No abstract

No 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.

Negative-charge-biased zwitterionic nanodrugs showed "stealthy" in blood circulation and "sticky" to sialic acid abundant tumor cells in the tumor microenvironment (TME), thereby prolonging blood circulation, increasing tumor targeting, and reducing accumulation in healthy liver and kidney. However, the correlation between the particle size, one of the crucial parameters of these nanodrugs, and their interactions with biological systems is unclear. Here, KEKDCDEKE (EK9) small peptide was used to replace zwitterionic polypeptides to prepare doxorubicin (DOX)-conjugated nanodrugs with well-controlled size, which is, respectively, 30, 60, and 90 nm diameter, for investigating the size effect on cancer therapy. Results showed that the size increase of these zwitterionic nanodrugs improves their blood circulation and retention in tumor but reduces the internalization rate and tumor tissue penetration, although all nanodrugs were self-assembled by the same conjugates. There is an optimal particle size, 60 nm in this work, for the zwitterionic nanodrugs to balance these effects, thereby improving their ability to inhibit tumor growth. These findings suggest that the particle size of zwitterionic nanodrugs also plays a particularly important role in controlling the behaviors of zwitterionic peptide-based nanodrugs.

Functional oligopeptides derived from natural proteins are often used as targeting groups or therapeutic drugs but always suffer from a dramatic bioaffinity decrease due to the loss of conformational restriction in proteins, which increases their entropy state. It is worth noting that the linear Cys-Arg-Gly-Asp-Ser (CRGDS) oligopeptide can spontaneously restore its natural conformation by anchoring one terminus and forming hydrogen bonds on another terminus, on protein-like zwitterionic fifth-generation polyamide-amine (G5 PAMAM) nanocarriers, thus exhibiting high bioaffinity. However, the different physicochemical properties of nanocarriers have an impact on the bioaffinity recovery of linear CRGDS. In this work, it is found that the bioaffinity decreases with the reduction of generation of PAMAM and zwitterionic G3 PAMAM is a turning point for bioaffinity recovery via a series of in vitro experiments. This indicates that the spontaneous restoration of the native conformation of the RGD segment requires proper surface group density and structural rigidity of the zwitterionic nanocarrier for reducing the entropic energy of CRGDS peptides before binding. This approach paves a way for functional reproduction of protein molecules using low-cost synthetic polymers for extensive biomedical applications.