Modular platform for therapeutic drug delivery using trifunctional bio-orthogonal macromolecular conjugates

Area of Science:

• Bioconjugation Chemistry
• Drug Delivery Systems
• Molecular Therapeutics

Background:

• Targeted delivery of macromolecular therapeutics is crucial for advanced treatments like modulating protein-protein interactions and genome editing.
• Conventional small molecules face limitations, necessitating novel delivery strategies for larger therapeutic agents.
• Efficient, safe, and cell type-specific delivery of macromolecules remains a significant hurdle in biomedical research.

Purpose of the Study:

• To develop a versatile and modular platform for synthesizing heterotrifunctional bio-orthogonal macromolecular conjugates (BMCs).
• To engineer BMCs capable of targeted delivery, intracellular trafficking, and specific biological activities.
• To demonstrate the broad applicability of BMCs across various biomedical applications, including diagnostics and therapeutics.

Main Methods:

• Engineered heterotrifunctional bio-orthogonal macromolecular conjugates (BMCs) by combining targeting ligands, cell-penetrating peptides (CPPs), and bioactive cargos.
• Utilized facile bioconjugation chemistries to optimize BMC synthesis for yield, structural integrity, and activity.
• Assayed BMC utility through fluorescent cargo for endosomal escape, peptidomimetic inhibitors for anti-leukemic activity, and CRISPR-Cas9 for gene editing.

Main Results:

• Developed modular BMCs accommodating diverse components like antibodies, CPPs, optical probes, therapeutic peptidomimetics, and CRISPR-Cas9.
• Demonstrated successful endosomal escape and intracellular accumulation of fluorescently labeled BMCs.
• Showcased potent anti-leukemic activity of MYB inhibitor BMCs and efficient, cell type-specific gene editing with Cas9 BMCs in human cells.

Conclusions:

• The modular BMC platform enables customizable delivery of functional macromolecules.
• BMCs offer a broadly applicable solution for overcoming challenges in macromolecular drug delivery and targeted therapies.
• This approach facilitates precise modulation of cellular functions and holds significant promise for diverse biomedical applications.