Design, Synthesis, and Antitumor Evaluation of an Opioid Growth Factor Bioconjugate Targeting Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) presents a formidable challenge with high lethality and limited effective drug treatments. Its heightened metastatic potential further complicates the prognosis. Owing to the significant toxicity of current chemotherapeutics, compounds like [Met5]-enkephalin, known as opioid growth factor (OGF), have emerged in oncology clinical trials. OGF, an endogenous peptide interacting with the OGF receptor (OGFr), plays a crucial role in inhibiting cell proliferation across various cancer types. This in vitro study explores the potential anticancer efficacy of a newly synthesized OGF bioconjugate in synergy with the classic chemotherapeutic agent, gemcitabine (OGF-Gem). The study delves into assessing the impact of the OGF-Gem conjugate on cell proliferation inhibition, cell cycle regulation, the induction of cellular senescence, and apoptosis. Furthermore, the antimetastatic potential of the OGF-Gem conjugate was demonstrated through evaluations using blood platelets and AsPC-1 cells with a light aggregometer. In summary, this article demonstrates the cytotoxic impact of the innovative OGF-Gem conjugate on pancreatic cancer cells in both 2D and 3D models. We highlight the potential of both the OGF-Gem conjugate and OGF alone in effectively inhibiting the ex vivo pancreatic tumor cell-induced platelet aggregation (TCIPA) process, a phenomenon not observed with Gem alone. Furthermore, the confirmed hemocompatibility of OGF-Gem with platelets reinforces its promising potential. We anticipate that this conjugation strategy will open avenues for the development of potent anticancer agents.

Hypoxia-Activated Theragnostic Prodrugs (HATPs): Current State and Future Perspectives

“…Similar to PROTACs and other prodrugs, the effect of the linker is highly influential toward the overall bioactivity profile of the final HATP and should be selected in a prudent manner [ 16 , 33 , 34 ]. Additional decorations: The utilization of additional modalities like tumor-homing elements (e.g., peptides [ 35 , 36 , 37 ], D-biotin [ 6 , 38 ]) or nano-formulations [ 39 ] can help ameliorate particular challenges. They are typically invoked to enhance tumor specificity by offering more precise delivery and the overall potency of the developed HATP.…”

“…Additional decorations: The utilization of additional modalities like tumor-homing elements (e.g., peptides [ 35 , 36 , 37 ], D-biotin [ 6 , 38 ]) or nano-formulations [ 39 ] can help ameliorate particular challenges. They are typically invoked to enhance tumor specificity by offering more precise delivery and the overall potency of the developed HATP.…”