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Relevant academic research and scientific papers

Multifunctional polymeric micelles for enhanced intracellular delivery of doxorubicin to metastatic cancer cells

Purposes. To develop multifunctional RGD-decorated poly(ethylene oxide)-b-poly(ester) based micelles and assess their pH-triggered core degradation and targeted drug release in tumor cells that overexpress RGD receptors. Methods. Novel poly(ethylene oxide)-b-poly(ε-caprolactone) (PEO-b-PCL) based copolymers modified with RGD ligands on PEO and pendent functional groups on PCL, i.e., GRGDS-PEO-b-poly(α-benzylcarboxylate- ε-caprolactone) (GRGDS-PEO-b-PBCL) and GRGDS-PEO-b-poly(α-carboxyl- ε-caprolactone) (GRGDS-PEO-b-PCCL), were synthesized. Chemical conjugation of doxorubicin (DOX) to PCCL core produced GRGDS-PEO-b-P(CL-DOX) micellar conjugates, while GRGDS-PEO-b-PBCL were used to physically encapsulate DOX. For both systems, micellar core degradation, drug release, intracellular drug uptake/disposition, and cytotoxicity against B16F10 metastatic cells were investigated. Results. The PBCL and P(CL-DOX) cores were found resistant to degradation in pH 7.2, but showed 10% and 40% loss in core molecular weight in pH 5.0 within 144 h, respectively. Preferential release of DOX and DOX derivatives from PBCL and P(CL-DOX) cores was noted in pH 5.0, respectively. The GRGDS-modified micelles showed enhanced cellular internalization through endocytosis, increased intracellular DOX release, nuclear localization, and improved cytotoxicity against metastatic B16F10 cells compared to their unmodified counterparts. Conclusions. The results clearly suggest a promise for the development of multifunctional polymeric micelles with RGD ligand decorated shell and endosomal pH-triggered degradable core for selective DOX delivery to metastatic cancer cells.

Synthesis and evaluation of functional carboxylic acid based poly(εCL-st-αCOOHεCL)-b-PEG-b-poly(εCL-st-αCOOHεCL) copolymers for neodymium and cerium complexation

Original carboxylic acid-based copolymers have been developed for the complexation of actinides. For such purpose, ring-opening copolymerizations of α-benzyl carboxylate-ε-caprolactone (BzCL) and ε-caprolactone (εCL) have been carried out with poly(ethylene glycol) (PEG) as macro-initiator and tin(II) octanoate, as catalyst, to afford poly(εCL-st-αBzεCL)-b-PEG-b-poly(εCL-st-αBzεCL) (PB) copolymers. Three different εCL/BzCL ratios were targeted (90/10, 75/25 and 50/50), leading to PB10%, PB25% and PB50%, respectively. Then, hydrogenation of the prepared copolymers allowed the deprotection of benzyl esters to carboxylic acids groups, leading to poly(εCL-st-αCOOHεCL)-b-PEG-b-poly(εCL-st-αCOOHεCL) copolymers (PA10%, PA25% and PA50%). All materials were fully characterized by 1H NMR, 13C NMR and size exclusion chromatography. Experimental ratios were found to be close from theoretical ones as equal to 92/08, 75/25, and 60/40. Molecular weight was the same for all copolymers (4000 g.mol?1). Complexing properties of the different copolymers were studied by Isothermal Titration Calorimetry (ITC) with neodymium (Nd(III)) and cerium (Ce(III)), used as actinide surrogates. ITC enabled the determination of the full thermodynamic profile (ΔG, ΔH, TΔS, Ka, and stoichiometry). The results showed that PA25% was the polymer with the highest sorption capacity (13.6 mg.g?1 for Nd(III) and 13.7 mg.g?1 for Ce(III)) and the highest binding constant (8500 M?1 and 5500 M?1 for Nd(III) and Ce(III), respectively). This demonstrated that by increasing the amount of complexing carboxylic acid functions, the complexing capacity did not necessarily increase as well, reaching a maximum with PA25%. In a more general manner, all developed copolymers are very promising for cation complexation.