Pancreatic ductal adenocarcinoma (PDAC) is a devastating lethal malignancy, accounting for more than 90 % of pancreatic cancers and ranking as the seventh leading cause of cancer-related deaths worldwide (Siegel et al., 2024, Wong et al., 2017). With a 5-year survival rate of less than 10 %, PDAC is one of the deadliest cancers, primarily due to the challenges associated with early diagnosis and its rapid progression (Rawla et al., 2019). Despite advancements in surgical techniques, the 5-year survival rate for patients following surgery remains below 30 %, and only 15–20 % of patients are eligible for surgery due to factors such as distant metastasis, vascular involvement, and the impact on digestive and metabolic functions (Halbrook et al., 2023). Chemotherapy remains a mainstay treatment for PDAC. Approved chemotherapeutic agents include gemcitabine, oxaliplatin, and albumin-bound paclitaxel (Springfeld et al., 2019). However, the limited efficacy and adverse effects associated with these small molecules have hindered their clinical success. Therefore, PDAC is in urgent need of more effective and less toxic new therapeutic options.

FOLFIRINOX, a multi-agent chemotherapy regimen consisting of folinic acid, fluorouracil, irinotecan, and oxaliplatin, has gain acceptance as a front-line treatment protocol in clinical practice (Park et al., 2021). Among these agents, irinotecan, a water-soluble derivative of 7-ethyl-10-hydroxycamptothecin (SN38), has garnered attention for its potent antitumor activity. SN38 is a powerful inhibitor of DNA topoisomerase I, effectively suppressing tumor cell proliferation (Pommier, 2006). Unfortunately, its clinical use is hampered by dose-limiting toxicity and extremely low aqueous solubility. Irinotecan must be converted to the active form, SN38, by carboxylesterases in the body, but this conversion efficiency is inefficient, typically occurring at rates below 8 %, leading to suboptimal therapeutic outcomes (Rivory, 1996). Since SN38 is 100–1000 times more potent than irinotecan in cytotoxicity assays, using SN38 directly could bypass the inefficient conversion process, thereby improving its antitumor efficacy. Nanoparticle-mediated drug delivery systems offer a promising approach to enhance the solubility, circulation time, tumor targeting, and overall therapeutic index of a given agent, while minimizing side effects (Shi et al., 2017, Xian et al., 2024, Ren et al., 2024). However, formulating SN38 into nanoparticles is technically challenging due to its inherent planar structure and moderate polarity (Bala et al., 2013). Several research groups, including ours, have demonstrated that SN38 can be chemically engineered to create new entities that self-assemble or co-assemble with other delivery matrices to produce injectable nanomedicines (Xie et al., 2016, Wang et al., 2014, Wang et al., 2021, Kwak et al., 2012). Therefore, designing novel SN38 prodrugs with intravenous injectability, and exploiting the hydrolytic release of active SN38 independent of enzymatic activation, could substantially improve the therapeutic potential of the SN38 molecule.

Unsaturated fatty acids are essential for human health and play critical physiological roles. Due to their favorable biocompatibility, potential pharmacological benefits, and structural flexibility, unsaturated fatty acids have been explored as building blocks for the development of efficient drug delivery systems in oncology (Sun et al., 2017, Pinot et al., 2014). In previous studies, we demonstrated that polyunsaturated fatty acids (PUFAs), such as linoleic acid (LA), can effectively enhance the lipophilicity of SN38 by esterifying the 10-OH position (Fang et al., 2016). This chemical modification increased the compatibility of SN38 derivatives with drug delivery vehicles, leading to the improved in vivo performance when delivered through self-assembled nanoparticles, polymeric micelles, or liposomes. However, the rapid hydrolysis of the phenyl ester linkage in the prodrug scaffold led to suboptimal stability and pharmacokinetics. Inspired by studies that reported the modification of the 20-OH position of SN38 (Kwak et al., 2012), we hypothesized that dual modification of both the 10-OH and 20-OH positions with unsaturated fatty acids could enhance the compatibility of the resulting prodrugs with polymer matrices, thereby increasing the overall stability and antitumor efficacy.

To test our hypothesis, we covalently modified the hydroxyl groups of SN38 using PUFAs as pro-moieties to generate mono- or dual-engineered prodrugs that were further developed into cytotoxic nanotherapeutics using amphiphilic polymers for intravenous injection (Fig. 1a). Characterization of these formulations allowed for the identification of prodrug candidates that were colloidally stable and well-suited for preclinical studies. Further investigations involving in vitro cell-based assays and in vivo studies using a PDAC tumor-bearing mouse model confirmed the enhanced antitumor efficacy and safety of the SN38 prodrug-loaded nanoparticles. In an additional orthotopic PDAC tumor model, we demonstrated that compared to the clinically used drugs, the optimized nanotherapeutic showed superior pharmacokinetics and in vivo antitumor efficacy. Our results underscore the value of rational prodrug engineering in optimizing the physicochemical properties of therapeutic agents, improving their compatibility with delivery systems, and ultimately enhancing their therapeutic potential.