Dual-functional bio-derived nanoparticulates for apoptotic antitumor therapy

Area of Science:

• Biomaterials Science
• Nanotechnology
• Drug Delivery Systems

Background:

• Bio-derived nanoparticulates offer promising sustained-release, site-targeted, and biodegradable drug delivery for chemotherapeutics.
• Gambogic acid (GA) is a therapeutic agent for apoptotic antitumor therapy, but requires effective delivery systems.

Purpose of the Study:

• To develop a dual-functionalized biomimetic nanovector, cell-penetrating peptide (CPP)-anchored recombinant high density lipoproteins (cp-rHDL), for enhanced gambogic acid (GA) delivery.
• To evaluate the targeting, cellular internalization, and therapeutic efficacy of cp-rHDL/GA nanoparticles in apoptotic antitumor therapy.

Main Methods:

• Constructed GA-loaded cp-rHDL nanoparticles with a hydrophobic core, apolipoprotein A-I (apo A-I), and a pH-responsive CPP (R6H4).
• Investigated physicochemical properties, biostability, and proton sponge effect of cp-rHDL/GA.
• Assessed intracellular delivery mechanisms including scavenger receptor class B type I (SR-BI)-mediated transport and pH-responsive endocytosis with endo-lysosomal escape.
• Evaluated cytotoxicity, apoptotic effects via p53 pathway, and in vivo tumor inhibition in HepG2 xenograft models.

Main Results:

• cp-rHDL/GA nanoparticles exhibited desirable physicochemical properties, superior biostability, and a proton sponge effect.
• Demonstrated synergistic intracellular delivery via SR-BI and pH-responsive CPP-mediated pathways with rapid endo-lysosomal escape.
• cp-rHDL/GA showed significant cytotoxicity and apoptotic effects, with a 5-fold increase in IC50 compared to free GA.
• Achieved superior tumor accumulation and significant tumor growth inhibition in vivo without adverse effects.

Conclusions:

• Bio-derived cp-rHDL/GA nanoparticles possess pH-responsive penetrating potential and efficient cellular internalization.
• This dual-functionalization biomimetic strategy offers a promising platform for multi-functional bio-derived drug delivery in apoptotic anticancer therapy.