric bulk of the chelating ligands and the type of metals used had a dramatic effect on the initiation of the LA polymerization and the tendency of the ring opening of the CPT lactone. The CPT/(BDI)ZnN (TMS) 2 -mediated LA polymerization yielded CPT-PLA conjugates with well controlled molecular weights and narrow molecular weight distributions (1.02-1.18). The nanoprecipitation of CPT-PLA led to the formation of NCs around 100 nm in size with narrow particle size distributions. Sustained release of CPT from CPT-PLA NCs was achieved without burst release. CPT-PLA NCs were toxic to PC-3 cells with tunable IC 50 possible by adjusting the drug loading of the CPT-PLA NCs.

Evaluation of the cytotoxic effect of camptothecin solid lipid nanoparticles on MCF7 cells

“…Once placed in an aqueous solution at physiological pH, the lactone form of CPT is quickly transformed to its carboxylate form, which is highly toxic and therapeutically inactive. These pharmacological properties of CPT result in rapid deactivation and fast clearance from the circulation after it is intravenously administered (Tong & Cheng, 2010). To overcome these drawbacks, CPT analogs and prodrugs have been developed (Lansiaux et al, 2007).…”

“…Other alternatives for enhancing the therapeutic efficacy of CPT involve its conjugation onto various polymeric carriers which improved solubility, stability of its lactone form and reduced renal clearance (Tong & Cheng, 2010). Other alternatives include PEGylated polymers, liposomal particles, mesoporous silica nanoparticles or albumin-based nanoparticles (Schmid et al, 2007;Botella et al, 2011).…”

Hydroxyethyl starch–10-hydroxy camptothecin conjugate: synthesis, pharmacokinetics, cytotoxicity and pharmacodynamics research

“…It has been reported that the substitution on 20-OH group of 10-HCPT can substantially reduce the tendency for lactone ring opening and increase the solubility, and a variety of conjugates that link 10-HCPT via 20-OH group have been performed, including PEG-camptothecin conjugate, polyglutamate-camptothecin conjugate, PEG-SN38 conjugate and PAMAM-camptothecin conjugate, some of them have entered into the phase of clinical research (Bhatt et al, 2003;Cheng et al, 2004;Fleming et al, 2004;Samor et al, 2008;Joralemon et al, 2010;Tong & Cheng, 2010). Except improving the solubility and stability of 10-HCPT, polymer conjugate can also prolong circulation time through avoiding rapid clearance by the renal and reticuloendothelial systems (RES), decrease side effects, passive target tumor tissues via the enhanced permeability and retention (EPR) effect and improve bioavailability (Li & Wallace, 2008;Maeda et al, 2009;Torchilin, 2011).…”

Les nanoparticules polymères pour la délivrance de principes actifs anticancéreux

“…Même si les voies de synthèses proposées pour les deux premières méthodes (grafting to et grafting through) sont relativement complexes, le phénomène de burst release est absent et les taux de chargement en principe actif peuvent être augmentés. La troisième méthode (le principe actif amorceur) permet, quant à elle, de combiner simplicité et efficacité dans la mesure où un nombre minimal d'étapes de synthèse est requis et où des taux de chargement en principe actif élevés (> 30 % massiques) sont obtenus lorsque les chaînes de polymère sont courtes [44][45][46][47]. Les conjugués obtenus peuvent également être incorporés dans d'autres systèmes nanoparticulaires [48] ou utilisés comme conjugués solubles si un polymère hydrophile est synthétisé ( Figure 5C) [49], offrant ainsi une large gamme de modalités d'action.…”