Improving Cancer Detection and Treatment by pH‐Sensitive Peptide Nanoparticle Drug Delivery Platform: Pharmacokinetics, Toxicity, and Immunogenicity Profile

It was previously reported that a nanoparticle made of ultra pH-sensitive peptides (pH-NP) undergoes self-dissolution in moderately acidic (pH <= 6.9) condition that mimics the pH in extracellular tumor environment, leading to release of drug cargo molecules. Herein, it is demonstrated that this peptide-based nanodelivery platform can be used to formulate poorly water-soluble small molecules to improve cancer diagnosis and treatment. Indocyanine green (ICG) encapsulated in pH-NP (ICG-pH-NP) significantly increases tumor-specific accumulation compared with "free" ICG, leading to excellent invivo optical imaging contrast. An investigational cancer drug, OTS964, formulated in pH-NP (OTS-pH-NP), sensitizes the drug-resistant triple-negative breast cancer to chemotherapy (paclitaxel), resulting in a remarkable tumor regression, whereas OTS964 in standard formulation does not (P=0.0004). The potential immunogenicity and bone marrow toxicity of this nanoparticle are further investigated by administering drug-free pH-NP at nanoparticle dose regimens, representing 1.5x and 4.5x, respectively, of which are used in the treatment (OTS-pH-NP) study. The data show that the pH-NP is not immunogenic and is well-tolerated. Taken together, self-dissolution and the release of drug cargo in response to the tumor's acidic extracellular pH faciliates drug delivery when mediated by the pH-NP nano platform, making it a promising, clinical translational delivery platform for enhancing cancer detection and treatment.