Polyproline-Polyornithine Diblock Copolymers with Inherent Mitochondria Tropism
Mitochondria play critical roles in regulating cell fate, with dysfunction correlating with the development of multiple diseases, emphasizing the need for engineered nanomedicines that cross biological barriers. Said nanomedicines often target fluctuating mitochondrial properties and/or present inef...
| Autores: | , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Centro de Investigación Principe Felipe (CIPF) |
| Repositorio: | r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF) |
| OAI Identifier: | oai:cipf.fundanetsuite.com:p4565 |
| Acceso en línea: | https://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=4565 |
| Access Level: | acceso abierto |
| Palabra clave: | cardiolipin-specific mitochondrial targeting design of experiments (doe) membrane remodeling mitochondrial tropism polypeptide-based nanoconjugates polyproline, subcellular organelle targeting |
| Sumario: | Mitochondria play critical roles in regulating cell fate, with dysfunction correlating with the development of multiple diseases, emphasizing the need for engineered nanomedicines that cross biological barriers. Said nanomedicines often target fluctuating mitochondrial properties and/or present inefficient/insufficient cytosolic delivery (resulting in poor overall activity), while many require complex synthetic procedures involving targeting residues (hindering clinical translation). The synthesis/characterization of polypeptide-based cell penetrating diblock copolymers of poly-L-ornithine (PLO) and polyproline (PLP) (PLOn-PLPm, n:m ratio 1:3) are described as mitochondria-targeting nanocarriers. Synthesis involves a simple two-step methodology based on N-carboxyanhydride ring-opening polymerization, with the scale-up optimization using a "design of experiments" approach. The molecular mechanisms behind targetability and therapeutic activity are investigated through physical/biological processes for diblock copolymers themselves or as targeting moieties in a poly-L-glutamic (PGA)-based conjugate. Diblock copolymers prompt rapid cell entry via energy-independent mechanisms and recognize mitochondria through the mitochondria-specific phospholipid cardiolipin (CL). Stimuli-driven conditions and mitochondria polarization dynamics, which decrease efficacy depending on disease type/stage, do not compromise diblock copolymer uptake/targetability. Diblock copolymers exhibit inherent concentration-dependent anti-tumorigenic activity at the mitochondrial level. The diblock copolymer conjugate possesses improved safety, significant cell penetration, and mitochondrial accumulation via cardiolipin recognition. These findings may support the development of efficient and safe mitochondrial-targeting nanomedicines. |
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