Enhanced Antitumor Efficacy of Gemcitabine through Dual-Responsive Nanoparticle-Mediated Therapy in Pancreatic Cancer

• Indravesh Indravesh

  Kalinga University, Naya Raipur, Chhattisgarh, India

• Arvind Kumar Yadav

  Kalinga University, Naya Raipur, Chhattisgarh, India

One of the most deadly and malignant cancers is pancreatic cancer, and there is a very limited available therapy, and the patients die from the cancer. For treating pancreatic cancer, one of the most extensively used chemotherapeutic agents is gemcitabine, and its clinical efficiency is hindered by its rapid metabolism, minimal tumor accumulation, and systemic toxicity. The aim of this study is to construct a dual-responsive nanoparticle system for targeting and controlled release of gemcitabine in the pancreatic tumor microenvironment for enhanced therapeutic outcome of the drug. These prepared nanoparticles were sensitive to pH as well as temperature and consequently showed tumor-specific release of gemcitabine with reduced off-target side effects. In vitro and in vivo studies with pancreatic cancer models were performed to assess the therapeutic activity of the formulation. The cellular uptake experiments showed efficient uptake of the nanoparticles by PANC-1 pancreatic cancer cells, leading to improved drug delivery into cells. Evaluation of the cytotoxicity showed that the anticancer activity of the therapy using the nanoparticles was significantly better with an IC50 value of 4.8µM versus 12.5µM for free gemcitabine. In a murine pancreatic tumor xenograft, gemcitabine-loaded nanoparticles were able to inhibit tumor growth by 45%, while free gemcitabine was able to inhibit tumor growth by 20%. Moreover, the dual-responsive system showed controlled and sustained drug release in tumor-relevant conditions, which improved the therapeutic targeting. The plasma exposure of the drug in the nanoparticle formulation was enhanced by about 4-fold (AUC0-24h 86.4 vs. 21.7 µg·h/mL) and the tumor accumulation of the drug was enhanced by about 5-fold (8.4 vs. 1.6 %ID/g) compared to free gemcitabine, and the plasma level of hepatic enzymes was within normal range in the nanoparticle animals, while plasma exposure of free gemcitabine showed significant elevation in levels of ALT (p = 0.01), directly supporting the reduced systemic toxicity of the formulation. The results show that delivery of gemcitabine using nanoparticles with dual responsiveness can significantly improve the antitumor activity and drug bioavailability and decrease systemic toxicity based on preclinical pharmacokinetic and biochemical evidence in a single xenograft model. The proposed strategy is a promising proof-of-concept strategy for the enhancement of pancreatic cancer treatment and an example of stimulus-responsive nanomedicine platforms in precision oncology. Additional preclinical studies are needed to prove long-term safety and to translate it into clinical use.

[1] Li Z, Shu R, Li M, Wang X, Chen X, Chen H, Chen J. Recent progress in gemcitabine-loaded nanoparticles for pancreatic cancer therapy: a review. Nanoscale 2025; 17(30): 17480-17507.

[2] Kafi DK, Ayyash AN. Density functional theory and molecular docking study to lutein molecule for COVID-19 protease inhibitors. Applied Nanoscience (Switzerland) 2023; 13(8): 5477-5488.

[3] Nakka NMR, Rachamala HK, Angom RS, Indla NR, Dutta SK, Wang E, Mukhopadhyay D. Dual drug-loaded tumor-targeted polymeric nanoparticles for enhancing therapeutic response in pancreatic ductal adenocarcinoma. Materials Today Bio 2024; 28: 101199.

[4] Raghuram G. Synthesis and Characterization of Novel Nanoparticles for Targeted Cancer Therapy. Clinical Journal for Medicine, Health and Pharmacy 2024; 2(4): 21-30.

[5] Song H, Chen H, Chen Q, Fan H, Li C, Wang Y, Jiang C. Size and Charge Dual‐Switchable Nanoparticles for Achieving Chemosensitization and Immune Infiltration against Pancreatic Ductal Adenocarcinoma. Advanced Functional Materials 2025; 35(1): 2411643.

[6] Iyer R, Deshpande N. Nanotechnology and their Applications in Chiral and Achiral Separating Mechanisms. Engineering Perspectives in Filtration and Separation 2024; 2(4): 7-13.

[7] Olajubutu O, Ogundipe OD, Adebayo A, Adesina SK. Drug delivery strategies for the treatment of pancreatic cancer. Pharmaceutics 2023; 15(5): 1318.

[8] Aslian HA, Taherizadeh M, Rafienia M, Raeisi P, Bidram E. Green synthesis of gold nanoparticles using Spirulina platensis microalgae extract and its impact on the blood lipid profile in male wistar rats. Journal of Animal Environment 2025; 17(2): 31–40.

[9] Li C, Chen Q, Jiang C. Intelligent micelles for on-demand drug delivery targeting extracellular matrix of pancreatic cancer. Journal of Controlled Release 2024; 373: 879-889.

[10] Musa KM, Alshemary KKH. The Role of Nanoparticles in Sunscreen: UV Protection and Particle Size. International Academic Journal of Science and Engineering 2024; 11(1): 153–164.

[11] Umar S, Catazaro J, Wachira J, Samokhvalov A. Mechano-chemical encapsulation of gemcitabine hydrochloride on metal-organic framework, preparation of shaped pellets, delayed drug release, and time-dependent toxicity to PANC− 1 cancer cells. Journal of Drug Delivery Science and Technology 2025; 111: 107195.

[12] Yugatama A, Huang YL, Hsu MJ, Lin JP, Chao FC, Lam JK, Hsieh CM. Oral delivery of photopolymerizable nanogels loaded with gemcitabine for pancreatic cancer therapy: formulation design, and in vitro and in vivo evaluations. International Journal of Nanomedicine 2024: 3753-3772.

[13] Luo W, Zhang T. The new era of pancreatic cancer treatment: application of nanotechnology breaking through bottlenecks. Cancer Letters 2024; 594: 216979.

[14] Wang X, Yin X, Li Y, Zhang S, Hu M, Wei M, Li Z. Novel insight and perspectives of nanoparticle-mediated gene delivery and immune-modulating therapies for pancreatic cancer. Journal of nanobiotechnology 2024; 22(1): 771.

[15] Wu HM, Wang SL, Li XX, Ai KX. Fabrication of gemcitabine and mitoxantrone loaded PLG/mesoporous silica nanofibers: investigation of in vitro drug release and anticancer activity in pancreatic cancer cells. BioNanoScience 2025; 15(1): 166.

[16] Dubey S, Patel SK, Das C, Singh S, Sharma G, Kundu CN, Minz S. Formulation and in vitro evaluation of lipid-polymer hybrid nanoparticles for targeted delivery of gemcitabine hydrochloride in the treatment of hepatocellular carcinoma. 3 Biotech 2026; 16(1): 2.

[17] Panja S, Kapoor E, Siddhanta K, Jogdeo CM, Sil D, Khan RI, Oupický D. Bioactive polymers as stimulus-responsive anti-metastatic combination agents to treat pancreatic cancer. Biomaterials 2025; 320: 123255.

[18] Conte M, Cauda V. Multimodal therapies against pancreatic ductal adenocarcinoma: a review on synergistic approaches toward ultimate nanomedicine treatments. Advanced Therapeutics 2022; 5(11): 2200079.

[19] Kang X, Bu F, Feng W, Liu F, Yang X, Li H, Wang X. Dual‐cascade responsive nanoparticles enhance pancreatic cancer therapy by eliminating tumor‐resident intracellular bacteria. Advanced Materials 2022; 34(49): 2206765.

[20] Bai X, Smith ZL, Wang Y, Butterworth S, Tirella A. Sustained drug release from smart nanoparticles in cancer therapy: a comprehensive review. Micromachines 2022; 13(10): 1623.

• PDF

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.