Bone Marrow Targeted Therapy

Bone Marrow Targeted Therapy

Bone marrow drug delivery refers to a method of administering medication directly into the bone marrow, a crucial component of the body’s immune and circulatory systems, to treat various conditions such as cancer, blood disorders, and autoimmune diseases. This form of drug delivery allows doctors to achieve higher drug concentrations at the site of the disease compared to oral medication or intravenous injections, while minimizing the side effects that can arise from systemic treatment. Targeted therapy approaches are predicted to be more effective than traditional therapeutic approaches, as well as less harmful to cells. The approach of using bone marrow in drug delivery is based on the unique properties of bone marrow, such that it has a rich blood supply, allowing drugs to be efficiently delivered to cells within the tissue, and it is protected by the blood-bone marrow barrier (BMB) which regulates homeostasis and prevents damage from inflammation and autoimmune disorders.

New targeted drug delivery systems using nanoparticles are being researched to advance therapeutic approaches within the hematopoietic system. Current treatments for blood cancers consist of radiotherapy, immunotherapy, chemotherapy, and transplantation. The primary treatment currently is chemotherapy, in which anticancer agents are administered through the bloodstream. This approach is associated with a high patient relapse rate due to a lack of efficiency of the anticancer agents. Because of this, targeted drug delivery systems have grown in popularity over recent years due to their ability to directly target malignant cells and tumors using nanoparticles and biomarkers.

Targeting Bone Marrow Microenvironment

The bone marrow microenvironment (BMM) is a complex system consisting of different cells, molecules, and physical structures that play a critical role in regulating the production, differentiation, and survival of hematopoietic stem cells (HSCs), which give rise to all blood cell types. Additionally, the BMM is directly involved in the development and progression of hematological disorders such as multiple myeloma, leukemia, and lymphoma. The BMM is both highly vascular and permeable, resulting in enhanced drug transport and retention in tissues. However, this same environment acts as a shield towards malignant cells, shielding them from both chemotherapy and immunotherapy. The BMM is known for being a complex system, containing cellular components, extracellular matrix, signaling molecules, and physical structures. Understanding the mechanisms that regulate this environment can provide insight into the development of new therapies for hematological disorders..

Passive Targeting

Passive targeting for bone marrow involves the use of nanoparticles or liposomes that can circulate in the bloodstream until they reach the bone marrow. The size of particles being delivered is crucial due to the transcellular route occurring through the fenestrae within the bone marrow. Therefore these carriers must be designed to have a size and surface chemistry that enables them to evade recognition by the immune system and avoid clearance from the bloodstream. It is noted that negatively charged nanoparticles between 50 and 100 nm are the ideal size to reach bone marrow. Once they reach the bone marrow, they can accumulate in the tissue through passive diffusion or by interacting with the extracellular matrix components.

Active Targeting

Active targeting is a drug delivery approach that involves the use of targeting ligands or antibodies to deliver drugs selectively to the bone marrow. Many blood cancer cells express surface biomarkers, and Active targeting for bone marrow involves the design of drug carriers that have targeting ligands or antibodies that can recognize and bind to specific molecules or receptors on the surface of bone marrow cells. Different targeting ligands and antibodies are used depending on the specific bone marrow cell or disease that is being treated. For example, in regards to leukemia or lymphoma an antibody may be used to recognize and bind to the CD19, CD20, or CD22 receptors, which are overexpressed on malignant B-cells. However, in the case of multiple myeloma a targeting ligand will need to recognize and bind to CD138 receptors due to their overexpression in malignant plasma cells.

Liposomal Based Delivery

Liposomes are often used in targeted drug delivery systems due their flexible biological properties. These properties allow for efficient and effective delivery while minimizing toxicity.

Liposomes are a lipid-based vesicle that can be used for bone marrow drug delivery because of their unique ability to shield drugs from degradation and clearance by the immune system. Liposomes that target the bone marrow specifically are modified with ligands that bind to the receptors on the surface of bone marrow. The CXCR4 receptor is one of the most common ligands used due to it being expressed on the surface of hematopoietic stem cells and playing a crucial role in the migration to the bone marrow. Liposomal carriers have been studied for a variety of bone marrow diseases, including cancers. Cytarabine is an example of a liposomal carrier that is used to treat acute myeloid leukemia (AML). Liposomal cytarabine has been shown to be more effective than conventional cytarabine in treating AML while also having fewer side effects.

More recently, liposomal nanoparticles have been studied on their effectiveness to deliver RNA to bone marrow cells, in an in vivo directed evolution process. In a 2022 study, it was found that a nanoparticle, named “NANO-11” was highly effective at delivering RNA to BM1 cells in mice. NANO-11 had a unique surface chemistry that allowed this delivery to be possible. The nanoparticle had a high density of positively charged amino acid groups on its surface, allowing it to bind and protect negatively charged RNA molecules. Additionally, a 2018 study using an in vitro 3D bone marrow model for multiple myeloma showed that the liposomal delivery of doxorubicin was more effective at killing malignant cells than the free drug. The drug-loaded liposomes were able to penetrate the BMM, resulting in a greater cytotoxicity due to drug uptake.

Exosomal Based Delivery

Exosomes are extracellular vesicles released from cells upon the fusion of a multivesicular body.

Exosomes are small, extracellular vesicles generated by all cells that carry nucleic acids, proteins, lipids, and metabolites. Exosomes play a critical role in intercellular communication and are involved in physiological development, immune response, and tissue repair. In recent years, exosomes have been studied for potential applications in drug delivery and diagnostic testing. Much like liposomes, exosomes can cross biological barriers such as the BMM, as well as low immunogenicity. One key advantage of using exosomes in bone tissue drug delivery is they have been shown to stimulate bone cell activity.

In a 2021 study, exosomal drug delivery was used to guide Antagomir-188, a molecule proven to stimulate bone formation and reduce loss, to bone tissues. The authors used bone marrow-derived mesenchymal stem cells (MSCs) to produce exosomes loaded with Antagomir-188. Results from the study effectively showed bone formation and reduced bone loss. Additionally, a 2020 study of exosomes and their impact on bone diseases showed that exosomes could be a promising drug delivery agent to treat osteoporosis. A rat model of osteoporosis showed that exosomes derived from MSCs improve bone mineral density. Exosomes derived from osteoblasts also reduced bone resorption and have anti-inflammatory effects, which could be beneficial due to the thought that inflammation plays a role in the pathogenesis of osteoporosis. In a 2023 study, exosome-based bone-targeting drug delivery was explored to treat bone loss in patients with inflammatory bowel diseases (IBD). This was tested using a mouse model of IBD and exosomes loaded with the bone forming drug BMP-2. The results showed that the exosomes were able to directly target and interact with the bone cells of the mice, leading to both improved bone density and reduced bone loss.

Stem Cell Based Delivery

Stem cells are being explored to treat numerous diseases and conditions throughout the body. These cells serve as the essential component for tissues, organs, blood, and the immune system.

Because stem cells can differentiate into various types of cells in the body, they are regarded as a promising target in cancer treatment. Stem cells can be engineered to target and kill malignant cells while leaving healthy cells untouched. One approach regarding using stem cells for bone-marrow cancer treatment involves modifying stem cells to produce and release specific anti-tumor agents. Another involves using stem cells to regenerate healthy tissues that could have been harmed through chemo or radiation therapy.

In a 2015 study, mice containing osteosarcoma tumors were treated with cytosine deaminase modified MSCs. Cytosine deaminase was used as an enzyme to convert the non-toxic prodrug 5-FC into a potent chemotherapeutic agent 5-FU. The results showed that the MSCs were able to specifically migrate to and target the tumor site causing tumor growth inhibition and prolonged survival rate in comparison to the control group. In a 2019 study, MSCs were engineered with mRNA encoding for interferon-beta and BMP-2, a cytokine that has anti-tumor effects and a protein shown to have therapeutic effects in relation to bone regeneration, respectively. The engineered MSCs were delivered to mice with bone metastasis from breast cancer, and cancer growth was significantly inhibited while bone regeneration was promoted.

Limitations

There are several areas of limitations that apply to bone marrow targeted therapy. Regarding liposomal drug delivery, complications can arise from stability of the liposomes, release of the drug, target ligands, clearance by the immune system, and actual clinical prevalence. For example, liposomes can be prone to aggregation or degradation which could lower their efficacy. Additionally, liposomal delivery has shown great promise in preclinical studies, but issues such as manufacturing scalability, cost-effectiveness, and regulatory matters must be addressed. There are also limitations that arise from using exosomal targeted therapy, such as the limited understanding in which exosomes target and enter bone cells. There are some studies suggesting that exosomes enter the bone cells through endocytosis or membrane fusion, but the process is not well defined or understood. Additionally, concerns arise from the potential of exosomes being immunogenic or toxic. Because exosomes are derived from cells, and could contain proteins or other biomolecules, they could cause unwanted side effects such as an immune response. Stem cell bone targeted therapy also has many areas of concern such as tumor resistance, immune rejection, and cost. Additionally, if stem cells are not properly targeted then they can promote growth of unwanted cells, causing adverse side effects

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