Development of an Integrated High Serum Stability Zwitterionic Polypeptide-Based Nanodrug with Both Rapid Internalization and Endocellular Drug Releasing for Efficient Targeted Chemotherapy

Abstract

Chemotherapeutic nanodrugs have to penetrate through many biological barriers before reaching the tumor cells. Thus, high stability of the nanocarrier before reaching tumor cells and fast release of the carried drugs in targeted tumor cells are required. In this work, inspired by the intrinsic zwitterionic surface property, mainly formed by glutamic acid and lysine residues, of the plasma protein surface, the zwitterionic poly(glutamyl lysine-co-aspartic acid-cocysteine) peptide (P(EK-D-C)) was synthesized for conjugating n-mercaptoalkanoic acid (MA) with different chain lengths on cysteine residues through a disulfide linkage to load hydrophobic doxorubicin (DOX). The results showed that the slightly negative-biased zwitterionic nanodrugs were very stable in both resistance to nonspecific plasma protein adsorption and prevention of premature DOX release at physiological pH 7.4 due to the zwitterionic polypeptide shell and the sharp contrast in polarity between the shell and DOX-loaded core, while they can quickly release the loaded DOX through responding to both low pH values in the endosome/lysosome and high glutathione concentrations in the tumor cell cytoplasm. Furthermore, the enhanced internalization of these nanodrugs led to about 60% higher in vitro cytotoxicity against MCF-7 cells at pH 6.7 than at pH 7.4, whereas the in vitro cytotoxicity of DOX•HCl at pH 6.7 was only 75% of the value at pH 7.4. In vivo results revealed that the stable nanodrugs conjugated with the long hydrophobic 12-mercaptododecanoic acid had higher tumor inhibition rate and lower systematic toxicity on MCF-7 tumor-bearing mice than the less stable nanodrugs conjugated with the short 8-mercaptooctaoic acid and were significantly superior to DOX•HCl. These results indicate that the combination of high stability in circulation and fast release in tumor cells of nanodrugs can enhance high efficacy targeted chemotherapy. This pH/redox-sensitive zwitterionic polypeptide nanocarrier might provide an excellent vehicle for solid tumor treatment.

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

“…[ 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. Although poly(EK) has been applied for surface coatings, [ 26 , 34 ] protein conjugation, [ 35 , 36 ] and drug delivery, [ 37 , 38 , 39 ] the study of poly(EK) hydrogels remains scarce due to the difficulties associated with the synthesis of the alternating polypeptides. Despite there having been attempts to develop EK hydrogels, the process has relied on N‐carboxyanhydride (NCA) ring‐opening random polymerization, resulting in hydrogels lacking a precisely defined zwitterionic alternating structure.…”

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

“…The nanodrugs, which are encapsulated by them, showed the characteristics of albumin, a major zwitterionic biomacromolecule covered by abundant glutamic acid (E) and lysine (K) with a negative charge bias in blood . This leads to efficient drug accumulation and release in tumors, thus highly inhibiting tumor growth. − However, it is still a challenging issue to improve the stability of nanodrugs and the responsive transition of stability and affinity of nanodelivery systems to tumor cells from circulation to the slightly acidic TME.…”