NIR pH-Responsive PEGylated PLGA Nanoparticles as Effective Phototoxic Agents in Resistant PDAC Cells
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals and Reagents
2.2. Synthesis and Characterization of Bromine-Substituted Cyanine Dye (BrCY7)
2.2.1. Synthesis of BrCY7 Dye
2.2.2. Spectroscopic Characterization of BrCY7 Dye
2.3. Activation and PEGylation of PLGA Resomer
2.4. Preparation of BrCY7-Loaded PEGylated PLGA Nanoparticles
2.5. Yield and Encapsulation Efficiency (EE%)
2.6. Characterization of BrCY7-Loaded PEG-PLGA Nanoparticles
2.7. Measurement of Reactive Oxygen Species (ROS) and Evaluation of the Photodegradation
2.8. Biological Assessment
2.8.1. Cell Culture
2.8.2. Cytotoxicity and Photoactivity
2.8.3. IC50 Determination
2.9. Statistical Analysis
3. Results and Discussion
3.1. Synthesis and Physicochemical Characterization of BrCY7
3.2. Physicochemical Characterization of BrCY7-Loaded PEG-PLGA NPs
3.3. Spectroscopic Characterization of BrCY7-PEG-PLGA NPs and In Vitro Photodegradation Analysis
3.4. ROS Measurement
3.5. In Vitro Photoactivity of BrCY7-Loaded PEG-PLGA
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Mercanti, L.; Sindaco, M.; Mazzone, M.; Di Marcantonio, M.C.; Piscione, M.; Muraro, R.; Mincione, G. PDAC, the Influencer Cancer: Cross-Talk with Tumor Microenvironment and Connected Potential Therapy Strategies. Cancers 2023, 15, 2923. [Google Scholar] [CrossRef] [PubMed]
- Webb, B.A.; Chimenti, M.; Jacobson, M.P.; Barber, D.L. Dysregulated PH: A Perfect Storm for Cancer Progression. Nat. Rev. Cancer 2011, 11, 671–677. [Google Scholar] [CrossRef]
- Riemann, A.; Schneider, B.; Ihling, A.; Nowak, M.; Sauvant, C.; Thews, O.; Gekle, M. Acidic Environment Leads to ROS-Induced MAPK Signaling in Cancer Cells. PLoS ONE 2011, 6, e22445. [Google Scholar] [CrossRef]
- Andreucci, E.; Peppicelli, S.; Ruzzolini, J.; Bianchini, F.; Biagioni, A.; Papucci, L.; Magnelli, L.; Mazzanti, B.; Stecca, B.; Calorini, L. The Acidic Tumor Microenvironment Drives a Stem-like Phenotype in Melanoma Cells. J. Mol. Med. 2020, 98, 1431–1446. [Google Scholar] [CrossRef]
- Audero, M.M.; Carvalho, T.M.A.; Ruffinatti, F.A.; Loeck, T.; Yassine, M.; Chinigò, G.; Folcher, A.; Farfariello, V.; Amadori, S.; Vaghi, C.; et al. Acidic Growth Conditions Promote Epithelial-to-Mesenchymal Transition to Select More Aggressive PDAC Cell Phenotypes In Vitro. Cancers 2023, 15, 2572. [Google Scholar] [CrossRef]
- Park, W.; Chawla, A.; O’Reilly, E.M. Pancreatic Cancer. JAMA 2021, 326, 851. [Google Scholar] [CrossRef] [PubMed]
- Hu, Z.I.; O’Reilly, E.M. Therapeutic Developments in Pancreatic Cancer. Nat. Rev. Gastroenterol. Hepatol. 2024, 21, 7–24. [Google Scholar] [CrossRef] [PubMed]
- Carvalho, T.M.A.; Audero, M.M.; Greco, M.R.; Ardone, M.; Maggi, T.; Mallamaci, R.; Rolando, B.; Arpicco, S.; Ruffinatti, F.A.; Pla, A.F.; et al. Tumor Microenvironment Modulates Invadopodia Activity of Non-Selected and Acid-Selected Pancreatic Cancer Cells and Its Sensitivity to Gemcitabine and C18-Gemcitabine. Cells 2024, 13, 730. [Google Scholar] [CrossRef]
- Niculescu, A.-G.; Grumezescu, A.M. Photodynamic Therapy—An Up-to-Date Review. Appl. Sci. 2021, 11, 3626. [Google Scholar] [CrossRef]
- Shackley, D.C.; Whitehurst, C.; Clarke, N.W.; Betts, C.; Moore, J. V Photodynamic Therapy. J. R. Soc. Med. 1999, 92, 562–565. [Google Scholar] [CrossRef]
- Correia, J.H.; Rodrigues, J.A.; Pimenta, S.; Dong, T.; Yang, Z. Photodynamic Therapy Review: Principles, Photosensitizers, Applications, and Future Directions. Pharmaceutics 2021, 13, 1332. [Google Scholar] [CrossRef] [PubMed]
- Allison, R.R.; Moghissi, K. Photodynamic Therapy (PDT): PDT Mechanisms. Clin. Endosc. 2013, 46, 24. [Google Scholar] [CrossRef]
- Wang, S.; Zhang, C.; Fang, F.; Fan, Y.; Yang, J.; Zhang, J. Beyond Traditional Light: NIR-II Light-Activated Photosensitizers for Cancer Therapy. J. Mater. Chem. B 2023, 11, 8315–8326. [Google Scholar] [CrossRef] [PubMed]
- Dereje, D.M.; Pontremoli, C.; Moran Plata, M.J.; Visentin, S.; Barbero, N. Polymethine Dyes for PDT: Recent Advances and Perspectives to Drive Future Applications. Photochem. Photobiol. Sci. 2022, 21, 397–419. [Google Scholar] [CrossRef] [PubMed]
- Pontremoli, C.; Chinigò, G.; Galliano, S.; Moran Plata, M.J.; Dereje, D.M.; Sansone, E.; Gilardino, A.; Barolo, C.; Fiorio Pla, A.; Visentin, S.; et al. Photosensitizers for Photodynamic Therapy: Structure-Activity Analysis of Cyanine Dyes through Design of Experiments. Dye. Pigment. 2023, 210, 111047. [Google Scholar] [CrossRef]
- Ciubini, B.; Visentin, S.; Serpe, L.; Canaparo, R.; Fin, A.; Barbero, N. Design and Synthesis of Symmetrical Pentamethine Cyanine Dyes as NIR Photosensitizers for PDT. Dye. Pigment. 2019, 160, 806–813. [Google Scholar] [CrossRef]
- Lange, N.; Szlasa, W.; Saczko, J. Potential of Cyanine Derived Dyes in Photodynamic Therapy. Pharmaceutics 2021, 13, 818. [Google Scholar] [CrossRef]
- Zheng, Y.; Li, Z.; Chen, H.; Gao, Y. Nanoparticle-Based Drug Delivery Systems for Controllable Photodynamic Cancer Therapy. Eur. J. Pharm. Sci. 2020, 144, 105213. [Google Scholar] [CrossRef]
- Jiao, L.; Liu, Y.; Zhang, X.; Hong, G.; Zheng, J.; Cui, J.; Peng, X.; Song, F. Constructing a Local Hydrophobic Cage in Dye-Doped Fluorescent Silica Nanoparticles to Enhance the Photophysical Properties. ACS Cent. Sci. 2020, 6, 747–759. [Google Scholar] [CrossRef]
- Zhou, H.; Hou, X.; Liu, Y.; Zhao, T.; Shang, Q.; Tang, J.; Liu, J.; Wang, Y.; Wu, Q.; Luo, Z.; et al. Superstable Magnetic Nanoparticles in Conjugation with Near-Infrared Dye as a Multimodal Theranostic Platform. ACS Appl. Mater. Interfaces 2016, 8, 4424–4433. [Google Scholar] [CrossRef]
- Zhang, B.; Wei, L.; Chu, Z. Development of Indocyanine Green Loaded Au@Silica Core Shell Nanoparticles for Plasmonic Enhanced Light Triggered Therapy. J. Photochem. Photobiol. A Chem. 2019, 375, 244–251. [Google Scholar] [CrossRef]
- Makadia, H.K.; Siegel, S.J. Poly Lactic-Co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier. Polymers 2011, 3, 1377–1397. [Google Scholar] [CrossRef]
- Gaglio, S.C.; Donini, M.; Denbaes, P.E.; Dusi, S.; Perduca, M. Oxyresveratrol Inhibits R848-Induced Pro-Inflammatory Mediators Release by Human Dendritic Cells Even When Embedded in PLGA Nanoparticles. Molecules 2021, 26, 2106. [Google Scholar] [CrossRef]
- Ghitman, J.; Biru, E.I.; Stan, R.; Iovu, H. Review of Hybrid PLGA Nanoparticles: Future of Smart Drug Delivery and Theranostics Medicine. Mater. Des. 2020, 193, 108805. [Google Scholar] [CrossRef]
- Korbelik, M.; Madiyalakan, R.; Woo, T.; Haddadi, A. Antitumor Efficacy of Photodynamic Therapy Using Novel Nanoformulations of Hypocrellin Photosensitizer SL052. Photochem. Photobiol. 2012, 88, 188–193. [Google Scholar] [CrossRef] [PubMed]
- Ricci-Júnior, E.; Marchetti, J.M. Zinc(II) Phthalocyanine Loaded PLGA Nanoparticles for Photodynamic Therapy Use. Int. J. Pharm. 2006, 310, 187–195. [Google Scholar] [CrossRef]
- Verderio, P.; Bonetti, P.; Colombo, M.; Pandolfi, L.; Prosperi, D. Intracellular Drug Release from Curcumin-Loaded PLGA Nanoparticles Induces G2/M Block in Breast Cancer Cells. Biomacromolecules 2013, 14, 672–682. [Google Scholar] [CrossRef]
- Sah, H.; Thoma, L.A.; Desu, H.R.; Sah, E.; Wood, G.C. Thoma Concepts and Practices Used to Develop Functional PLGA-Based Nanoparticulate Systems. Int. J. Nanomed. 2013, 8, 747–765. [Google Scholar] [CrossRef]
- Chen, Y.; Hasan Huda, N.; AE Benson, H. Development and Analysis of Functionalized Poly(Lactide-Co-Glycolide)Polymer for Drug Delivery. SOJ Pharm. Pharm. Sci. 2017, 4, 1–8. [Google Scholar] [CrossRef]
- El-Hammadi, M.M.; Arias, J.L. Recent Advances in the Surface Functionalization of PLGA-Based Nanomedicines. Nanomaterials 2022, 12, 354. [Google Scholar] [CrossRef]
- Sims, L.B.; Curtis, L.T.; Frieboes, H.B.; Steinbach-Rankins, J.M. Enhanced Uptake and Transport of PLGA-Modified Nanoparticles in Cervical Cancer. J. Nanobiotechnology 2016, 14, 33. [Google Scholar] [CrossRef] [PubMed]
- Serpe, L.; Ellena, S.; Barbero, N.; Foglietta, F.; Prandini, F.; Gallo, M.P.; Levi, R.; Barolo, C.; Canaparo, R.; Visentin, S. Squaraines Bearing Halogenated Moieties as Anticancer Photosensitizers: Synthesis, Characterization and Biological Evaluation. Eur. J. Med. Chem. 2016, 113, 187–197. [Google Scholar] [CrossRef]
- Okoh, O.A.; Bisby, R.H.; Lawrence, C.L.; Rolph, C.E.; Smith, R.B. Promising Near-Infrared Non-Targeted Probes: Benzothiazole Heptamethine Cyanine Dyes. J. Sulfur. Chem. 2014, 35, 42–56. [Google Scholar] [CrossRef]
- El-Hammadi, M.M.; Delgado, Á.V.; Melguizo, C.; Prados, J.C.; Arias, J.L. Folic Acid-Decorated and PEGylated PLGA Nanoparticles for Improving the Antitumour Activity of 5-Fluorouracil. Int. J. Pharm. 2017, 516, 61–70. [Google Scholar] [CrossRef] [PubMed]
- Dereje, D.M.; Pontremoli, C.; García, A.; Galliano, S.; Colilla, M.; González, B.; Vallet-Regí, M.; Izquierdo-Barba, I.; Barbero, N. Poly Lactic-Co-Glycolic Acid (PLGA) Loaded with a Squaraine Dye as Photosensitizer for Antimicrobial Photodynamic Therapy. Polymers 2024, 16, 1962. [Google Scholar] [CrossRef]
- Rojas-Buzo, S.; Pontremoli, C.; De Toni, S.; Bondar, K.; Galliano, S.; Paja, H.; Civalleri, B.; Fiorio Pla, A.; Barolo, C.; Bonino, F.; et al. Hafnium-Based Metal-Organic Framework Nanosystems Entrapping Squaraines for Efficient NIR-Responsive Photodynamic Therapy. ACS Appl. Mater. Interfaces 2024, 17, 524–536. [Google Scholar] [CrossRef]
- Ortega-Forte, E.; Rovira, A.; Ashoo, P.; Izquierdo-García, E.; Hally, C.; Abad-Montero, D.; Jordà-Redondo, M.; Vigueras, G.; Deyà, A.; Hernández, J.L.; et al. Achieving Red-Light Anticancer Photodynamic Therapy under Hypoxia Using Ir(III)–COUPY Conjugates. Inorg. Chem. Front. 2025. [Google Scholar] [CrossRef]
- Tang, Y.; Li, Y.; Li, B.; Song, W.; Qi, G.; Tian, J.; Huang, W.; Fan, Q.; Liu, B. Oxygen-Independent Organic Photosensitizer with Ultralow-Power NIR Photoexcitation for Tumor-Specific Photodynamic Therapy. Nat. Commun. 2024, 15, 2530. [Google Scholar] [CrossRef]
- Mustafa, S.; Devi, V.K.; Pai, R.S. Effect of PEG and Water-Soluble Chitosan Coating on Moxifloxacin-Loaded PLGA Long-Circulating Nanoparticles. Drug Deliv. Transl. Res. 2017, 7, 27–36. [Google Scholar] [CrossRef]
- Arya, G.; Das, M.; Sahoo, S.K. Evaluation of Curcumin Loaded Chitosan/PEG Blended PLGA Nanoparticles for Effective Treatment of Pancreatic Cancer. Biomed. Pharmacother. 2018, 102, 555–566. [Google Scholar] [CrossRef]
- Öztürk, K.; Kaplan, M.; Çalış, S. Effects of Nanoparticle Size, Shape, and Zeta Potential on Drug Delivery. Int. J. Pharm. 2024, 666, 124799. [Google Scholar] [CrossRef] [PubMed]
- Yusuf, A.; Almotairy, A.R.Z.; Henidi, H.; Alshehri, O.Y.; Aldughaim, M.S. Nanoparticles as Drug Delivery Systems: A Review of the Implication of Nanoparticles’ Physicochemical Properties on Responses in Biological Systems. Polymers 2023, 15, 1596. [Google Scholar] [CrossRef] [PubMed]
- de Oliveira, A.M.; Jäger, E.; Jäger, A.; Stepánek, P.; Giacomelli, F.C. Physicochemical Aspects behind the Size of Biodegradable Polymeric Nanoparticles: A Step Forward. Colloids Surf. A Physicochem. Eng. Asp. 2013, 436, 1092–1102. [Google Scholar] [CrossRef]
- Dereje, D.M.; García, A.; Pontremoli, C.; González, B.; Colilla, M.; Vallet-Regí, M.; Izquierdo-Barba, I.; Barbero, N. Squaraine-Loaded Mesoporous Silica Nanoparticles for Antimicrobial Photodynamic Therapy against Bacterial Infection. Microporous Mesoporous Mater. 2024, 372, 113096. [Google Scholar] [CrossRef]
- Thews, O.; Riemann, A. Tumor PH and Metastasis: A Malignant Process beyond Hypoxia. Cancer Metastasis Rev. 2019, 38, 113–129. [Google Scholar] [CrossRef]
- Boedtkjer, E.; Pedersen, S.F. The Acidic Tumor Microenvironment as a Driver of Cancer. Annu. Rev. Physiol. 2020, 82, 103–126. [Google Scholar] [CrossRef]
- Luo, J.; Meng, X.; Su, J.; Ma, H.; Wang, W.; Fang, L.; Zheng, H.; Qin, Y.; Chen, T. Biotin-Modified Polylactic-Co-Glycolic Acid Nanoparticles with Improved Antiproliferative Activity of 15,16-Dihydrotanshinone I in Human Cervical Cancer Cells. J. Agric. Food Chem. 2018, 66, 9219–9230. [Google Scholar] [CrossRef]
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Dereje, D.M.; Bianco, F.; Pontremoli, C.; Fiorio Pla, A.; Barbero, N. NIR pH-Responsive PEGylated PLGA Nanoparticles as Effective Phototoxic Agents in Resistant PDAC Cells. Polymers 2025, 17, 1101. https://doi.org/10.3390/polym17081101
Dereje DM, Bianco F, Pontremoli C, Fiorio Pla A, Barbero N. NIR pH-Responsive PEGylated PLGA Nanoparticles as Effective Phototoxic Agents in Resistant PDAC Cells. Polymers. 2025; 17(8):1101. https://doi.org/10.3390/polym17081101
Chicago/Turabian StyleDereje, Degnet Melese, Francesca Bianco, Carlotta Pontremoli, Alessandra Fiorio Pla, and Nadia Barbero. 2025. "NIR pH-Responsive PEGylated PLGA Nanoparticles as Effective Phototoxic Agents in Resistant PDAC Cells" Polymers 17, no. 8: 1101. https://doi.org/10.3390/polym17081101
APA StyleDereje, D. M., Bianco, F., Pontremoli, C., Fiorio Pla, A., & Barbero, N. (2025). NIR pH-Responsive PEGylated PLGA Nanoparticles as Effective Phototoxic Agents in Resistant PDAC Cells. Polymers, 17(8), 1101. https://doi.org/10.3390/polym17081101