Folate Receptor-Targeting and Reactive Oxygen Species-Responsive Liposomal Formulation of Methotrexate for Treatment of Rheumatoid Arthritis

Published on Nov 6, 2019in Pharmaceutics4.421
· DOI :10.3390/PHARMACEUTICS11110582
Minglei Chen9
Estimated H-index: 9
(CPU: China Pharmaceutical University),
Kambere Amerigos Daddy J.C.3
Estimated H-index: 3
(CPU: China Pharmaceutical University)
+ 4 AuthorsQineng Ping45
Estimated H-index: 45
(CPU: China Pharmaceutical University)
Sources
Abstract
Multifunctional nanomedicines with active targeting and stimuli-responsive drug release function utilizing pathophysiological features of the disease are regarded as an effective strategy for treatment of rheumatoid arthritis (RA). Under the inflammatory environment of RA, activated macrophages revealed increased expression of folate receptor and elevated intracellular reactive oxygen species (ROS) level. In this study, we successfully conjugated folate to polyethylene glycol 100 monostearate as film-forming material and further prepared methotrexate (MTX) and catalase (CAT) co-encapsulated liposomes, herein, shortened to FOL-MTX&CAT-L, that could actively target to activated macrophages. Thereafter, elevated intracellular hydrogen peroxide, the main source of ROS, diffused into liposomes and encapsulated CAT catalyzed the decomposition of hydrogen peroxide into oxygen and water. Continuous oxygen-generation inside liposomes would eventually disorganize its structure and release the encapsulated MTX. We characterized the in vitro drug release, cellular uptake and cytotoxicity studies as well as in vivo pharmacokinetics, biodistribution, therapeutic efficacy and safety studies of FOL-MTX&CAT-L. In vitro results revealed that FOL-MTX&CAT-L possessed sufficient ROS-sensitive drug release, displayed an improved cellular uptake through folate-mediated endocytosis and exhibited a higher cytotoxic effect on activated RAW264.7 cells. Moreover, in vivo results showed prolonged blood circulation time of PEGylated liposomes, enhanced accumulation of MTX in inflamed joints of collagen-induced arthritis (CIA) mice, reinforced therapeutic efficacy and minimal toxicity toward major organs. These results imply that FOL-MTX&CAT-L may be used as an effective nanomedicine system for RA treatment.
📖 Papers frequently viewed together
38 Citations
1 Citations
35 Citations
References83
Newest
#1Pramina Kumari Pandey (Government of India)H-Index: 1
#2Rahul Maheshwari (Government of India)H-Index: 14
Last. Rakesh K. Tekade (Government of India)H-Index: 36
view all 6 authors...
Abstract This investigation reports a novel nanoGold-core multifunctional dendrimer for pulsatile chemo-, photothermal- and photodynamic- therapy of rheumatoid arthritis (RA). Architecturally, the nanocomposites comprised of a nanoGold (Au) at the focal whose surface is functionalized by hydroxy-terminated thiolated-dendrons following Au-thiol bond formation to produce nanoGold-core multifunctional dendrimer (Au-DEN). The surface hydroxyl groups of Au-DEN were then conjugated with methotrexate (...
31 CitationsSource
#1Jonghoon Kim (SNU: Seoul National University)H-Index: 30
#1Jong Hoon KimH-Index: 29
Last. Taeghwan HyeonH-Index: 147
view all 13 authors...
Poor O2 supply to the infiltrated immune cells in the joint synovium of rheumatoid arthritis (RA) up-regulates hypoxia-inducible factor (HIF-1α) expression and induces reactive oxygen species (ROS) generation, both of which exacerbate synovial inflammation. Synovial inflammation in RA can be resolved by eliminating pro-inflammatory M1 macrophages and inducing anti-inflammatory M2 macrophages. Because hypoxia and ROS in the RA synovium play a crucial role in the induction of M1 macrophages and re...
74 CitationsSource
#1Durga M. S. H. Chandrupatla (VUmc: VU University Medical Center)H-Index: 6
#2Carla F. M. Molthoff (VUmc: VU University Medical Center)H-Index: 30
Last. Gerrit Jansen (VUmc: VU University Medical Center)H-Index: 65
view all 5 authors...
Macrophages play a key role in the pathophysiology of rheumatoid arthritis (RA). Notably, positive correlations have been reported between synovial macrophage infiltration and disease activity as well as therapy outcome in RA patients. Hence, macrophages can serve as an important target for both imaging disease activity and drug delivery in RA. Folate receptor β (FRβ) is a glycosylphosphatidyl (GPI)-anchored plasma membrane protein being expressed on myeloid cells and activated macrophages. FRβ ...
26 CitationsSource
#1Chaopin Yang (Guangzhou Medical University)H-Index: 3
#2Yue Li (Guangzhou Medical University)H-Index: 4
Last. Zhiyi Chen (Guangzhou Medical University)H-Index: 8
view all 4 authors...
AbstractAs a non-invasive and real-time diagnostic technique, ultrasound has provided a novel strategy for targeted treatment. With the rapid development of ultrasonic technique and ultrasound contrast agents (UCAs), spatiotemporally controllable application of ultrasound with or without UCAs makes it possible for site-specific delivery of therapeutic agents and targeted modulation with minimal side effects, which indicated a promising therapy in clinical use. This review will describe the main ...
25 CitationsSource
#1Wan-Ying Wang (MUST: Macau University of Science and Technology)H-Index: 3
#2Hua Zhou (MUST: Macau University of Science and Technology)H-Index: 29
Last. Liang Liu (MUST: Macau University of Science and Technology)H-Index: 31
view all 3 authors...
Abstract Methotrexate (MTX) is used as an anchor disease-modifying anti-rheumatic drugs (DMARDs) in treating rheumatoid arthritis (RA) because of its potent efficacy and tolerability. MTX benefits a large number of RA patients but partially suffered from side effects. A variety of side effects can be associated with MTX when treating RA patients, from mild to severe or discontinuation of the treatment. In this report, we reviewed the possible side effects that MTX might cause from the most commo...
91 CitationsSource
#1Nikolaj Sten Andersen (DTU: Technical University of Denmark)H-Index: 2
#2Jorge Peiró Cadahía (DTU: Technical University of Denmark)H-Index: 4
Last. Mads Hartvig Clausen (DTU: Technical University of Denmark)H-Index: 27
view all 8 authors...
Abstract Methotrexate (MTX) is the standard of care in the treatment of rheumatoid arthritis (RA), a common autoimmune disease that is characterized by chronic inflammation in the synovial membrane of joints. Unfortunately, MTX suffers from high discontinuation rates due to a large variability in efficacy and, in particular, adverse effects. As inflammation is associated with elevated levels of reactive oxygen species (ROS) like H2O2, we propose to improve treatment through site-selective delive...
12 CitationsSource
Background The transcription factor NF-kB plays an important role in the pathogenesis of rheumatoid arthritis (RA). Effective treatment of RA is hindered due to the lack of specificity of small molecules in the inflamed joints. In this study, we aimed to develop a unique hybrid-nanoparticles system comprised of calcium phosphate/liposome to deliver NF-kB-targeted siRNA and methotrexate (MTX) to diseased site.
36 CitationsSource
#1Meiling ZhouH-Index: 4
#2Jierong HouH-Index: 1
Last. Chunhong LiH-Index: 4
view all 6 authors...
AbstractRheumatoid arthritis (RA) is a chronic, systemic inflammatory disease. Long-term, high-dose glucocorticoid therapy can be used to treat the disease, but the fact that the drug distributes systemically can give rise to severe adverse effects. Here we develop a targeted system for treating RA in which the glucocorticoid prednisolone (PD) is encapsulated within solid lipid nanoparticles (SLNs) coated with hyaluronic acid (HA), giving rise to HA-SLNs/PD. HA binds to hyaluronic receptor CD44,...
34 CitationsSource
#1Olusiji A. Akinrinmade (UCT: University of Cape Town)H-Index: 4
#2Shivan Chetty (UCT: University of Cape Town)H-Index: 8
Last. Stefan Barth (UCT: University of Cape Town)H-Index: 32
view all 6 authors...
To date, no curative therapy is available for the treatment of most chronic inflammatory diseases such as atopic dermatitis, rheumatoid arthritis, or autoimmune disorders. Current treatments require a lifetime supply for patients to alleviate clinical symptoms and are unable to stop the course of disease. In contrast, a new series of immunotherapeutic agents targeting the Fc γ receptor I (CD64) have emerged and demonstrated significant clinical potential to actually resolving chronic inflammatio...
21 CitationsSource
#1Hanna Hirvonen (UH: University of Helsinki)H-Index: 2
#2Hannu Kautiainen (UH: University of Helsinki)H-Index: 91
Last. Marjatta Leirisalo-Repo (UH: University of Helsinki)H-Index: 75
view all 5 authors...
Patients with rheumatoid arthritis (RA) have increased oxidative stress, decreased antioxidant levels, and impaired antioxidant capacity. Cold treatments are used to relieve joint inflammation and pain. Therefore, we measured the effect of cold treatments on the antioxidative capacity of RA patients with active disease. Sixty patients were randomized to (1) whole body cryotherapy at −110 °C, (2) whole body cryotherapy at −60 °C, or (3) local cryotherapy. Each treatment was given three times dail...
14 CitationsSource
Cited By10
Newest
#1Lobna Abdel Salam (Cairo University)H-Index: 2
#2Amal Aldarwesh (KSU: King Saud University)H-Index: 2
Last. Hatem H. Eleishi (Cairo University)H-Index: 3
view all 3 authors...
Abstract Aim of the work To preliminary study polymorphisms in a set of genes of relevance to methotrexate (MTX) response based on the Drug Bank database in Egyptian rheumatoid arthritis (RA) patients. Patients and methods The study included 10 consecutive adult female RA patients categorized according their response and adverse events (AEs) to MTX; patients with good response, ACR50 after 4 weeks was considered. Variant Call Format files were annotated and filtered via Drug Bank (11/9/2017) dat...
2 CitationsSource
#1Allen B. Tu (UC Davis: University of California, Davis)
#2Jamal S. Lewis (UC Davis: University of California, Davis)H-Index: 13
Rheumatoid arthritis (RA) is an extremely painful autoimmune disease characterized by chronic joint inflammation leading to the erosion of adjacent cartilage and bone. Rheumatoid arthritis pathology is primarily driven by inappropriate infiltration and activation of immune cells within the synovium of the joint. There is no cure for RA. As such, manifestation of symptoms entails lifelong management via various therapies that aim to generally dampen the immune system or impede the function of imm...
Source
#1Zhaoyi Wang (ZJU: Zhejiang University)H-Index: 3
#2Shuqin Wang (ZJU: Zhejiang University)H-Index: 2
Last. Changyou Gao (ZJU: Zhejiang University)H-Index: 90
view all 0 authors...
Osteoarthritis (OA) is a common chronic inflammatory disease in the joints. It is one of the leading causes of disability with increasing morbidity, which has become one of the serious clinical issues. Current treatments would only provide temporary relief due to the lack of early diagnosis and effective therapy, and thus the replacement of joints may be needed when the OA deteriorates. Although the intra-articular injection and oral administration of drugs are helpful for OA treatment, they are...
Source
#1Amin Mahoutforoush (IAU: Islamic Azad University)
#2Atefeh Solouk (AUT: Amirkabir University of Technology)H-Index: 20
Last. Soheil Abbaspour-Ravasjani (Tabriz University of Medical Sciences)H-Index: 4
view all 5 authors...
Abstract Cancer-targeted co-delivery of therapeutic agents has been recognized as an effective strategy for increasing efficacy and reducing side effects of therapeutic agents. In this study, we used methotrexate (MTX) alone as a targeting moiety and chemotherapeutic agent and in combination with docetaxel (DTX) and doxorubicin (DOX) as chemotherapeutic agents to stop cancer cell proliferation with the aid of newly designed nanostructured lipid carriers (NLCs). The physicochemical properties of ...
1 CitationsSource
Abstract null null Reactive Oxygen Species (ROS) plays an important role in biological metabolism and intercellular signalling pathways in living organisms. Researchers have been driving their attention towards active chemical species through variety of advances in nanotechnology utilizing appropriate nanomaterial showing some excellent ROS regulating properties in biological system to contribute in novel upcoming therapeutic methodology. Mesoporous silica nanoparticles (MSNs) have received more...
Source
#1Margarida Ferreira-Silva (University of Lisbon)H-Index: 1
#2Catarina Faria-Silva (University of Lisbon)H-Index: 1
Last. M.L. Corvo (University of Lisbon)H-Index: 11
view all 6 authors...
Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints and results in reduced patient quality of life due to its chronic nature and several comorbidities. RA is also associated with a high socioeconomic burden. Currently, several available therapies minimize symptoms and prevent disease progression. However, more effective treatments are needed due to current therapies' severe side-effects, especially under long-term use. Drug delivery systems have demonstrated their clinical...
1 CitationsSource
#1Qin Wang (Southwest Jiaotong University)H-Index: 3
#1Qin Wang (Southwest Jiaotong University)
Last. Xun Sun (Sichuan University)H-Index: 50
view all 4 authors...
Abstract Increasing understanding of the pathogenesis of rheumatoid arthritis (RA) has remarkably promoted the development of effective therapeutic regimens of RA. Nevertheless, the inadequate response to current therapies in a proportion of patients, the systemic toxicity accompanied by long-term administration or distribution in non-targeted sites and the comprised efficacy caused by undesirable bioavailability, are still unsettled problems lying across the full remission of RA. So far, these ...
Source
#1Lina Guo (CSU: Central South University)H-Index: 2
#2Yang Chen (CSU: Central South University)H-Index: 2
Last. Wenhu Zhou (CSU: Central South University)H-Index: 16
view all 9 authors...
Abstract Methotrexate (MTX) has been used as an anchor drug for the treatment of rheumatoid arthritis (RA), while the patients with chronic MTX administration suffer from severe side-effects. To this end, targeted delivery of MTX by nanomedicine has attracted great interest. In this work, we aimed to employ metal-organic frameworks (MOFs) as nanocarrier to deliver MTX by virtue of its facile and green preparation and exceptionally high drug loading. While MTX could be easily and effectively load...
4 CitationsSource
#1Yin Dou (Third Military Medical University)H-Index: 15
#2Chenwen Li (Third Military Medical University)H-Index: 8
Last. Jianxiang Zhang (Third Military Medical University)H-Index: 33
view all 5 authors...
Abstract Inflammation is intimately related to the pathogenesis of numerous acute and chronic diseases like cardiovascular disease, inflammatory bowel disease, rheumatoid arthritis, and neurodegenerative diseases. Therefore anti-inflammatory therapy is a very promising strategy for the prevention and treatment of these inflammatory diseases. To overcome the shortcomings of existing anti-inflammatory agents and their traditional formulations, such as nonspecific tissue distribution and uncontroll...
14 CitationsSource
#1Yingsi Xie (Guangzhou Medical University)H-Index: 1
#2Ruslan G. Tuguntaev (Guangzhou Medical University)H-Index: 1
Last. Weisheng Guo (Guangzhou Medical University)H-Index: 26
view all 8 authors...
Rheumatoid arthritis (RA) is a long-term inflammatory disease derived from an autoimmune disorder of the synovial membrane. Current therapeutic strategies for RA mainly aim to hamper the macrophages' proliferation and reduce the production of pro-inflammatory cytokines. Therefore, the accumulation of therapeutic agents targeted at the inflammatory site should be a crucial therapeutic strategy. Nowadays, the nanocarrier system incorporated with stimuli-responsive property is being intensively stu...
1 CitationsSource