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 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) (PLO<sub>n</sub>-PLP<sub>m</sub>, 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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Publication Details

Journal
Advanced Materials
Published
2025-01-10
DOI
https://doi.org/10.1002/adma.202411595
Citations
11
Primary Topic
Advanced biosensing and bioanalysis techniques
Type
article
Field-Weighted Citation Impact
8.87

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article

Polyproline‐Polyornithine Diblock Copolymers with Inherent Mitochondria Tropism

Pavel Arsenyan, Pāvels Dimitrijevs, Svetozar Gavrilović, Esther Masiá et al.
11 citations
Advanced Materials
Advanced biosensing and bioanalysis techniques
8.87
article

Polyproline‐Polyornithine Diblock Copolymers with Inherent Mitochondria Tropism

Pavel Arsenyan, Pāvels Dimitrijevs, Svetozar Gavrilović, Esther Masiá, Inmaculada Conejos‐Sánchez, Ekaterina Karpova, Yusuf Qutbuddin, Carles Felip‐León, Aroa Duro‐Castaño, Maria Jesus Vicent, Petra Schwille, Cristián Huck‐Iriart, Camilla Pegoraro
article en
11 citations

Abstract

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) (PLO<sub>n</sub>-PLP<sub>m</sub>, 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.

Advanced MaterialsVol. 37(8)
Instituto de Salud Carlos III (ES), ALBA Synchrotron (Spain) (ES), Latvijas Organiskās Sintēzes Institūts (LV), Max Planck Institute of Biochemistry (DE), Centro de Investigación Biomédica en Red de Cáncer (ES), Centro de Investigacion Principe Felipe (ES)
Australian Government, International Max Planck Research School for Environmental, Cellular and Molecular Microbiology, Bundesministerium für Bildung und Forschung, Fundación Científica Asociación Española Contra el Cáncer, Generalitat Valenciana, Universitat de València, Ministerio de Ciencia e Innovación, International Max Planck Research School for Advanced Methods in Process and Systems Engineering, Horizon 2020 Framework Programme, HORIZON EUROPE Framework Programme, European Regional Development Fund, Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana, H2020 Marie Skłodowska-Curie Actions, HORIZON EUROPE Reforming and enhancing the European Research and Innovation system
Openalex Percentile: Top 2%
Advanced biosensing and bioanalysis techniques
8.87
DOIOpen Access PDFOpenAlex
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