Hybrid block and graft copolymers made from macrolactones and a-amino acids for applications as drug delivery nanosystems
- Autores: Ernesto Tinajero Díaz
- Directores de la Tesis: Sebastián Muñoz Guerra (dir. tes.), Antxon Martínez de Ilarduya Sáez Asteasu (dir. tes.)
- Lectura: En la Universitat Politècnica de Catalunya (UPC) ( España ) en 2019
- Idioma: español
- Tribunal Calificador de la Tesis: Virginia Cádiz Deleito (presid.), Jordi J. Bou Serra (secret.), Xavier Ramis Juan (voc.), Abdelilah Alla Bedahnane (voc.), María Violante de Paz Báñez (voc.)
- Programa de doctorado: Programa de Doctorado en Polímeros y Biopolímeros por la Universidad Politécnica de Catalunya
- Materias:
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- Resumen
Naturally produced peptides or proteins can be regarded as highly refined polymers. When synthetic polymers are married to proteins or peptides, the resulting bioconjugates can synergistically combine the properties of the individual components and overcome their separate limitations. This Thesis is focused on the study of hybrid copolymers based on polypeptides and polymacrolactones. Block and graft copolymers have been synthesized by making use of the ring opening polymerization method (ROP) mainly and extensively characterized including both their chemical structure and their structure in the solid state. The self-assembly properties of the new copolymers have been preliminary examined regarding their potential application as nanocarriers for pharmaceutical compounds.
This Thesis initially reports the ROP of w-pentadecalactone (PDL) using different amino-ended initiators and assisted by either organic or enzymatic catalysts. This method was then extended for the ROP of PDL using bisamino-ended poly(ethylene glycol) (PEG) for the preparation of poly(w-pentadecalactone)-b-poly(ethylene glycol)-b-poly(wpentadecalactone) [PPDLx-PEG-PPDLx] triblock copolymers. These amphiphilic ABA-type copolymers were able to selfassemble in water to form nanoparticles with diameters between 100 and 200 nm.
Hybrid copolymers of poly(ester-peptide) or poly(ether-ester-peptide) type exhibiting different architectures (e.g. diblock, triblock, graft or triblock/grafted) respectively, were then synthesized using as building blocks: poly(w-pentadecalactone), poly(globalide) (PGl), PEG as well as polypeptides derived from the L-glutamic acid (Glu), L-lysine (Lys), L-alanine (Ala) and L-phenylalanine (Phe) a-amino acids. The hybrid copolymers were synthesized through several stages depending on the desired architecture. The first stage in the preparation of these copolymers was the synthesis of macroinitiators from PDL or PGl containing either an amino group at the end of the chain or multiple amine groups along their polymeric chain. In the second stage, such macroinitiators were used to trigger the polymerization of the a-amino acid N-carboxyanhyrides (NCA) with the COOH group of L-glutamic acid and NH2 of L-lysine duly protected as g-benzyl-L-glutamate (BLG) and eNcarbobenzoxy-L-lysine (ZLL) respectively. Some copolymers containing BLG or ZLL units were treated with acids to render copolymers bearing the amino acids residues with their COOH or NH2 functionalities in the free form.
All of the synthesized copolymers were fully characterized through GPC and NMR spectroscopy. The thermal properties were studied by TGA and DSC techniques. The conformation adopted by the peptide-based copolymers in the solid-state was assessed by FTIR, and their crystalline structure was examined by X-ray diffraction using synchrotron radiation in most cases. The conformation in aqueous solution of water-soluble copolymers containing Glu or Lys residues in the free form was explored by circular dichroism.
The self-assembly behavior in aqueous medium of all the amphiphilic copolymers was investigated with the purpose of obtaining nanoparticles with the appropriated diameters required for their application as biomedical nanocarriers. The nanoparticles were duly characterized by light scattering and SEM and TEM microscopies. Block and graft copolymers were able to load doxorubicin and release it under pH control. Copolymers containing L-lysine were shown to be able of condensing DNA. The potential of these copolymers as DDS of anticancer drugs and vectors for transfection have been evidenced.
