Principles of Amino-Acid-Nucleotide Interactions Revealed by Binding Affinities between Homogeneous Oligopeptides and Single-Stranded DNA Molecules.

We have determined the binding strengths between nucleotides of adenine, thymine, guanine and cytosine in homogeneous single stranded DNAs and homo-octapeptides consisting of 20 common amino acids. We use a bead-based fluorescence assay for these measurements in which octapeptides are immobilized on the bead surface and ssDNAs are in solutions. Comparative analyses of the distribution of the binding energies reveal unique binding strength patterns assignable to each DNA nucleotide and amino acid originating from the chemical structures. Pronounced favorable (such as Arg-G, etc.) and unfavorable (such as Ile-T, etc.) binding interactions can be identified in selected groups of amino acid and nucleotide pairs that could provide basis to elucidate energetics of amino-acid-nucleotide interactions. Such interaction selectivity, specificity and polymorphism establish the contributions from DNA backbone, DNA bases, as well as main chain and side chain of the amino acids.

A Nucleus-Targeting WT1 Antagonistic Peptide Encapsulated in Polymeric Nanomicelles Combats Refractory Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is recognized as a classic clonal myeloproliferative disorder. Given the limited treatment options for CML patients in the accelerated phase (AP) and blast phase (BP), there is an evident need to develop new therapeutic strategies. This has the potential to improve outcomes for individuals in the advanced stages of CML. A promising therapeutic target is Wilms' tumor 1 (WT1), which is highly expressed in BP-CML cells and plays a crucial role in CML progression. In this study, a chemically synthesized nucleus-targeting WT1 antagonistic peptide termed WIP2W was identified. The therapeutic implications of both the peptide and its micellar formulation, M-WIP2W, were evaluated in WT1+ BP-CML cell lines and in mice. The findings indicate that WIP2W can bind specifically to the WT1 protein, inducing cell cycle arrest and notable cytotoxicity in WT1+ BP-CML cells. Moreover, subcutaneous injections of M-WIP2W were observed to significantly enhance intra-tumoral accumulation and to effectively inhibit tumor growth. Thus, WIP2W stands out as a potent and selective WT1 inhibitor, and the M-WIP2W nanoformulation appears promising for the therapeutic treatment of refractory CML as well as other WT1-overexpressing malignant cancers.

A nucleus-targeting peptide antagonist towards EZH2 displays therapeutic efficacy for lung cancer.

EZH2 is an overexpressed nuclear protein associated with relatively poor survival and chemoresistance in lung cancer. In this study, a nucleus-targeting peptide antagonist EIP103 capable of penetrating cell membrane and nuclear envelope was identified, and has high binding affinity towards EZH2 localized in the nucleus of lung cancer cells. To improve the stability and therapeutic efficacy of EIP103, PEG-PE micelle encapsulated EIP103 (M-EIP103) was successfully conducted. In vitro results indicated that M-EIP103 exhibited better stability, higher intracellular uptake and stronger cytotoxicity than free EIP103 in H446 and A549 cells. Mechanistic studies suggested that M-EIP103 inhibited proliferation by down-regulating the H3K27me3 expression level in cancer cells. In vivo assays further confirmed that both EIP103 and M-EIP103 significantly inhibited lung cancer progression. Notably, enhanced therapeutic efficacy of EIP103 by PEG-PE micelle encapsulation could be identified. The observed anti-tumor activity of EIP103 and M-EIP103 demonstrated a promising therapy to improve clinical treatment of lung cancers as well as other EZH2-overexpressing malignant cancers. This study also illustrates the feasibility of developing targeted delivery of therapeutic peptides to nucleus for cancer therapy.

Peptide-Enabled Targeted Delivery Systems for Therapeutic Applications.

Receptor-targeting peptides have been extensively pursued for improving binding specificity and effective accumulation of drugs at the site of interest, and have remained challenging for extensive research efforts relating to chemotherapy in cancer treatments. By chemically linking a ligand of interest to drug-loaded nanocarriers, active targeting systems could be constructed. Peptide-functionalized nanostructures have been extensively pursued for biomedical applications, including drug delivery, biological imaging, liquid biopsy, and targeted therapies, and widely recognized as candidates of novel therapeutics due to their high specificity, well biocompatibility, and easy availability. We will endeavor to review a variety of strategies that have been demonstrated for improving receptor-specificity of the drug-loaded nanoscale structures using peptide ligands targeting tumor-related receptors. The effort could illustrate that the synergism of nano-sized structures with receptor-targeting peptides could lead to enrichment of biofunctions of nanostructures.

Enhancement of gold-nanocluster-mediated chemotherapeutic efficiency of cisplatin in lung cancer.

A novel delivery system for cisplatin was constructed based on electrostatics-mediated assemblies of gold nanoclusters and PEGylated cationic peptide (cisplatin@GC-pKs). Encapsulated cisplatin in the as-formed micelle like assemblies was observed to demonstrate improved cellar uptake and enhanced chemotherapeutic efficiency in the cisplatin-resistant lung cancer cells. In vivo assays further confirmed that cisplatin@GC-pKs had profound anti-tumor efficiency due to deep penetration and accumulation of nanoscale cisplatin@GC-pKs via the enhanced permeability and retention (EPR) effect at tumor tissues. The constructed cisplatin@GC-pKs in this work demonstrated enhanced anti-tumor activity for lung cancer therapy, as well as a potential treatment strategy for a variety of cisplatin-resistance related malignancies.

[Comparison of the IL-27 level in gingival crevicular fluid of cross-quadrant and the upper and lower half-mouth subgingival scaling].

PURPOSE: To investigate the changes of IL-27 in gingival crevicular fluid (GCF) before and after treatment with different methods for chronic periodontitis. METHODS: Sixty patients with moderate or severe chronic periodontitis were selected as study group to divide into group A (cross-quadrant) and group B (upper and lower half-mouth) randomly. Another 30 healthy people were selected as group C. Gingival crevicular fluid of group A and B were collected at baseline and each week during treatment. At the same time, the clinical parameters including PD, AL, BI and PLI were recorded. And the levels of IL-27 in GCF were measured by ELISA. SPSS 17.0 software package was used for statistical analysis. RESULTS: The levels of IL-27 in GCF 2 and 3 weeks after treatment were higher in study group compared with those at baseline, while PD, AL, BI and PLI showed significant reduction. The changes except PLI in group A was more obvious than group B, which had a significant difference. After three-week treatment, IL-27 in group A had no remarkable difference compared with group C. There were significantly negative correlation between PD, AL, BI, PLI and IL-27. CONCLUSIONS: IL-27 in GCF can be considered as a potential target for prevention and treatment of chronic periodontitis. Compared with the upper and lower half-mouth subgingival scaling, cross-quadrant has more pronounced short-term effect.