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<p>Wilson disease (WD), a rare autosomal-recessive disorder caused by impaired copper metabolism, leads to hepatic dysfunction and copper overaccumulation, debilitating neurological symptoms. Current treatments, primarily metal chelating agents and antioxidants, have limitations like sub-optimal efficacy, limited blood–brain barrier transport, and systemic side effects. This study aims to deliver monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA), a novel next-generation chelator encapsulated in a liposomal nanocarrier coated with apolipoprotein E (ApoE) to enhance brain targeting and copper chelation. ApoE-coated liposomal formulation is optimized using the Box-Behnken design (BBD). This was followed by comprehensive characterization like dynamic light scattering, scanning electron microscopy, drug-excipient compatibility studies, and in vitro drug release kinetics. Additionally, the developed formulation was investigated on the human neuroblastoma cells (SH-SY5Y) demonstrating safety, biocompatibility, and cell internalization efficacy within 24 h. Bioimaging studies further demonstrated significant brain permeability of the ApoE-coated MiADMSA liposomes, comparable to uncoated MiADMSA liposomes, followed by pharmacodynamic evaluations. Morphometric analysis, behavioral studies, biochemical estimations, and histopathological assessments confirmed the efficacy of ApoE-coated MiADMSA liposomes. The optimized formulation demonstrated sustained release, excellent encapsulation efficiency of up to 90.29%, and a nanosized spherical shape (141.3 ± 1.26 nm). Effective internalization, biocompatibility, and neuroprotection were validated by cellular investigations. ApoE-MiADMSA-LPS showed notable BBB penetration in in vivo imaging. Biochemical examination indicated less oxidative stress (lower MDA, higher SOD, CAT, and GSH levels), while behavioral investigations demonstrated enhanced cognitive and motor abilities. The optimized liposomal formulation demonstrated enhanced brain targeting, cellular uptake, and neuroprotection, making it a promising therapeutic approach for Wilson disease.</p> Graphical Abstract <p></p>

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Apolipoprotein-decorated drug loaded liposomes mitigating copper intoxication: an in vitro and in vivo evidence-based study intervening Wilson disease

  • 期刊论文

  • 发表日期：

    2025年5月14日

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  • Akanksha Chaturvedi,
  • Gagandeep Kaur,
  • Rahul Shukla

摘要

Wilson disease (WD), a rare autosomal-recessive disorder caused by impaired copper metabolism, leads to hepatic dysfunction and copper overaccumulation, debilitating neurological symptoms. Current treatments, primarily metal chelating agents and antioxidants, have limitations like sub-optimal efficacy, limited blood–brain barrier transport, and systemic side effects. This study aims to deliver monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA), a novel next-generation chelator encapsulated in a liposomal nanocarrier coated with apolipoprotein E (ApoE) to enhance brain targeting and copper chelation. ApoE-coated liposomal formulation is optimized using the Box-Behnken design (BBD). This was followed by comprehensive characterization like dynamic light scattering, scanning electron microscopy, drug-excipient compatibility studies, and in vitro drug release kinetics. Additionally, the developed formulation was investigated on the human neuroblastoma cells (SH-SY5Y) demonstrating safety, biocompatibility, and cell internalization efficacy within 24 h. Bioimaging studies further demonstrated significant brain permeability of the ApoE-coated MiADMSA liposomes, comparable to uncoated MiADMSA liposomes, followed by pharmacodynamic evaluations. Morphometric analysis, behavioral studies, biochemical estimations, and histopathological assessments confirmed the efficacy of ApoE-coated MiADMSA liposomes. The optimized formulation demonstrated sustained release, excellent encapsulation efficiency of up to 90.29%, and a nanosized spherical shape (141.3 ± 1.26 nm). Effective internalization, biocompatibility, and neuroprotection were validated by cellular investigations. ApoE-MiADMSA-LPS showed notable BBB penetration in in vivo imaging. Biochemical examination indicated less oxidative stress (lower MDA, higher SOD, CAT, and GSH levels), while behavioral investigations demonstrated enhanced cognitive and motor abilities. The optimized liposomal formulation demonstrated enhanced brain targeting, cellular uptake, and neuroprotection, making it a promising therapeutic approach for Wilson disease.

Graphical Abstract