Auxiliary in vitro and in vivo biological evaluation of hydrogen peroxide sensitive prodrugs of methotrexate and aminopterin for the treatment of rheumatoid arthritis (2022)

Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes severe joints damage and other extra-articular alterations. Despite the efficacy of low-dose methotrexate (LD-MTX) in RA treatment, adverse effects are the predominant reasons for discontinuation of therapy. As a therapeutic targeting strategy, the presence of increased concentrations of reactive oxygen species (ROS) in the inflammatory environment can serve as the stimulus for prodrug activation in siteselective drug delivery systems. Our group has previously reported novel ROS sensitive prodrugs (1– 3) of MTX and aminopterin (AMT) for site-selective delivery to inflammatory tissue associated with RA, with the aim of reducing side effects in RA therapy. Herein, we investigate the effect and toxicity of the same prodrugs in a rat CIA (collagen-induced arthritis) model of RA. We find that prodrug 1, an arylboronic acid ROS-sensitive MTX-prodrug, displays similar in vivo efficacy as MTX at an equimolar dose, while avoiding adverse effects known to restrict MTX treatment. To further characterize prodrug 1 and its ROS mediated activation, we synthesized compound 4, a negative control lacking the boronic acid moiety. We then investigated the effect of molecules on cell proliferation and cytotoxicity in the presence of the ROS scavenger pyruvate, as well as their stability in buffer and cell media, demonstrating a direct correlation between ROS concentration and the prodrug activity. Moreover, the in vitro ADME properties were investigated, including permeability, rat plasma and microsomal stability.

Original languageEnglish
Article number115247
Journal
Volume28
Issue number2
ISSN0968-0896
DOIs
Publication statusPublished - 2020
  • Rheumatoid arthritis
  • Inflammation
  • Methotrexate
  • Aminopterin
  • Prodrug
  • Boronic acids
  • Reactive oxygen species
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  • Author
  • BIBTEX
  • Harvard
  • Standard
  • RIS
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Previtali, V., Petrovic, K., Peiro Cadahía, J., Troelsen, N. S. (2020). Auxiliary in vitro and in vivo biological evaluation of hydrogen peroxide sensitive prodrugs of methotrexate and aminopterin for the treatment of rheumatoid arthritis. , 28(2), [115247]. https://doi.org/10.1016/j.bmc.2019.115247

Previtali, Viola ; Petrovic, Katarina ; Peiro Cadahía, Jorge ; Troelsen, Nikolaj Sten ; Clausen, Mads Hartvig. / Auxiliary in vitro and in vivo biological evaluation of hydrogen peroxide sensitive prodrugs of methotrexate and aminopterin for the treatment of rheumatoid arthritis. In: . 2020 ; Vol. 28, No. 2.

@article{cd3d973c2256473fbd20589287736b18,

title = "Auxiliary in vitro and in vivo biological evaluation of hydrogen peroxide sensitive prodrugs of methotrexate and aminopterin for the treatment of rheumatoid arthritis",

abstract = "Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes severe joints damage and other extra-articular alterations. Despite the efficacy of low-dose methotrexate (LD-MTX) in RA treatment, adverse effects are the predominant reasons for discontinuation of therapy. As a therapeutic targeting strategy, the presence of increased concentrations of reactive oxygen species (ROS) in the inflammatory environment can serve as the stimulus for prodrug activation in siteselective drug delivery systems. Our group has previously reported novel ROS sensitive prodrugs (1– 3) of MTX and aminopterin (AMT) for site-selective delivery to inflammatory tissue associated with RA, with the aim of reducing side effects in RA therapy. Herein, we investigate the effect and toxicity of the same prodrugs in a rat CIA (collagen-induced arthritis) model of RA. We find that prodrug 1, an arylboronic acid ROS-sensitive MTX-prodrug, displays similar in vivo efficacy as MTX at an equimolar dose, while avoiding adverse effects known to restrict MTX treatment. To further characterize prodrug 1 and its ROS mediated activation, we synthesized compound 4, a negative control lacking the boronic acid moiety. We then investigated the effect of molecules on cell proliferation and cytotoxicity in the presence of the ROS scavenger pyruvate, as well as their stability in buffer and cell media, demonstrating a direct correlation between ROS concentration and the prodrug activity. Moreover, the in vitro ADME properties were investigated, including permeability, rat plasma and microsomal stability. ",

keywords = "Rheumatoid arthritis, Inflammation, Methotrexate, Aminopterin, Prodrug, Boronic acids, Reactive oxygen species",

author = "Viola Previtali and Katarina Petrovic and {Peiro Cadah{\'i}a}, Jorge and Troelsen, {Nikolaj Sten} and Clausen, {Mads Hartvig}",

year = "2020",

doi = "10.1016/j.bmc.2019.115247",

language = "English",

volume = "28",

journal = "Bioorganic & Medicinal Chemistry",

issn = "0968-0896",

publisher = "Pergamon Press",

number = "2",

}

Previtali, V, Petrovic, K, Peiro Cadahía, J, Troelsen, NS 2020, 'Auxiliary in vitro and in vivo biological evaluation of hydrogen peroxide sensitive prodrugs of methotrexate and aminopterin for the treatment of rheumatoid arthritis', , vol. 28, no. 2, 115247. https://doi.org/10.1016/j.bmc.2019.115247

Auxiliary in vitro and in vivo biological evaluation of hydrogen peroxide sensitive prodrugs of methotrexate and aminopterin for the treatment of rheumatoid arthritis. / Previtali, Viola; Petrovic, Katarina; Peiro Cadahía, Jorge; Troelsen, Nikolaj Sten; Clausen, Mads Hartvig.

In: , Vol. 28, No. 2, 115247, 2020.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Auxiliary in vitro and in vivo biological evaluation of hydrogen peroxide sensitive prodrugs of methotrexate and aminopterin for the treatment of rheumatoid arthritis

AU - Previtali, Viola

AU - Petrovic, Katarina

AU - Peiro Cadahía, Jorge

AU - Troelsen, Nikolaj Sten

AU - Clausen, Mads Hartvig

PY - 2020

Y1 - 2020

N2 - Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes severe joints damage and other extra-articular alterations. Despite the efficacy of low-dose methotrexate (LD-MTX) in RA treatment, adverse effects are the predominant reasons for discontinuation of therapy. As a therapeutic targeting strategy, the presence of increased concentrations of reactive oxygen species (ROS) in the inflammatory environment can serve as the stimulus for prodrug activation in siteselective drug delivery systems. Our group has previously reported novel ROS sensitive prodrugs (1– 3) of MTX and aminopterin (AMT) for site-selective delivery to inflammatory tissue associated with RA, with the aim of reducing side effects in RA therapy. Herein, we investigate the effect and toxicity of the same prodrugs in a rat CIA (collagen-induced arthritis) model of RA. We find that prodrug 1, an arylboronic acid ROS-sensitive MTX-prodrug, displays similar in vivo efficacy as MTX at an equimolar dose, while avoiding adverse effects known to restrict MTX treatment. To further characterize prodrug 1 and its ROS mediated activation, we synthesized compound 4, a negative control lacking the boronic acid moiety. We then investigated the effect of molecules on cell proliferation and cytotoxicity in the presence of the ROS scavenger pyruvate, as well as their stability in buffer and cell media, demonstrating a direct correlation between ROS concentration and the prodrug activity. Moreover, the in vitro ADME properties were investigated, including permeability, rat plasma and microsomal stability.

AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes severe joints damage and other extra-articular alterations. Despite the efficacy of low-dose methotrexate (LD-MTX) in RA treatment, adverse effects are the predominant reasons for discontinuation of therapy. As a therapeutic targeting strategy, the presence of increased concentrations of reactive oxygen species (ROS) in the inflammatory environment can serve as the stimulus for prodrug activation in siteselective drug delivery systems. Our group has previously reported novel ROS sensitive prodrugs (1– 3) of MTX and aminopterin (AMT) for site-selective delivery to inflammatory tissue associated with RA, with the aim of reducing side effects in RA therapy. Herein, we investigate the effect and toxicity of the same prodrugs in a rat CIA (collagen-induced arthritis) model of RA. We find that prodrug 1, an arylboronic acid ROS-sensitive MTX-prodrug, displays similar in vivo efficacy as MTX at an equimolar dose, while avoiding adverse effects known to restrict MTX treatment. To further characterize prodrug 1 and its ROS mediated activation, we synthesized compound 4, a negative control lacking the boronic acid moiety. We then investigated the effect of molecules on cell proliferation and cytotoxicity in the presence of the ROS scavenger pyruvate, as well as their stability in buffer and cell media, demonstrating a direct correlation between ROS concentration and the prodrug activity. Moreover, the in vitro ADME properties were investigated, including permeability, rat plasma and microsomal stability.

KW - Rheumatoid arthritis

KW - Inflammation

KW - Methotrexate

KW - Aminopterin

KW - Prodrug

KW - Boronic acids

KW - Reactive oxygen species

U2 - 10.1016/j.bmc.2019.115247

DO - 10.1016/j.bmc.2019.115247

M3 - Journal article

C2 - 31843461

VL - 28

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

SN - 0968-0896

IS - 2

M1 - 115247

ER -

Previtali V, Petrovic K, Peiro Cadahía J, Troelsen NS, Clausen MH. Auxiliary in vitro and in vivo biological evaluation of hydrogen peroxide sensitive prodrugs of methotrexate and aminopterin for the treatment of rheumatoid arthritis. . 2020;28(2). 115247. https://doi.org/10.1016/j.bmc.2019.115247

FAQs

Is rheumatoid arthritis a disease? ›

Rheumatoid arthritis, or RA, is an autoimmune and inflammatory disease, which means that your immune system attacks healthy cells in your body by mistake, causing inflammation (painful swelling) in the affected parts of the body. RA mainly attacks the joints, usually many joints at once.

What does rheumatoid arthritis affect? ›

The joints most often affected by RA are in the hands, wrists, feet, ankles, knees, shoulders, and elbows. Symptoms may include joint pain, stiffness, and swelling; decreased and painful movement; bumps over small joints; and fatigue or fever.

How do you cope with RA? ›

How to Manage RA Pain: 9 Tips
  1. Tell your doctor how you feel. They may want to change your medications or their doses. ...
  2. Take a breathing break. Quietly tune in to your breaths. ...
  3. Keep doing things you enjoy. ...
  4. Use heat, cold, and massage. ...
  5. Notice your emotions. ...
  6. Join a support group. ...
  7. Exercise. ...
  8. Eat a balanced diet.
16 Oct 2020

What is Stage 1 rheumatoid arthritis? ›

Many people feel joint pain, stiffness, or swelling. During stage 1, there's inflammation inside the joint. The tissue in the joint swells up. There's no damage to the bones, but the joint lining, called the synovium, is inflamed.

What is the difference between arthritis & rheumatoid arthritis? ›

Osteoarthritis, the most common form of arthritis, involves the wearing away of the cartilage that caps the bones in your joints. Rheumatoid arthritis is a disease in which the immune system attacks the joints, beginning with the lining of joints.

Is rheumatoid arthritis worse than arthritis? ›

Two of the most common types are rheumatoid arthritis (RA) and osteoarthritis (OA). OA is more common than RA. Both involve inflammation in the joints, but RA causes much more inflammation.

How long can you live with rheumatoid arthritis? ›

Outlook for people with rheumatoid arthritis

Nevertheless, with the right treatment, many people can live past the age of 80 or even 90 years while experiencing relatively mild symptoms and only minor limitations on day-to-day life.

Can you live a normal life with rheumatoid arthritis? ›

Your life will undoubtedly change after being diagnosed with a chronic condition, but people living with rheumatoid arthritis can thrive by doing what they already enjoy or by finding new activities that they love.

What are the 4 stages of rheumatoid arthritis? ›

The four stages of rheumatoid arthritis are known as synovitis, pannus, fibrous ankylosis, and bony ankylosis.
  • Stage I: Synovitis. During stage I, you may start having mild symptoms, including joint pain and joint stiffness. ...
  • Stage II: Pannus. ...
  • Stage III: Fibrous Ankylosis. ...
  • Stage IV: Bony Ankylosis.
12 Oct 2021

What emotions cause RA? ›

Stress is a common part of life, but prolonged stress over time can cause rheumatoid arthritis pain to become worse. People with osteoarthritis may also feel their joint pain more prominently when they are experiencing high periods of stress.

Can you fully recover from RA? ›

There's no cure for rheumatoid arthritis. However, early diagnosis and appropriate treatment enables many people with the condition to have periods of months or even years between flares. This can help them to lead full lives and continue regular employment.

When is rheumatoid arthritis serious? ›

If rheumatoid arthritis is not treated early or is not well controlled, the inflammation in your joints could lead to significant and permanent damage. Problems that can affect the joints include: damage to nearby bone and cartilage (a tough, flexible material that covers the surface of joints)

What are symptoms of an RA flare? ›

People with RA also report these common symptoms of flares:
  • increased stiffness in joints.
  • pain throughout the entire body.
  • increased difficulty doing everyday tasks.
  • swelling of hands and feet as well as large joints.
  • intense fatigue.
  • flu-like symptoms.

Can rheumatoid arthritis affect your brain? ›



People with RA are more likely to have narrowed or blocked arteries in the brain – the result of systemic inflammation. This can cause problems with memory, thinking and reasoning.

What type of arthritis is the most painful? ›

Rheumatoid arthritis can be one of the most painful types of arthritis; it affects joints as well as other surrounding tissues, including organs. This inflammatory, autoimmune disease attacks healthy cells by mistake, causing painful swelling in the joints, like hands, wrists and knees.

What are the 3 types of rheumatoid arthritis? ›

Types of Rheumatoid Arthritis – Seropositive or Seronegative RA
  • Rheumatoid Factor Positive (Seropositive) RA. ...
  • Rheumatoid Factor Negative (Seronegative) RA. ...
  • Overlapping Conditions.
11 Feb 2016

What is commonly mistaken for rheumatoid arthritis? ›

Lupus. Lupus, or systemic lupus erythematosus (SLE), is a potentially fatal autoimmune disease that affects many parts of the body, including the joints, skin, blood vessels, and internal organs. "The arthritis of lupus can mimic very closely that of rheumatoid arthritis," noted Dr.

When is rheumatoid arthritis pain the worst? ›

The joint pain associated with rheumatoid arthritis is usually a throbbing and aching pain. It is often worse in the mornings and after a period of inactivity.

How painful is severe rheumatoid arthritis? ›

A person with RA may feel intense pain in their joints during flares. This may feel like sustained pressure, a burning sensation, or a sharp pain. However, people with RA may also experience periods of remission when they feel few to no symptoms. In addition to causing pain in the joints, RA can affect the whole body.

What is end stage rheumatoid arthritis? ›

End-stage rheumatoid arthritis (RA) is an advanced stage of disease in which there is severe joint damage and destruction in the absence of ongoing inflammation.

What is the best drug to treat rheumatoid arthritis? ›

Methotrexate is usually the first medicine given for rheumatoid arthritis, often with another DMARD and a short course of steroids (corticosteroids) to relieve any pain. These may be combined with biological treatments.
...
The DMARDs that may be used include:
  • methotrexate.
  • leflunomide.
  • hydroxychloroquine.
  • sulfasalazine.

Can you reverse rheumatoid arthritis? ›

Like other forms of arthritis, RA can't be reversed. Even if you show evidence of low inflammation and your joints aren't swollen and tender, your doctor may want you to continue taking some medication to avoid a flare of the disease. With the right combination of treatments, RA can go into remission.

Can vitamin D reverse rheumatoid arthritis? ›

Another study revealed that a higher intake of vitamin D and omega-3 fatty acids may be associated with better treatment results in patients with early rheumatoid arthritis.

What foods should be avoided with rheumatoid arthritis? ›

Foods to Avoid With RA
  • Red meat and dairy. They're our main sources of saturated fats, which can cause inflammation in fat tissue. ...
  • Corn oil. The culprit here is omega-6 fatty acids. ...
  • Fried food, fast food, and processed foods.
13 Mar 2022

What is the most common cause of death in patients with rheumatoid arthritis? ›

Compared with people without the disease, people with rheumatoid arthritis are nearly twice as likely to die before the age of 75 and are more likely to succumb to cardiovascular disease and respiratory problems, study finds.

Is rheumatoid arthritis a disability? ›

Is Rheumatoid Arthritis a Disability? Simply being diagnosed with rheumatoid arthritis does not qualify you for disability. However, if your ability to work is greatly affected or impaired by your condition, then with the proper documentation, you may be entitled to SSA disability benefits.

Is rheumatoid arthritis a disability UK? ›

Rheumatoid arthritis is not listed as a medical condition that entitles a person to free prescriptions in England. But you may be able to get your medicine for free if your condition falls under the category of "a continuing physical disability which means the person cannot go out without the help of another person".

What is the average life expectancy of someone with rheumatoid arthritis? ›

RA can shorten your life expectancy by an average of 10 years compared to people who don't have the disease. But people with RA are living longer than ever before. Though the disease may still affect life expectancy, it doesn't have as much impact as it did in the past.

Is rheumatoid arthritis a permanent disease? ›

There is no cure for rheumatoid arthritis. But clinical studies indicate that remission of symptoms is more likely when treatment begins early with medications known as disease-modifying antirheumatic drugs (DMARDs).

What is the best drug to treat rheumatoid arthritis? ›

Methotrexate is usually the first medicine given for rheumatoid arthritis, often with another DMARD and a short course of steroids (corticosteroids) to relieve any pain. These may be combined with biological treatments.
...
The DMARDs that may be used include:
  • methotrexate.
  • leflunomide.
  • hydroxychloroquine.
  • sulfasalazine.

Can you live a normal life with rheumatoid arthritis? ›

Your life will undoubtedly change after being diagnosed with a chronic condition, but people living with rheumatoid arthritis can thrive by doing what they already enjoy or by finding new activities that they love.

What are the 4 stages of rheumatoid arthritis? ›

The four stages of rheumatoid arthritis are known as synovitis, pannus, fibrous ankylosis, and bony ankylosis.
  • Stage I: Synovitis. During stage I, you may start having mild symptoms, including joint pain and joint stiffness. ...
  • Stage II: Pannus. ...
  • Stage III: Fibrous Ankylosis. ...
  • Stage IV: Bony Ankylosis.
12 Oct 2021

What is the most painful type of arthritis? ›

Rheumatoid arthritis can be one of the most painful types of arthritis; it affects joints as well as other surrounding tissues, including organs. This inflammatory, autoimmune disease attacks healthy cells by mistake, causing painful swelling in the joints, like hands, wrists and knees.

What foods should be avoided with rheumatoid arthritis? ›

Foods to Avoid With RA
  • Red meat and dairy. They're our main sources of saturated fats, which can cause inflammation in fat tissue. ...
  • Corn oil. The culprit here is omega-6 fatty acids. ...
  • Fried food, fast food, and processed foods.
13 Mar 2022

Can rheumatoid arthritis affect your brain? ›



People with RA are more likely to have narrowed or blocked arteries in the brain – the result of systemic inflammation. This can cause problems with memory, thinking and reasoning.

What is end stage rheumatoid arthritis? ›

End-stage rheumatoid arthritis (RA) is an advanced stage of disease in which there is severe joint damage and destruction in the absence of ongoing inflammation.

Can stress cause rheumatoid arthritis? ›

The longer you're exposed to stress, the more destructive the inflammation can become. In a PLoS One study, people with RA identified stress as a trigger for disease flare-ups. Arthritis symptoms contribute to stress, especially when they're unrelenting. Constant pain, fatigue, and poor sleep create a vicious cycle.

What is the most common cause of death in patients with rheumatoid arthritis? ›

Compared with people without the disease, people with rheumatoid arthritis are nearly twice as likely to die before the age of 75 and are more likely to succumb to cardiovascular disease and respiratory problems, study finds.

What is the permanent cure for arthritis? ›

There's no cure for arthritis, but there are treatments that can help you manage the condition. Your treatment plan will depend on the severity of the arthritis, its symptoms and your overall health.

What are the 3 types of rheumatoid arthritis? ›

Types of Rheumatoid Arthritis – Seropositive or Seronegative RA
  • Rheumatoid Factor Positive (Seropositive) RA. ...
  • Rheumatoid Factor Negative (Seronegative) RA. ...
  • Overlapping Conditions.
11 Feb 2016

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