Zwitterionic Polypeptide-Based Nanodrug Augments pH-Triggered Tumor Targeting via Prolonging Circulation Time and Accelerating Cellular Internalization

Abstract

To augment the antitumor efficacy and minimize the significant side effects of chemotherapeutic drugs on health organs, a novel albumin-mimicking nanodrug, which is based on zwitterionic poly(glutamatyl lysine-co-cysteine) peptides scaffold, is developed to enhance pH-triggered tumor targeting via prolonging circulation time and accelerating cellular internalization. Results showed that the internalization of the nanodrug by MCF-7 cells is much faster than that by Doxil and even comparable to that by free doxorubicin (Dox) at tumor microenvironmental pH 6.7, whereas the internalization of the nanodrug is only 27.4 ± 7.6% of the Doxil by RAW-264.7 cells. Moreover, the significantly prolonged circulation time of the "stealthy" nanodrug was also comparable to that of the long circulating Doxil. As a result, the accumulation of the nanodrug in the tumor is much higher than that in the liver and kidney before the circulation half-life, which is significantly different from most other nanodrugs accumulated in the liver and kidney in this time scale. The tumor inhibition rate of the nanodrug was much higher than that of Doxil (93.2 ± 3.0% vs 54.2 ± 6.5%) after 18 day treatment, while the average bodyweight of the mice treated by the nanodrug was 26.9 ± 6.7% higher than that by Doxil. This indicated that the synergetic effect of long circulation time and fast cellular internalization of the nanodrug can significantly augment tumor targeting. This method might rejuvenate the traditional chemotherapeutic treatment.

Liver Targeting of Daclatasvir via Tailoring Sterically Stabilized Bilosomes: Fabrication, Comparative In Vitro/In Vivo Appraisal and Biodistribution Studies

“…Therefore, to elongate the in vivo circulation time of nanoparticles, it is essential to modify the nanoparticle surface to make it more hydrophilic. To address this problem, various hydrophilic polymers, including poly(vinyl alcohol), poly(N-vinylpyrrolidone), poly(2-oxazoline), and poly(ethylene glycol) (PEG), and zwitterionic polymers, such as poly(carboxybetaine methacrylate), 12 have been introduced to yield more hydrophilic nanoparticles and to decrease MPS reuptake. [12][13][14] PEG is one of the most hydrophilic molecules that is commonly used as an example of a stealthy polymer.…”

“…To address this problem, various hydrophilic polymers, including poly(vinyl alcohol), poly(N-vinylpyrrolidone), poly(2-oxazoline), and poly(ethylene glycol) (PEG), and zwitterionic polymers, such as poly(carboxybetaine methacrylate), 12 have been introduced to yield more hydrophilic nanoparticles and to decrease MPS reuptake. [12][13][14] PEG is one of the most hydrophilic molecules that is commonly used as an example of a stealthy polymer. The PEGylation of nanovesicles results in a reduction in their electrostatic charge, by forming an aqueous layer surrounding them, thus avoiding their renal clearance.…”

Recent Advances in Zwitterionic Hydrogels: Preparation, Property, and Biomedical Application

“…However, in practical research, whether nanocarriers can produce enough effect is seriously determined by the biological immune system. Targeted binding and metabolic clearance have become a racing relationship [ 142 ]. Among them, the rate of metabolic clearance is often greater than the ability of targeted binding.…”

“…However, there is still interaction between PEG and protein, especially in complex biological environments (such as whole plasma environment) [ 11 ], and the PEG antibodies found in recent years also show that the application of PEGylated drugs will be limited [ 146 ]. Realizing true non-fouling is the key point to avoid reticuloendothelial system recognition and achieve real long blood circulation [ 142 ].…”

Stimuli‐responsive polypeptide nanoassemblies: Recent progress and applications in cancer nanomedicine

“…(d) Illustration of targeted and pH‐triggered zwitterionic polypeptide nanoparticles p(EK‐ co ‐C‐SPA + DOX). Reprinted with permission from Xue et al (2020). Copyright 2020.…”