Enhancement of irinotecan oral bioavailability through quality by design approach in nanobubble formulation development
DOI:
https://doi.org/10.1590/s2175-97902026e24587Keywords:
Box-Behnken design, Colorectal cancer, Dextran sulphate, Nanobubbles, IrinotecanAbstract
Irinotecan (IRO), a potential drug approved by the USFDA used in colorectal cancer, hinders its therapeutic applications due to low solubility and very poor bioavailability. The current research aims to use Dextran sulphate (DEX) nanobubbles (NBs) as a delivery system for IRO to improve the bioavailability and enhance its beneficial effect. Using emulsification technique we formulated IRO-loaded dextran sulphate NBs and optimized utilizing a Box Behnken design with input of process and formulation parameters. The characterization of NBs checked for particle size, drug loading, entrapment efficiency, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimeter (DSC), X-ray diffraction studies, and also stability studies, in vitro and in-vivo studies on rats. The optimized NBs presented 89.8 ± 9.5 nm of particle size, -18.6 ± 1.2 mV of zeta potential, and 0.284 ± 0.108 of polydispersity index. NBs showed 72.86 ± 1.54% of entrapment efficiency and 33.57 ± 2.10% of drug loading, while in vitro study showed that ultrasound enhanced the release of drugs by 99%, compared to plain drug, which was only 35%. Characterization studies confirmed the absence of drug-polymer interaction. In conclusion, the findings of this study suggested that this type of formulation might be an alternative for cancer treatment.
Downloads
References
Abdelnabi D, Lastakchi S, Watts C, Atkins H, Hingtgen S, Valdivia A, et al. Local administration of irinotecan using an implantable drug delivery device stops high-grade glioma tumor recurrence in a glioblastoma tumor model. Drug Deliv Transl Res. 2024;14(11):3070-3088.
Baroni S, Argenziano M, La Cava F, Soster M, Garello F, Lembo D, et al. Hard-Shelled Glycol Chitosan Nanoparticles for Dual MRI/US Detection of Drug Delivery/Release: A Proof-of-Concept Study. Nanomaterials (Basel). 2023 Aug 1;13(15):2227.
Basak D, Arrighi S, Darwiche Y, Deb S. Comparison of Anticancer Drug Toxicities: Paradigm Shift in Adverse Effect Profile. Life (Basel). 2021 Dec 29;12(1):48.
Bhaskaran NA, Jitta SR, Salwa, Cheruku S, Kumar N, Kumar L. Orally delivered solid lipid nanoparticles of irinotecan coupled with chitosan surface modification to treat colon cancer: Preparation, in-vitro and in-vivo evaluations. Int J Biol Macromol. 2022 Jun 30;211:301-315. doi: 10.1016/j.ijbiomac.2022.05.060.
Campos FL, de Alcântara Lemos J, Oda CMR, de Oliveira Silva J, Fernandes RS, Miranda SEM, et al. Irinotecan-Loaded Polymeric Micelles as a Promising Alternative to Enhance Antitumor Efficacy in Colorectal Cancer Therapy. Polymers (Basel). 2022 Nov 14;14(22):4905.
Cavalli R, Bisazza A, Giustetto P, Civra A, Lembo D, Trotta G, et al. Preparation and characterization of dextran nanobubbles for oxygen delivery. Int J Pharm. 2009 Nov 3;381(2):160-5. doi: 10.1016/j.ijpharm.2009.07.010. Epub 2009 Jul 17. PMID: 19616610.
Chabot GG. Clinical pharmacokinetics of irinotecan. Clin Pharmacokinet. 1997 Oct;33(4):245-59.
Chen F, Huang G, Huang H. Preparation and application of dextran and its derivatives as carriers. Int J Biol Macromol. 2020 Feb 15;145:827-834. doi: 10.1016/j.ijbiomac.2019.11.151.
Chinna Babu P, Sundaraganesan N, Sudha S, Aroulmoji V, Murano E. Molecular structure and vibrational spectra of Irinotecan: a density functional theoretical study. Spectrochim Acta A Mol Biomol Spectrosc. 2012;98:1-6.
Din FU, Jin SG, Choi HG. Particle and Gel Characterization of Irinotecan-Loaded Double-Reverse Thermosensitive Hydrogel. Polymers (Basel). 2021 Feb 13;13(4):551.
Duan B, Zhao Y, Bai J, Wang J, Duan X, Luo X, et al. Colorectal Cancer: An Overview. In: Morgado-Diaz JA, editor. Gastrointestinal Cancers. Brisbane (AU): Exon Publications. 2022; Sep 30. Chapter 1.
Duan L, Yang L, Jin J, Yang F, Liu D, Hu K et al. Micro/nano-bubble-assisted ultrasound to enhance the EPR effect and potential theranostic applications. Theranostics. 2020 Jan 1;10(2):462-483.
Ette EI. Stability and performance of a population pharmacokinetic model. J Clin Pharmacol. 1997 Jun;37(6):486-95. doi: 10.1002/j.1552-4604.1997.tb04326.x. PMID: 9208355.
Fujita K, Kubota Y, Ishida H, Sasaki Y. Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer. World J Gastroenterol. 2015 Nov 21;21(43):12234-48.
Gagliardi A, Giuliano E, Venkateswararao E, Fresta M, Bulotta S, Awasthi V, et al. Biodegradable Polymeric Nanoparticles for Drug Delivery to Solid Tumors. Front Pharmacol. 2021 Feb 3;12:601626.
Iliescu RI, Andronescu E, Ghitulica CD, Voicu G, Ficai A, Hoteteu M. Montmorillonite-alginate nanocomposite as a drug delivery system--incorporation and in vitro release of irinotecan. Int J Pharm. 2014 Mar 25;463(2):184-92.
Kancheva M, Aronson L, Pattilachan T, Sautto F, Daines B, Thommes D, et al. Bubble-Based Drug Delivery Systems: Next-Generation Diagnosis to Therapy. J Funct Biomater. 2023 Jul 17;14(7):373.
Karimi M, Solati N, Amiri M, Mirshekari H, Mohamed E, Taheri M, et al. Carbon nanotubes part I: preparation of a novel and versatile drug-delivery vehicle. Expert Opin Drug Deliv. 2015 Jul;12(7):1071-87.
Kciuk M, Marciniak B, Kontek R. Irinotecan-Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview. Int J Mol Sci. 2020 Jul 12;21(14):4919.
Kishore MK, Jaya PD, Basava Rao VV. Chitosan nanobubbles development and evaluation for the delivery of Sunitinib-an anticancer agent. Int J App Pharm. 2022;14(6):58-67.
Kümler I, Sørensen PG, Palshof J, Høgdall E, Skovrider-Ruminski W, Theile S, et al. Oral administration of irinotecan in patients with solid tumors: an open-label, phase I, dose escalating study evaluating safety, tolerability and pharmacokinetics. Cancer Chemother Pharmacol. 2019 Jan;83(1):169-178.
Laizure SC, Herring V, Hu Z, Witbrodt K, Parker RB. The role of human carboxylesterases in drug metabolism: have we overlooked their importance? Pharmacotherapy. 2013 Feb;33(2):210-22.
Lintoiu-Ursut B, Tulin A, Constantinoiu S. Recurrence after hepatic resection in colorectal cancer liver metastasis -Review article-. J Med Life. 2015;8 Spec Issue (Spec Issue):12-4.
Mahdy MS, Azmy AF, Dishisha T, Mohamed WR, Ahmed KA, Hassan A, et al. Irinotecan-gut microbiota interactions and the capability of probiotics to mitigate Irinotecan-associated toxicity. BMC Microbiol. 2023 Mar 2;23(1):53.
Malatesta L, Cosco D, Paolino D, Cilurzo F, Costa N, Di Tullio A, et al. Simultaneous quantification of Gemcitabine and Irinotecan hydrochloride in rat plasma by using high performance liquid chromatography-diode array detector. J Pharm Biomed Anal. 2018 Sep 10;159:192-199.
Messerschmidt V, Ren W, Tsipursky M, Irudayaraj J. Characterization of Oxygen Nanobubbles and In Vitro Evaluation of Retinal Cells in Hypoxia. Transl Vis Sci Technol. 2023 Feb 1;12(2):16.
Milano G, Innocenti F, Minami H. Liposomal irinotecan (Onivyde): Exemplifying the benefits of nanotherapeutic drugs. Cancer Sci. 2022 Jul;113(7):2224-2231.
Mirón-Barroso S, Correia JS, Frampton AE, Lythgoe MP, Clark J, Tookman L, et al. Polymeric Carriers for Delivery of RNA Cancer Therapeutics. Noncoding RNA. 2022;8(4):58.
Navarro-Becerra JA, Borden MA. Targeted Microbubbles for Drug, Gene, and Cell Delivery in Therapy and Immunotherapy. Pharmaceutics. 2023 May 30;15(6):1625.
Nicolas J, Mura S, Brambilla D, Mackiewicz N, Couvreur P. Design, functionalization strategies and biomedical applications of targeted biodegradable/biocompatible polymer-based nanocarriers for drug delivery. Chem Soc Rev. 2013 Feb 7;42(3):1147-235.
Patel K, Shah S, Patel J. Solid dispersion technology as a formulation strategy for the fabrication of modified release dosage forms: A comprehensive review. Daru. 2022 Jun;30(1):165-189.
Ponnaganti M, Babu AK, Palanati M. Formulation and optimization of Ceritinib loaded nanobubbles by Box-Behnken Design. Int J App Pharm. 2022;14(4):219-226.
Rahmani S, Park TH, Dishman AF, Lahann J. Multimodal delivery of irinotecan from microparticles with two distinct compartments. J Control Release. 2013 Nov 28;172(1):239-245.
Ramasundaram S, Saravanakumar G, Sobha S, Oh TH. Dextran Sulfate Nanocarriers: Design, Strategies and Biomedical Applications. Int J Mol Sci. 2022 Dec 26;24(1):355.
Sachdeva B, Sachdeva P, Negi A, Ghosh S, Han S, Dewanjee S, et al. Chitosan Nanoparticles-Based Cancer Drug Delivery: Application and Challenges. Mar Drugs. 2023 Mar 28;21(4):211.
Sohaib M, Shah SU, Shah KU, Khan NR, Irfan MM et al. Physicochemical Characterization of Chitosan-Decorated Finasteride Solid Lipid Nanoparticles for Skin Drug Delivery. Biomed Res Int. 2022 Aug 6;2022:7792180.
Stewart CF, Zamboni WC, Crom WR, Houghton PJ. Disposition of irinotecan and SN-38 following oral and intravenous irinotecan dosing in mice. Cancer Chemother Pharmacol. 1997;40(3):259-65. doi: 10.1007/s002800050656. PMID: 9219511.
Downloads
Published
Data Availability Statement
The data supporting the findings of this study are available from the corresponding author upon reasonable request.
Issue
Section
License
Copyright (c) 2026 Brazilian Journal of Pharmaceutical Sciences
This work is licensed under a Creative Commons Attribution 4.0 International License.
All content of the journal, except where identified, is licensed under a Creative Commons attribution-type BY.
The on-line journal has open and free access.
