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Targeted Nanotherapy: Fluorescence-guided Photoimmunotherapy To Manage Peritoneal Carcinomatosis

Workflow schematic. This shows the overall workflow of integrating targeted nanomedicine, medical laser endoscopy system, and fluorescence-guided intervention to improve the safety, efficacy, and consistency of photoimmunotherapy (PIT) for peritoneal metastasis. The targeted photo-activable multi-agent nanoliposome (TPMAL) co-delivers fluorophores, photosensitizer immunoconjugates (PICs), and chemotherapy drugs at high payloads for combined imaging, PIT, and chemotherapy of peritoneal tumors. A medical laser endoscopy system (ML7710) coupled with Modulight Cloud was engineered to perform PIT and fluorescence-guided intervention in the abdominal cavity of the patient. Specifically, fluorescence-guided drug delivery (FGDD) can reveal interpatient variability in PIC uptake, which prompts the need for intraoperative fluorescence-guided light dosimetry (FGLD) adjustment in study subjects. Credit: Science Advances (2023). DOI: 10.1126/sciadv.Adi3441

Fluorescence-guided intervention strategies can improve standard therapies to detect and treat microscopic tumors to thereby prevent lethal recurrence. Cancer biologists have made tremendous progress in photoimmunotherapy and nanotechnology to treat metastasis, although the effects of such techniques are limited by heterogeneous effects.

In a new report published in Science Advances, Barry J. Liang, and a team of researchers in bioengineering, cell biology and photomedicine at the University of Maryland, Baltimore, Harvard Medical School U.S. And the Modulight Corporation, Finland, integrated three technical advances for fluorescence-guided intervention in targeted photo-activatable multiagent liposome laser endoscopy for improved photoimmunotherapy.

The photoactivatable multiagent liposome contained a nanoliposome labeled with fluorophores to track and photosensitize immunoconjugates for photoimmunotherapy. The researchers conducted fluorescence-guided drug delivery during the experiments and fluorescence-guided light dosimetry to investigate peritoneal carcinomatosis in mouse models.

Fluorescence-guided drug delivery methods revealed that the targeted photoactivatable multiagent liposome enhanced drug delivery to metastases increased by 14-fold. The team combined the interventional methods to vary the treatment response for tumor control without side-effects.

Photodynamic therapy for ovarian cancer

Peritoneal metastasis or incomplete resection and drug resistance can make advanced ovarian cancer virtually incurable with the existing approaches in surgery and chemotherapy. While tumor recurrence is nearly universal, the five-year survival rate of 30% has not significantly changed in the past three decades.

At diagnosis, up to 70% of these patients are in advanced stages. The primary mechanism of serous carcinoma metastasis involves the high-grade deposition of numerous cancer nodules throughout the abdominal cavity. Women with advanced ovarian cancer who undergo surgery and chemotherapy have achieved complete remission, although the patients relapse due to residual sub-mm lesions.

While such aggregates are difficult to detect, they can develop resistance to standard treatments, therefore radical approaches that combine targeted therapy, imaging and monitoring should address drug-resistant micro-metastases.

Using targeted photoactivatable multiagent liposomes (TPMAL)

Although intraoperative photodynamic therapy for peritoneal carcinomatosis using non-targeted photosensitizers and a fixed light dose combination is safe for clinical use, the technology has not yet achieved complete responses or long-term tumor control due to tumor heterogeneity and a lack of specificity during the uptake of photosensitizer.

In this work, Liang and colleagues used targeted photoactivatable multiagent liposomes (TPMAL) for photochemotherapy engineered with molecular targeting and fluorescence-tracking features. The scientists integrated a laser endoscopy system to advance a two-pronged approach to ensure TPMAL-assisted photodynamic therapy for safe, and customized drug delivery. The outcomes highlight the efficiency and safety of photoimmunotherapy to reduce the metastatic burden in vivo.

Biodistribution of TPMAL (PIC-Nal-IRI), PIC, and Nal-BPD in peritoneal metastases and subcutaneous tumors. At 14 days after OVCAR-5 implantation, mice were intraperitoneally injected with PIC-Nal-IRI, PIC, or Nal-BPD (BPD: 0.25 mg/kg). Tissues were excised and imaged for BPD fluorescence according to Materials and Methods at 24 hours after injection. (A) Representative bright-field (BF) and fluorescence images of tissues with peritoneal metastases from no treatment (NT), Nal-BPD, PIC, and PIC-Nal-IRI groups. Scale bar, 1.5 mm. (B) Quantification of BPD accumulation in excised tissues at 24 hours after injection with BPD standards of known concentrations. Asterisks denote significance compared to PIC group. Data are represented as mean ± SEM values (N ≥ 3 animals per group, *P Science Advances (2023). DOI: 10.1126/sciadv.Adi3441 Activating photoimmunotherapy in the lab

To activate photoimmunotherapy, the scientists covalently attached five benzoporphyrin derivative photosensitizer molecules to each anti-epidermal growth factor receptor monoclonal antibody through carbodiimide chemistry. Using click chemistry, they covalently linked photoimmunotherapy to the nanoliposomes to synthesize targeted photoactivatable multilayer liposomes.

The resulting photosensitizer immunoconjugates-nanoliposomes-carboxyfluorescein compounds (abbreviated PIC-Nal-CF) showed an average size in the nano-scale range with a storage capacity of up to 18 weeks. By conjugating the compound, Liang and colleagues did not alter the absorption of the emission spectra of benzoporphyrin derivatives and carboxyfluorescein. They noted a stronger fluorescent signal at 700 nm from the conjugates and noted the activity of the material to be more than five times greater than the free elements.

In vivo experiments in mice

Liang and colleagues used intralipid; a light scattering agent in the clinic for intraperitoneal photodynamic therapy of peritoneal carcinomatosis. They examined intralipid alters and fluorescence emission spectra of the photoimmunotherapy conjugates (PIC-Nal-CF).

Using 0.03% ink as a light absorber, they studied the turbid environment of peritoneal carcinomatosis, where the serosanguinous fluid of the tumor reduced the fluorescence signal from the carboxyfluorescein to benzoporphyrin, while intralipid aided the fluorescence monitoring of the compound.

The team studied the biodistribution of photosensitizer immunoconjugate-nanoliposome-carboxyfluorescein compounds in a mouse model of disease and detected the compound in the peritoneal cavity of mice to highlight enhanced tumor selectivity and retention capacity.

Improving the efficiency of photosensitizer immunoconjugates to peritoneal metastasis

The team assessed the biodistribution of the theranostic compound by tracking fluorescence signals to indicate their capacity to "lock-in" and "co-deliver" by designing drug ratios to target sites. When compared to the normal tissues, they observed an increased accumulation of the compound in metastatic tumors and noted high levels of benzoporphyrin accumulation in tumor tissues after injecting the compound of interest.

Photoimmunotherapy is typically limited by a poor uptake of photosensitizer by tumor cells. The team studied whether the photosensitizer and nanoliposomes with irinotecan (PIC-Nal-IRI) could improve the delivery of benzoporphyrin immunoconjugates alone.

After 24 hours of intraperitoneal injection, the animals treated with the conjugates showed the highest accumulation of benzoporphyrin fluorescence signal in the tumor regions with low signals in all healthy tissues. The drug conjugates showed the highest tumor to normal tissue ratios. The team also studied intraoperative fluorescence-guided drug delivery in different animal models.

Outlook

In this way, Liang and colleagues examined the use of photodynamic therapy as a promising treatment strategy for peritoneal carcinomatosis. Ovarian cancer is a lethal gynecologic malignancy in the U.S., with a five-year survival rate of stage 1 disease at 92%, although with a 75% diagnosis of patients at advanced stages and limited treatment options to impact the overall survival rate.

Photodynamic therapy offers a promising treatment strategy for peritoneal carcinomatosis. Photoimmunotherapy is a targeted version of the process introduced in 1983 to enhance tumor selectivity in complex sites such as the peritoneal cavity.

The method can produce cytotoxic reactive oxygen species to kill cancer cells and activate local and systemic antitumor immune responses under appropriate doses of light and photosensitizer.

The cancer-targeted photoactivated multiagent liposomes developed in this work can be co-delivered with photosensitive immunoconjugates and carboxyfluorescein dyes or irinotecan chemotherapy to explore the dynamics of an ideal cancer treatment strategy for drug delivery and treatment by providing insights to the underlying mechanisms of antitumor immune responses to photoimmunotherapy compounds.

More information: Barry J. Liang et al, Fluorescence-guided photoimmunotherapy using targeted nanotechnology and ML7710 to manage peritoneal carcinomatosis, Science Advances (2023). DOI: 10.1126/sciadv.Adi3441

Willemien J. Van Driel et al, Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer, New England Journal of Medicine (2018). DOI: 10.1056/NEJMoa1708618

Citation: Targeted nanotherapy: Fluorescence-guided photoimmunotherapy to manage peritoneal carcinomatosis (2023, September 25) retrieved 28 September 2023 from https://phys.Org/news/2023-09-nanotherapy-fluorescence-guided-photoimmunotherapy-peritoneal-carcinomatosis.Html

This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.

Danaher Lowers Price Of Tuberculosis Test After Pressure Campaign

Topline

Washington, D.C.-based drugmaker Danaher has agreed to lower the cost of test cartridges used to diagnose tuberculosis by 20% and sell them at cost, the company announced Tuesday, a move that comes after a public pressure campaign from a group of health nonprofits, and one experts say will greatly expand access to the tests in developing countries where it is needed most.

A GeneXpert machine is pictured inside a mobile testing unit June 9, 2020, in Fort Worth, Texas.

Tom Pennington/Getty Images Key Facts

Danaher and its subsidiary Cepheid, which develops the tests, have committed to reducing the price of its Xpert test cartridges from $9.98 to $7.97, which it says is what it costs the company to make, and will not earn any profit—and it says it will allow a third-party organization to validate their costs to confirm this on an annual basis.

The cartridges are used in the GeneXpert machine to diagnose tuberculosis in under an hour and are essential to detecting and treating the disease.

Without the GeneXpert tests, doctors are forced to test for the disease by examining a sputum sample collected from the patient's airway under a microscope, but that method is imperfect. The Global Fund to Fight AIDS, Tuberculosis and Malaria—one of the organizations that facilitated the agreement with Danaher—said this reduced price will allow those who need them to purchase 5 million more tests worldwide, with Peter Sands, the Global Fund's executive director, saying it "should enable significantly expanded access to the communities most in need."

The company's higher-end test cartridge, which can detect extensively drug-resistant forms of tuberculosis, will not see its price reduced.

Key Background

Tuberculosis kills around 1.5 million people annually, according to the World Health Organization, making it the world's deadliest infectious disease and the thirteenth-leading cause of death globally, even though the disease is completely curable. However, because of the high cost of both treatment and testing, the cure is out of reach for many in developing countries like Lesotho, India, the Democratic Republic of the Congo, Nigeria and Peru. Danaher and Cepheid's GeneXpert machine was released in 2005 and developed using more than $252 million of public funding, mostly from the U.S.

Tangent

Danaher's announcement comes after a pressure campaign from a cohort of international health and aid organizations that includes the Global Fund, Stop TB Partnership and USAID. The organizations had originally lobbied the company to lower the price 50% to around $5, but said Tuesday that they welcomed Danaher's ultimate cost reduction. The campaign also included efforts from John Green, the popular novelist behind The Fault In Our Stars, educational YouTube creator and a board member at Partners In Health, who created YouTube videos about the situation and repeatedly urged his viewers on social media to contact Danaher and Cepheid, asking them to reduce their price. Partners In Health, the nonprofit he works with, similarly launched a publicity campaign. Green and many of the same organizations were also involved in a similar effort to pressure drugmaker Johnson & Johnson to allow its patent to expire on bedaquiline, the medicine used to treat tuberculosis, which was similarly out of reach for many in developing countries due to its price. Johnson & Johnson ultimately agreed to allow Stop TB Partnership to distribute a generic version of the drug in many developing countries with lots of tuberculosis, which is expected to greatly expand its access in those countries.

Contra

While many were happy with the news of this announcement, some still had questions, including Carole Mitnick, a tuberculosis specialist with Partners in Health and a professor of global health and social medicine at Harvard Medical School, who in a statement sent to Forbes said she wants to know if and when the company will commit to lower its costs on the higher-end test cartridges. Mitnick said, "We've got much more to do and important questions that need urgent answers, but I'm deeply thankful for everyone—activists, clinicians, scientists, everyone—who acts in solidarity with those suffering from a disease too often ignored."

High Systemic Immune-inflammation Index Tied To Higher Mortality With Peritoneal Dialysis

An elevated systemic immune-inflammation index (SII) is independently associated with increased risks for all-cause and cardiovascular-specific mortality in patients undergoing peritoneal dialysis, according to a study published online Aug. 31 in the Journal of Inflammation Research.

Guanglan Li, from the First Affiliated Hospital at Sun Yat-sen University in Guangzhou, China, and colleagues investigated the relationship between the SII and all-cause and cardiovascular-specific mortality in patients undergoing peritoneal dialysis. The analysis included 1,419 patients receiving peritoneal dialysis (2007 through 2019) with a median follow-up of 42 months.

The researchers found that each one standard deviation increase in the SII was associated with increased all-cause mortality (hazard ratio, 1.202) and cardiovascular-specific mortality (hazard ratio, 1.280) in an adjusted analysis. Compared with low SII, high SII was significantly associated with increased risks for all-cause mortality (hazard ratio, 1.391) and cardiovascular-specific mortality (hazard ratio, 1.637). In subgroup analyses of participants younger than 65 years, results were similar.

"Elevated SII level was independently associated with increased risks of all-cause and cardiovascular disease mortalities in patients undergoing peritoneal dialysis, especially for those younger than 65 years old," the authors write. "Application of the SII in clinical practice in predicting mortality for patients undergoing peritoneal dialysis requires further multicenter prospective studies."

More information: Guanglan Li et al, Systemic Immune-Inflammation Index Was Significantly Associated with All-Cause and Cardiovascular-Specific Mortalities in Patients Receiving Peritoneal Dialysis, Journal of Inflammation Research (2023). DOI: 10.2147/JIR.S426961

Citation: High systemic immune-inflammation index tied to higher mortality with peritoneal dialysis (2023, September 22) retrieved 28 September 2023 from https://medicalxpress.Com/news/2023-09-high-immune-inflammation-index-higher-mortality.Html

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