Polyproline-Polyornithine Diblock Copolymers with Inherent Mitochondria Tropism
Por:
C. PEGORARO, E. KARPOVA, Y. QUTBUDDIN, E. SANCHIS, P. DIMITRIJEVS, C. HUCK-IRIART, S. GAVRILOVIC, P. ARSENYAN, P. SCHWILLE, C. FELIP-LEÓN, A. DURO-CASTANO, I. CONEJOS-SANCHEZ and M. VICENT
Publicada:
1 feb 2025
Ahead of Print:
1 ene 2025
Resumen:
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.
Filiaciones:
:
Principe Felipe Res Ctr, Polymer Therapeut Lab, Valencia 46012, Spain
E. KARPOVA:
Curapath, Ave Benjamin Franklin 19, Paterna 46980, Valencia, Spain
Y. QUTBUDDIN:
Max Planck Inst Biochem, Klopferspitz 18, D-82152 Martinsried, Germany
:
Principe Felipe Res Ctr, Polymer Therapeut Lab, Valencia 46012, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Canc CIBERONC, Madrid 28029, Spain
Principe Felipe Res Ctr, Screening Platform, Valencia 46012, Spain
P. DIMITRIJEVS:
Latvian Inst Organ Synth, Aizkraukles St 21, LV-1006 Riga, Latvia
C. HUCK-IRIART:
ALBA Synchrotron Light Source, Expt Div, Cerdanyola Del Valles 08209, Spain
S. GAVRILOVIC:
Max Planck Inst Biochem, Klopferspitz 18, D-82152 Martinsried, Germany
P. ARSENYAN:
Latvian Inst Organ Synth, Aizkraukles St 21, LV-1006 Riga, Latvia
P. SCHWILLE:
Max Planck Inst Biochem, Klopferspitz 18, D-82152 Martinsried, Germany
C. FELIP-LEÓN:
Curapath, Ave Benjamin Franklin 19, Paterna 46980, Valencia, Spain
:
Curapath, Ave Benjamin Franklin 19, Paterna 46980, Valencia, Spain
:
Principe Felipe Res Ctr, Polymer Therapeut Lab, Valencia 46012, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Canc CIBERONC, Madrid 28029, Spain
:
Principe Felipe Res Ctr, Polymer Therapeut Lab, Valencia 46012, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Canc CIBERONC, Madrid 28029, Spain
Principe Felipe Res Ctr, Screening Platform, Valencia 46012, Spain
Green Submitted, hybrid
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