Engineering Nanotherapeutic Strategies for Osteoarthritis Treatment
Doktorsavhandling, 2023
Osteoarthritis (OA), the most prevalent joint disorder, is characterized by the degeneration of cartilage tissue leading to pain, stiffness, and impaired mobility. Primarily affecting the elderly, OA can also impact athletes, postmenopausal women, and individuals with conditions like diabetes. Despite it being a predominant contributor to physical disability, the absence of disease-modifying treatments for OA highlights the critical demand for novel therapies that preserve the well-being of individuals who are at risk of developing the disease.
As conventional treatment options offer limited relief and are incapable of halting OA progression, the field of nanomedicine has emerged as a promising frontier in this pursuit. Nanoscale materials such as nanoparticles (NPs) can be designed to carry a variety of therapeutic agents directly to the affected areas of the joint enabling precise and controlled therapies. In particular, NPs can circumvent the challenges faced by traditional medicines and are able to enter the cells embedded within the dense and charged cartilage extracellular matrix. Nonetheless, the limited knowledge of their interactions with complex biological environments impedes their clinical applications.
The foundational principle of the nanocarrier systems explored in this thesis is based on the use of cationic NPs. By leveraging electrostatic interactions with negatively charged components within the joint, these NPs serve as optimal tools for addressing the overlooked aspects of OA drug delivery, such as a protein-rich synovial fluid (SF) and an active catabolic environment. The findings in this work cover the SF-induced protein corona formation and its substantial effects on the NP uptake into cartilage and joint-associated cells. An enzymatically active cartilage milieu was also found to hinder the NP uptake and dictate the immunological responses, thereby influencing their therapeutic potential.
By illustrating the complexity of the dynamic OA environment, the investigations of the nanomaterial-cartilage interface serve as the fundamental framework for developing optimal cartilage drug delivery strategies. Accurate disease models and extensive NP characterization in a physiologically relevant environment are necessary for paving the way toward personalized approaches in medical practice.
As conventional treatment options offer limited relief and are incapable of halting OA progression, the field of nanomedicine has emerged as a promising frontier in this pursuit. Nanoscale materials such as nanoparticles (NPs) can be designed to carry a variety of therapeutic agents directly to the affected areas of the joint enabling precise and controlled therapies. In particular, NPs can circumvent the challenges faced by traditional medicines and are able to enter the cells embedded within the dense and charged cartilage extracellular matrix. Nonetheless, the limited knowledge of their interactions with complex biological environments impedes their clinical applications.
The foundational principle of the nanocarrier systems explored in this thesis is based on the use of cationic NPs. By leveraging electrostatic interactions with negatively charged components within the joint, these NPs serve as optimal tools for addressing the overlooked aspects of OA drug delivery, such as a protein-rich synovial fluid (SF) and an active catabolic environment. The findings in this work cover the SF-induced protein corona formation and its substantial effects on the NP uptake into cartilage and joint-associated cells. An enzymatically active cartilage milieu was also found to hinder the NP uptake and dictate the immunological responses, thereby influencing their therapeutic potential.
By illustrating the complexity of the dynamic OA environment, the investigations of the nanomaterial-cartilage interface serve as the fundamental framework for developing optimal cartilage drug delivery strategies. Accurate disease models and extensive NP characterization in a physiologically relevant environment are necessary for paving the way toward personalized approaches in medical practice.
nanoparticles
nanomedicine
cartilage
osteoarthritis
KA Lecture Hall, Kemigården 4, Gothenburg
Opponent: Prof. Dr. Ingrid Meulenbelt, Leiden University, The Netherlands
Författare
Ula von Mentzer
Chalmers, Life sciences, Kemisk biologi
Synovial fluid profile dictates nanoparticle uptake into cartilage - implications of the protein corona for novel arthritis treatments
Osteoarthritis and Cartilage,;Vol. 30(2022)p. 1356-1364
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Artikel i vetenskaplig tidskrift
von Mentzer, U., Havemeister, F., Råberg, L., Erensoy, G., Esbjörner, E.K., Stubelius, A. Cationic Nanoparticle Interactions with Catabolic Cartilage Modifies Macrophage Cytokine Production
von Mentzer, U., Svensson, E., Ryskulov, R., Hultgård Ekwall, A-K., Jesorka, A., Stubelius, A. Engineering Dendrimers for Improved Zonal Distribution in Catabolic Cartilage
von Mentzer, U., Erensoy, G., Sonntag, P., Kama, M. A. M., Lee, S., Hultgård-Ekwall, A-K., Stubelius, A. Functionalizing nanoparticles: dual strategy for probing cartilage degradation
The ability to move freely is essential to our well-being. Our joints enable a wide range of motions, from basic activities like walking and writing to the intricate movements required in sports and dance. The combination of flexibility and stability of the joints facilitates an effortless execution of daily tasks, a capability we often take for granted until it begins to fade.
One of the most common causes of joint-related disability is osteoarthritis (OA). OA is a condition where the natural cushioning in the joints, also called cartilage, becomes inflamed, painful, and eventually degenerates. It results in a severe loss of mobility and a significant impairment in daily functioning. Although OA predominantly affects the elderly it can also occur in younger people due to a wide variety of causes ranging from injury to hormone-based imbalance. OA-associated changes in the joint are currently incurable. This poses a serious issue due to its significant impact on the well-being of affected individuals and their overall quality of life.
In the quest for improved treatments, nanomedicine has emerged as a promising strategy. Therapeutic nanoparticles (NPs) have the ability to penetrate areas inaccessible to conventional medications. These small NPs offer the possibility to provide targeted and effective relief to the joints while reducing side effects. This precision in drug delivery holds great potential for improving the lives of those with OA.
Nevertheless, the path to integrating nanomedicine into mainstream treatment is complicated. This thesis builds on the recent discoveries of NP applications in OA to provide new insights for improving drug delivery outcomes. By studying the interplay between NPs and joint components, this work addressed the impact of these interactions on NP efficacy. As a result, such interactions could hinder or enhance the NP journey toward the target and lead to specific immune system responses. The findings highlighted in this thesis pave the way for designing optimal, cartilage-specific drug delivery strategies for OA. Although the journey from research to clinical practice is extensive, the prospect of a personalized approach to managing OA underscores the value of this endeavor for future healthcare.
One of the most common causes of joint-related disability is osteoarthritis (OA). OA is a condition where the natural cushioning in the joints, also called cartilage, becomes inflamed, painful, and eventually degenerates. It results in a severe loss of mobility and a significant impairment in daily functioning. Although OA predominantly affects the elderly it can also occur in younger people due to a wide variety of causes ranging from injury to hormone-based imbalance. OA-associated changes in the joint are currently incurable. This poses a serious issue due to its significant impact on the well-being of affected individuals and their overall quality of life.
In the quest for improved treatments, nanomedicine has emerged as a promising strategy. Therapeutic nanoparticles (NPs) have the ability to penetrate areas inaccessible to conventional medications. These small NPs offer the possibility to provide targeted and effective relief to the joints while reducing side effects. This precision in drug delivery holds great potential for improving the lives of those with OA.
Nevertheless, the path to integrating nanomedicine into mainstream treatment is complicated. This thesis builds on the recent discoveries of NP applications in OA to provide new insights for improving drug delivery outcomes. By studying the interplay between NPs and joint components, this work addressed the impact of these interactions on NP efficacy. As a result, such interactions could hinder or enhance the NP journey toward the target and lead to specific immune system responses. The findings highlighted in this thesis pave the way for designing optimal, cartilage-specific drug delivery strategies for OA. Although the journey from research to clinical practice is extensive, the prospect of a personalized approach to managing OA underscores the value of this endeavor for future healthcare.
Styrkeområden
Nanovetenskap och nanoteknik
Ämneskategorier
Materialteknik
Medicinteknik
Medicinsk bioteknologi
Nanoteknik
ISBN
978-91-7905-979-8
Doktorsavhandlingar vid Chalmers tekniska högskola. Ny serie: 5445
Utgivare
Chalmers
KA Lecture Hall, Kemigården 4, Gothenburg
Opponent: Prof. Dr. Ingrid Meulenbelt, Leiden University, The Netherlands