Reconfigurable Peptide Nanotherapeutics at Tumor Microenvironmental pH

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Peptide nanomaterials show promise in biomedicine but suffer from poor bioavailability and efficacy.
• Developing effective nanotherapeutics requires overcoming challenges in drug delivery and activation within the tumor microenvironment.

Purpose of the Study:

• To develop reconfigurable nanotherapeutics that activate specifically within the tumor microenvironment.
• To enhance the therapeutic efficacy and bioavailability of peptide-based nanomaterials for cancer treatment.

Main Methods:

• Conjugation of pH-responsive (HLAH) and MMP2-sensitive peptides with PEG termini onto poly(β-thioester) backbones to form P-S-H copolymers.
• Self-assembly of copolymers into nanoparticles with PEG shells protecting HLAH cores under physiological conditions.
• Stimulation of nanoparticles by tumor microenvironment factors (MMP2, acidic pH) leading to PEG shedding and HLAH activation, causing nanoparticle reassembly with exposed cytotoxic peptides.

Main Results:

• P-S-H nanoparticles exhibited stable circulation due to moderate size and negative potential.
• Tumor microenvironment stimuli triggered PEG shell shedding and HLAH peptide activation, leading to nanoparticle reorganization.
• In vivo studies confirmed effective tumor accumulation, enhanced antitumor capacity, and no significant toxicity at therapeutic doses.

Conclusions:

• The on-site reorganization strategy enables the development of high-performance peptide nanomaterials for cancer therapy.
• Reconfigurable nanotherapeutics offer a promising approach to overcome limitations of traditional peptide-based treatments.
• This strategy enhances drug delivery and therapeutic efficacy by targeting tumor-specific conditions.