Albumin-mediated Delivery of Therapeutic Peptides for Pancreatic Cancer Therapy

Bioactive peptides are promising agents for therapeutic applications, however their small size results in poor stability, low bioavailability and rapid renal clearance, so its widespread use is limited. To address these issues, fusing or conjugating peptides to suitable molecular scaffolds is required. In this study, human serum albumin (HSA) is used as a delivery carrier for human β-defensin-2 peptides (HBD2) in the production of HSA-delivered defensin complex (ADDC) to facilitate its cellular uptake and transport to intracellular targets. Conjugation can improve the stability of HBD2, while extend the circulation time and promote its accumulation within tumor, thereby improving the therapeutic efficacy. Herein, ADDC provides a protective structure against the harsh external environment and serves as a passive tumor-targeted system. Our data showed that the combination of ADDC with clinically relevant drugs, such as Doxorubicin, Gemcitabine, Cisplatin, and Cetuximab can significantly increase the cytotoxicity of ADDC on human pancreatic cancer cells. The results of bioinformatics analysis also revealed that ADDC may affect the metabolic processes, gene transcription and apoptosis of pancreatic cancer cells. Collectively, ADDC exhibited specific tumor targeting capabilities, low systemic toxicity, and enhanced antitumor efficacy in a mouse model of pancreatic cancer. The whole genome microarray expression profiling was employed to research the molecular mechanism of ADDC action and identify its target genes, thereby facilitating ADDC development. The gene expression of MIA PaCa-2 cells treated with 15 μM ADDC, HSA, or HBD2 was analyzed, untreated cells served as a vehicle control.