Smart delivery of lethal poly-peptide composite for effective cancer therapy

In the past decade, multifunctional peptides have attracted increasing attention in the biomedical field. Peptides possess many impressive advantages, such as high penetration ability, low cost, and etc. However, the short half-life and instability of peptides limit their application. In this study, a poly-peptide drug loading system (called HKMA composite) was designed based on the different functionalities of four peptides. The peptide compositions of HKMA composite from N-terminal to C-terminal were HCBP1, KLA, MMP-2-cleavable peptide and ABD. The targeting and lethality of HKMA to NSCLC cell line H460 sphere cells and the half-life of the system were measured in vivo. The results showed that the HKMA composite had a long half-life and specific killing effect on H460 sphere cells in vitro and in vivo. Our result proposed smart peptide drug loading system and provided a potential methodology for effective cancer treatment.

Development of novel bone targeting peptide–drug conjugate of 13-aminomethyl-15-thiomatrine for osteoporosis therapy

13-Aminomethyl-15-thiomatrine (M19) previously developed by our research group was a promising candidate for novel anti-osteoporosis drug development.

Routes and barriers associated with protein and peptide drug delivery system

Published in August 2021

Melphalan flufenamide is an Anticancer medication used to treat multiple Myeloma: A Review

Melphalan Flufenamide is a peptide-drug conjugate composed of a peptide conjugated, via an aminopeptidase-targeting linkage, to the alkylating agent melphalan, with potential antineoplastic and anti-angiogenic activities. Upon administration, the highly lipophilic melphalan flufenamide penetrates cell membranes and enters cells. In aminopeptidase-positive tumor cells, melphalan flufenamide is hydrolyzed by peptidases to release the hydrophilic alkylating agent melphalan. This results in the specific release and accumulation of melphalan in aminopeptidase-positive tumor cells. Melphalan alkylates DNA at the N7 position of guanine residues and induces DNA intra- and inter-strand cross-linkages. This results in the inhibition of DNA and RNA synthesis and the induction of apoptosis, thereby inhibiting tumor cell proliferation. Peptidases are overexpressed by certain cancer cells. The administration of melphalan flufenamide allows for enhanced efficacy and reduced toxicity compared to melphalan.1,2,3

Thymodepressin—Unforeseen Immunosuppressor

The paper summarizes the available information concerning the biological properties and biomedical applications of Thymodepressin. This synthetic peptide drug displays pronounced immunoinhibitory activity across a wide range of conditions in vitro and in vivo. The history of its unforeseen discovery is briefly reviewed, and the current as well as potential expansion areas of medicinal practice are outlined. Additional experimental evidence is obtained, demonstrating several potential advantages of Thymodepressin over another actively used immunosuppressor drug, cyclosporin A.

New Peptide-Drug Conjugates for Precise Targeting of SORT1-Mediated Vasculogenic Mimicry in the Tumor Microenvironment of TNBC-Derived MDA-MB-231 Breast and Ovarian ES-2 Clear Cell Carcinoma Cells

Vasculogenic mimicry (VM) is defined as the formation of microvascular channels by genetically deregulated cancer cells and is often associated with high tumor grade and cancer therapy resistance. This microcirculation system, independent of endothelial cells, provides oxygen and nutrients to tumors, and contributes also in part to metastasis. VM has been observed in ovarian cancer and in triple negative breast cancer (TNBC) and shown to correlate with decreased overall cancer patient survival. Thus, strategies designed to inhibit VM may improve cancer patient treatments. In this study, sortilin (SORT1) receptor was detected in in vitro 3D capillary-like structures formed by ES-2 ovarian cancer and MDA-MB-231 TNBC-derived cells when grown on Matrigel. SORT1 gene silencing or antibodies directed against its extracellular domain inhibited capillary-like structure formation. In vitro, VM also correlated with increased gene expression of matrix metalloproteinase-9 (MMP-9) and of the cancer stem cell marker CD133. In vivo ES-2 xenograft model showed PAS+/CD31- VM structures (staining positive for both SORT1 and CD133). TH1904, a Doxorubicin-peptide conjugate that is internalized by SORT1, significantly decreased in vitro VM at low nM concentrations. In contrast, VM was unaffected by unconjugated Doxorubicin or Doxil (liposomal Doxorubicin) up to μM concentrations. TH1902, a Docetaxel-peptide conjugate, altered even more efficiently in vitro VM at pM concentrations. Overall, current data evidence for the first time that 1) SORT1 itself exerts a crucial role in both ES-2 and MDA-MB-231 VM, and that 2) VM in these cancer cell models can be efficiently inhibited by the peptide-drug conjugates TH1902/TH1904. These new findings also indicate that both peptide-drug conjugates, in addition to their reported cytotoxicity, could possibly inhibit VM in SORT1-positive TNBC and ovarian cancer patients.