Internal cross-linked polymeric nanoparticles with dual sensitivity for combination therapy of muscle-invasive bladder cancer

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Abstract

Background

Chemotherapy is a standard cancer treatment which uses anti-cancer drugs to destroy or slow the growth of cancer cells. However, chemotherapy has limited therapeutic effects in bladder cancer. One of the reasons of this resistance to chemotherapy is that higher levels of glutathione in invasive bladder cancer cells. We have fabricated nanoparticles that respond to high concentrations of glutathione and near-infrared laser irradiation in order to increase the drug accumulation at the tumor sites and combine chemotherapy with photothermal therapy to overcome the challenges of bladder cancer treatment.

Methods

The DOX&IR780@PEG-PCL-SS NPs were prepared by co-precipitation method. We investigated the tumor targeting capability of NPs in vitro and in vivo. The orthotopic bladder cancer model in C57BL/6 mice was established for in vivo study and the photothermal effects and therapeutic efficacy of NPs were evaluated.

Results

The DOX&IR780@PEG-PCL-SS NPs were synthesized using internal cross-linking strategy to increase the stability of nanoparticles. Nanoparticles can be ingested by tumor cells in a short time. The DOX&IR780@PEG-PCL-SS NPs have dual sensitivity to high levels of glutathione in bladder cancer cells and near-infrared laser irradiation. Glutathione triggers chemical structural changes of nanoparticles and preliminarily releases drugs, Near-infrared laser irradiation can promote the complete release of the drugs from the nanoparticles and induce a photothermal effect, leading to destroying the tumor cells. Given the excellent tumor-targeting ability and negligible toxicity to normal tissue, DOX&IR780@PEG-PCL-SS NPs can greatly increase the concentration of the anti-cancer drugs in tumor cells. The mice treated with DOX&IR780@PEG-PCL-SS NPs have a significant reduction in tumor volume. The DOX&IR780@PEG-PCL-SS NPs can be tracked by in vivo imaging system and have good tumor targeting ability, to facilitate our assessment during the experiment.

Conclusion

A nanoparticle delivery system with dual sensitivity to glutathione and near-infrared laser irradiation was developed for delivering IR780 and DOX. Chemo-photothermal synergistic therapy of both primary bladder cancer and their metastases was achieved using this advanced delivery system.

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Most cited references 20

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EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines.

J. Alfred Witjes, Eva Comperat, Nigel Cowan … (2014)

The European Association of Urology (EAU) guidelines panel on Muscle-invasive and Metastatic bladder cancer (BCa) updates its guidelines yearly. This updated summary provides a synthesis of the 2013 guidelines document, with emphasis on the latest developments. To provide graded recommendations on the diagnosis and treatment of patients with muscle-invasive BCa (MIBC), linked to a level of evidence. For each section of the guidelines, comprehensive literature searches covering the past 10 yr in several databases were conducted, scanned, reviewed, and discussed both within the panel and with external experts. The final results are reflected in the recommendations provided. Smoking and work-related carcinogens remain the most important risk factors for BCa. Computed tomography (CT) and magnetic resonance imaging can be used for staging, although CT is preferred for pulmonary evaluation. Open radical cystectomy with an extended lymph node dissection (LND) remains the treatment of choice for treatment failures in non-MIBC and T2-T4aN0M0 BCa. For well-informed, well-selected, and compliant patients, however, multimodality treatment could be offered as an alternative, especially if cystectomy is not an option. Comorbidity, not age, should be used when deciding on radical cystectomy. Patients should be encouraged to actively participate in the decision-making process, and a continent urinary diversion should be offered to all patients unless there are specific contraindications. For fit patients, cisplatinum-based neoadjuvant chemotherapy should always be discussed, since it improves overall survival. For patients with metastatic disease, cisplatin-containing combination chemotherapy is recommended. For unfit patients, carboplatin combination chemotherapy or single agents can be used. This 2013 EAU Muscle-invasive and Metastatic BCa guidelines updated summary aims to increase the quality of care and outcome for patients with muscle-invasive or metastatic BCa. In this paper we update the EAU guidelines on Muscle-invasive and Metastatic bladder cancer. We recommend that chemotherapy be administered before radical treatment and that bladder removal be the standard of care for disease confined to the bladder. Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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Elucidating the fundamental mechanisms of cell death triggered by photothermal therapy.

Jilian R Melamed, Rachel S. Edelstein, Emily S Day (2015)

Photothermal therapy (PTT) utilizes nanoparticles embedded within tumors as exogenous energy absorbers to convert laser light energy into heat to ablate cancer cells. While PTT is a promising alternative to conventional cancer therapy, under certain irradiation conditions, it can produce cellular necrosis, and this necrosis may lead to pro-inflammatory responses that are detrimental to treatment success. Recent studies have shown that PTT can be modulated to induce apoptosis rather than necrosis, which is appealing since apoptosis discourages an inflammatory response. In this issue of ACS Nano, del Pino, Pardo, de la Fuente, and colleagues reveal the intracellular signaling cascades involved in the apoptotic response to PTT using cells harboring photothermal transducing nanoprisms. In this Perspective, we present an overview of nanoparticle-mediated PTT and discuss photothermally induced apoptosis as a potential therapeutic pathway.

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IR-780 dye loaded tumor targeting theranostic nanoparticles for NIR imaging and photothermal therapy.

Caixia Yue, Peng Liu, Mingbin Zheng … (2013)

IR-780 iodide is a near-infrared (NIR) fluorescence dye with higher and more stable fluorescence intensity than clinically applied dye indocyanine green (ICG). Meanwhile, IR-780 can be utilized in photothermal therapy with laser irradiation. IR-780 is an important theranostic agent but its lipophilicity limited its application. In this paper, we synthesize multifunctional heparin-folic acid-IR-780 nanoparticles (HF-IR-780 NPs) by self-assembly of the heparin-folic acid conjugate and IR-780 through ultrasonic sound method. The HF-IR-780 NPs exhibit good monodispersity, significant stability, and excellent molecular targeting to folate receptor over-expressing MCF-7 cells. Furthermore, the in vivo biodistribution experiments show that the HF-IR-780 NPs are specifically targeted to the tumor and can be used for tumor imaging. The in vitro cell viability assays and in vivo photothermal therapy experiments indicate that MCF-7 cells or MCF-7 xenograft tumors could be ablated by combining HF-IR-780 NPs with irradiation of an 808 nm laser. The photothermal therapy in vivo with a single-dose treatment has not caused significant adverse effect. The resulted HF-IR-780 NPs are a potential theranostic agent for imaging-guided cancer therapy.

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Author and article information

Contributors

Hongqian Guo: dr.ghq@nju.edu.cn

Journal

Journal ID (nlm-ta): J Nanobiotechnology

Journal ID (iso-abbrev): J Nanobiotechnology

Title: Journal of Nanobiotechnology

Publisher: BioMed Central (London )

ISSN (Electronic): 1477-3155

Publication date (Electronic): 4 September 2020

Publication date PMC-release: 4 September 2020

Publication date Collection: 2020

Volume: 18

Electronic Location Identifier: 124

Affiliations

[1 ]GRID grid.41156.37, ISNI 0000 0001 2314 964X, Department of Urology, Affiliated Drum Tower Hospital, , Medical School of Nanjing University, ; Nanjing, 210009 China

[2 ]GRID grid.260483.b, ISNI 0000 0000 9530 8833, School of Pharmacy, , Nantong University, ; Nantong, 226001 China

Article

Publisher ID: 686

DOI: 10.1186/s12951-020-00686-3

PMC ID: 7472706

PubMed ID: 32887622

SO-VID: 84ff9b9b-def6-49e9-918a-f420af2cd755

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 18 May 2020

Date accepted : 28 August 2020

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ScienceOpen disciplines: Biotechnology

Keywords: dual-sensitivity,nanoparticle delivery,bladder cancer,chemotherapy,photothermal therapy

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ScienceOpen disciplines: Biotechnology

Keywords: dual-sensitivity, nanoparticle delivery, bladder cancer, chemotherapy, photothermal therapy

Internal cross-linked polymeric nanoparticles with dual sensitivity for combination therapy of muscle-invasive bladder cancer

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Abstract

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Methods

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Most cited references 20

EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines.

Elucidating the fundamental mechanisms of cell death triggered by photothermal therapy.

IR-780 dye loaded tumor targeting theranostic nanoparticles for NIR imaging and photothermal therapy.

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