Peptides are a rapidly growing class of therapeutics with many advantages over conventional small molecule drugs. Dextrorotary (D)-peptides, with increased enzymatic stability and prolonged plasma half-life in comparison with natural L-peptides, are considered to have great potential as recognition molecules and therapeutic agents. However, the in vivo efficacy of current therapeutic D-peptides is hindered by their inefficient cellular uptake in diseased tissues. Methods: To overcome physiological and cellular barriers to D-peptides, we designed a gold-based ultra-small nanocarrier coupled with polylysine (PLL) and a receptor-targeted peptide to deliver therapeutic D-peptides. Using a D-peptide p53 activator (DPA) as a proof of concept, we synthesized, functionalized and characterized gold- and DPA-based nanoparticles termed AuNP-DPA. Results: AuNP-DPA were effectively enriched in tumor sites and subsequently internalized by cancer cells, thereby suppressing tumor growth via reactivating p53 signaling. More importantly, through a series of in vivo experiments, AuNP-DPA showed excellent biosafety without the common side effects that hinder p53 therapies in clinic trials. Conclusion: The present study not only sheds light on the development of AuNP-DPA as a novel class of antitumor agents for drugging the p53 pathway in vivo, but also supplies a new strategy to use D-peptides as intracellular PPI inhibitors for cancer-targeted therapy.
RNA interference (RNAi) has shown great potential for clinical treatment of a variety of diseases. As an effective post-transcriptional regulation, RNAi induces degradation of specific target mRNA, leading to a decreased level of disease related gene product, which could be resistant to conventional small molecule therapeutics. Because of the relatively small size of short interfering RNA (siRNA) as well as it's robustness in the design of efficient 20–22 nucleotide sequences targeting any known gene, delivery of siRNA in vitro and in vivo has achieved tremendous success by the design and fabrication of various carrier materials including peptides, lipids, and polymers. While siRNA delivery efficiency of these materials proved to be appreciable, their tissue specificity, biocompatibility and cytotoxicity still need much improvement. We report a novel siRNA delivery material designed by optimization of our previously reported peptidomimetic based lipoplex. The novel lipoplex, which bears a D-amino acid based dipeptide head group, possesses an ideal balance of increased stability in a tissue environment, and enhanced efficiency of tissue specific delivery as well as minimized cytotoxicity. The novel lipoplex carrying siRNA efficiently targeted mouse liver, initiated RNAi and knocked down the apoB dose dependently, which is confirmed by both RT-qPCR and Western blotting. Moreover, the novel lipoplex does not induce any apparent cytotoxicity, as confirmed by the measurement of liver enzyme levels in serum.
Qi Zhang,Zhe Zheng,Yiting Zhao,Qing Wu,Chu Wu,Xiuli Wang,Xia Wang,Qigang Wang,Peiru Wang
The transformation of O 2 is primarily facilitated by the catalytic action of redox enzymes, which play a pivotal role in sustaining cellular energy metabolism and redox balance. Bioinspired by O 2 distribution and ROS regulation related to cascade biocatalytic process, a D-peptide NapG D F D F D Y engineered hydrogel has been constructed with encapsulated dual-enzyme superoxide (SOD) and chloroperoxidase (CPO) cascade catalytic circuit and co-assembled photosensitizer of 5-aminolevulinic acid molecules (ALA). Multimodal oxygen modulation has been conducted by the concurrent oxygen generation via SOD-catalyzed ⋅O 2 − dismutation and oxygen consumption for 1 O 2 production by CPO and ALA, achieving self-sustaining enzymatic dynamic therapy (EDT)-photodynamic therapy (PDT) (EDT-PDT) synergy. The endogenous cascade-amplified EDT not only enhances the 1 O 2 efficacy in exogenous PDT therapy, but the intermediate O 2 can also alleviate local neuropathic pain caused by hypoxia for safe PDT treatment. This work pioneers enzyme-mediated dynamic control of tumor redox homeostasis, establishing a new therapeutic axis between biocatalytic amplification and photodynamic processes.
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