Enhancing the Antitumor Efficacy of Zwitterionic Peptide-Based Nanoscale Micelles through Sensitizing Their Response in Solid Tumors

Abstract

Although nanodelivery has made unprecedented progress in enhancing the efficacy of chemotherapeutic drugs, there is still much room for improvement. Zwitterionic nanodrugs have great potential to be a universal platform for nanodelivery because of the exceptional hemocompatibility and ultralow immunogenicity, although they are sensitive to the tumor microenvironment (TME) for tumor cell targeting and internalization. Here, a negatively biased zwitterionic peptide micelle, a mimic of albumin, was developed to improve two vital factors, which are the responsive transition of stability and affinity to tumor cells from circulation to the slightly acidic TME. The incorporation of positively charged hydrophobic phenformin into the camptothecin (CPT)-conjugated micelles (Pep-SSetc-CPT@Phen) can make the micelles more compact to reduce premature drug release in circulation while improving the sensitivity of the micelles to MCF-7-xenografted tumors by tuning their zeta potential in the TME. Thus, Pep-SSetc-CPT@Phen exhibited more tumor-preferred biodistribution and longer blood circulation than nonphenformin-incorporated micelles (Pep-SSetc-CPT), thereby enhancing tumor growth inhibition with lower side effects. Together, these results have provided a promising combinational method to enhance the transition of stability and the sensitivity to the TME for developing biomimetic zwitterionic nanodrugs with high antitumor efficacy.

Camptothecin-based prodrug nanomedicines for cancer therapy

“…22), 78 dextran (Table 1-no. 23), 79 triphenylphosphine, 80 oleic acid, 81 2-acetylphenylboronic acid, 82 undecanoic acid, 83 and hydrophobic phenformin 84 among others, has been developed for the fabrication of a variety of CPT nanoprodrugs. Imaging-guided cancer therapy exhibits real-time imaging capability, and high spatial resolution.…”

Poly(Glutamic Acid‐Lysine) Hydrogels with Alternating Sequence Resist the Foreign Body Response in Rodents and Non‐Human Primates

“…An intriguing observation is the large fractions of lysine (K) and glutamic acid (E) residuals on the human protein surface, which possess robust water‐binding capabilities but weak binding with surrounding amino acids. [ 23 , 24 ] The pseudo zwitterionic polypeptide material, synthesized through alternating copolymerization of glutamic acid and lysine or aspartic acid and lysine, [ 25 , 26 , 27 , 28 , 29 ] has demonstrated enzymatic degradability while retaining its inherent zwitterionic characteristics to resist nonspecific protein adsorption. [ 17 , 26 , 30 , 31 , 32 , 33 ] Furthermore, the degradation products consist of naturally occurring amino acids that can undergo metabolic processes within the natural protein metabolic pathway.…”