Cell-penetrating peptides (CPPs) are known for their effective intracellular transport of bioactives such as therapeutic proteins, peptides, nucleic acid, and small molecule drugs. However, the excessive cationic charges that promote their membrane permeability result in nonselective delivery and cellular toxicity. In this study, we report a decamer cell-penetrating peptidomimetic, , designed to selectively deliver anticancer drugs into tumor cells in response to the acidic microenvironment. The pH-sensitive histidine (H) imidazole side chain undergoes protonation in acidic environments, facilitating membrane permeability. The rigid cyclic dipeptide (CDP) core (kd) of has multiple hydrogen bond donor and acceptor sites, enabling selective interaction-driven cellular uptake. Pharmacokinetic studies revealed the excellent serum stability of . Cellular uptake studies of showed improved uptake at a lower pH than physiological pH. Conjugation of to the anticancer drug camptothecin (Cpt) reduced nonselective drug transport to normal cells while effectively delivering the drug into cancerous cells at the tumor microenvironment pH and retaining the therapeutic potential of the drug. The systematic design of pH-sensitive peptidomimetics offers a viable method to overcome the challenges of stability and selectivity faced by traditional highly cationic CPPs, potentially expanding the application range of this delivery system.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.biochem.4c00657 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Docetaxel-Loaded Electrospun Nanofibrous Mats for Local Chemotherapy Targeting Positive Surgical Margins in Prostate Cancer.
Mol Pharm
March 2025
Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Positive surgical margins following radical prostatectomy significantly contribute to tumor recurrence. While systemic chemotherapy demonstrates limited efficacy in this context, local chemotherapy drug delivery systems based on nanomaterials offer promising strategies to address this issue by modifying drug release kinetics and distribution, thereby enhancing antitumor effects while minimizing the toxicities associated with systemic chemotherapy. In this study, we utilized electrospun nanofibrous mats loaded with docetaxel for sustained drug delivery.
View Article and Find Full Text PDFCAD manipulates tumor intrinsic DHO/UBE4B/NF-κB pathway and fuels macrophage cross-talk, promoting hepatocellular carcinoma metastasis.
Hepatology
March 2025
Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China.
Background And Aims: Portal vein tumor thrombosis (PVTT), an indicator of clinical metastasis, significantly shortens hepatocellular carcinoma (HCC) patients' lifespan, and no effective treatment has been established. We aimed to illustrate mechanisms underlying PVTT formation and tumor metastasis, and identified potential targets for clinical intervention.
Approach And Results: Multi-omics data of 159 HCC patients (including 37 cases with PVTT) was analyzed to identify contributors to PVTT formation and tumor metastasis.
Plasmacytoid dendritic cell sensing of African swine fever virus-infected macrophages results in STING-dependent robust interferon-α production.
J Immunol
January 2025
Institute of Virology and Immunology, Mittelhäusern, Switzerland.
While several African swine fever virus (ASFV)-encoded proteins potently interfere with the cGAS-STING (cyclic GMP-AMP synthetase-stimulator of interferon genes) pathway at different levels to suppress interferon (IFN) type I production in infected macrophages, systemic IFN-α is induced during the early stages of AFSV infection in pigs. The present study elucidates a mechanism by which such responses can be triggered, at least in vitro. We demonstrate that infection of monocyte-derived macrophages (MDMs) by ASFV genotype 2 strains is highly efficient but immunologically silent with respect to IFN type I, IFN-stimulated gene induction, and tumor necrosis factor production.
View Article and Find Full Text PDFHeterogeneous cellular responses to hyperthermia support combined intraperitoneal hyperthermic immunotherapy for ovarian cancer mouse models.
Sci Transl Med
March 2025
Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, China.
The benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer remains controversial, hindering the development of rational combination therapies based on hyperthermia (HT). This study reports the preliminary results of the neoadjuvant HIPEC (NHIPEC) trial (ChiCTR2000038173), demonstrating enhanced tumor response in high-grade serous ovarian cancer with NHIPEC. Through single-cell RNA sequencing analysis, we identified both homogeneous and heterogeneous cellular responses to HT within the tumor and microenvironment.
View Article and Find Full Text PDFSOS1 inhibitor BI-3406 shows in vivo antitumor activity akin to genetic ablation and synergizes with a KRAS inhibitor in KRAS LUAD.
Proc Natl Acad Sci U S A
March 2025
Laboratorio 1. Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca and Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Salamanca 37007, Spain.
We evaluated the in vivo therapeutic efficacy and tolerability of BI-3406-mediated pharmacological inhibition of SOS1 in comparison to genetic ablation of this universal Ras-GEF in various KRAS-dependent experimental tumor settings. Contrary to the rapid lethality caused by SOS1 genetic ablation in SOS2 mice, SOS1 pharmacological inhibition by its specific inhibitor BI-3406 did not significantly affect animal weight/viability nor cause noteworthy systemic toxicity. Allograft assays using different KRAS cell lines showed that treatment with BI-3406 impaired RAS activation and RAS downstream signaling and decreased tumor burden and disease progression as a result of both tumor-intrinsic and -extrinsic therapeutic effects of the drug.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!