Dual Delivery of Gemcitabine and Paclitaxel by Wet‐Spun Coaxial Fibers Induces Pancreatic Ductal Adenocarcinoma Cell Death, Reduces Tumor Volume, and Sensitizes Cells to Radiation

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with surgical resection of the tumor in conjunction with systemic chemotherapy the only potential curative therapy. Up to 80% of diagnosed cases are deemed unresectable, prompting the need for alternative treatment approaches. Herein, coaxial polymeric fibers loaded with two chemotherapeutic agents, gemcitabine (Gem) and paclitaxel (Ptx), are fabricated to investigate the effect of local drug delivery on PDAC cell growth in vitro and in vivo. A wet-spinning fabrication method to form a coaxial fiber with a polycaprolactone shell and alginate core loaded with Ptx and Gem, respectively, is used. In vitro, Gem+Ptx fibers display significant cytotoxicity as well as radiosensitizing properties toward PDAC cell lines greater than the equivalent free drugs, which may be attributed to a radiosensitizing effect of the polymers. In vivo studies assessing Gem+Ptx fiber efficacy found that Gem+Ptx fibers reduce tumor volume in a xenograft mouse model of PDAC. Importantly, no difference in mouse weight, circulating cytokines, or liver function is observed in mice treated with Gem+Ptx fibers compared to the empty fiber controls confirming the safety of the implant approach. With further development, Gem+Ptx fibers can improve the treatment of unresectable PDAC in the future.

Examining the efficacy of localised gemcitabine therapy for the treatment of pancreatic cancer using a hybrid agent-based model

“…Full details for the fabrication and characterisation of alginate fibres loaded with our without gemcitabine are described in Wade et al . [13, 14]. Briefly, gemcitabine-loaded alginate fibres had a uniform surface area from 50 − 120 µm in diameter.…”

“…Full details for this experiment can be found in Wade et al . [13]. All animal experiments were conducted in accordance with the NHMRC Australian Code for the Care and Use of Animals for Scientific Purposes, which requires 3R compliance (replacement, reduction, and refinement) at all stages of animal care and use, and the approval of the Animal Ethics Committee of the University of Wollongong (Australia) under protocol AE18/13.…”

“…As such, there has been a growing interest in the development of localized targeted delivery systems which can modify the bio-distribution of drugs and achieve local drug accumulation in the tumour tissue [10][11][12] (Figure 1). For example, drug-eluting polymeric implants are designed to deliver high concentrations of chemotherapeutic drugs directly at the tumour site, overcoming transport and tissues barriers as well as limiting off-target toxicities [13]. Biodegradable implants, can be designed to provide sustained drug release over weeks or months, avoiding repeated external drug dosing, clinic visits and other surgical interventions.…”

Pancreatic Cancer: Challenges and Opportunities in Locoregional Therapies

“…Additionally, to deliver a combination of GEM and PTX, Wade and colleagues employed two biodegradable polymers, alginate (Alg) and polycaprolactone (PCL), for the synthesis of wet-spun fibres [ 128 ]. GEM was firstly loaded into the water-soluble Alg core while PTX was loaded into the PCL shell.…”

Drug‐Eluting Medical Textiles: From Fiber Production and Textile Fabrication to Drug Loading and Delivery

“…More than 94% of the gemcitabine was released in the first 10 h in the simulated body fluid (SBF) and phospholipase D, while nab‐paclitaxel exhibited a sustained release profile over three weeks with less than 39% of the drug released in PBS. [ 107 ]…”