Targeted Delivery of Chemotherapeutic Agents for Osteosarcoma Treatment

Abstract

Since osteosarcoma (OS) is an aggressive bone cancer with unknown molecular pathways of etiology and pathophysiology, improving patient survival has long been a challenge. The conventional therapy is a complex multidisciplinary management that include radiotherapy, chemotherapy which followed by surgery and then post-operative adjuvant chemotherapy. However, they have severe side effects because the majority of the medicines used have just a minor selectivity for malignant tissue. As a result, treating tumor cells specifically without damaging healthy tissue is currently a primary goal in OS therapy. The coupling of chemotherapeutic drugs with targeting ligands is a unique therapy method for OS that, by active targeting, can overcome the aforementioned hurdles. This review focuses on advances in ligands and chemotherapeutic agents employed in targeted delivery to improve the capacity of active targeting and provide some insight into future therapeutic research for OS.

Keywords: antibodies; chemotherapeutic agents; ligand-based delivery systems; osteosarcoma; targeted delivery.

Figure 1

Osteogenesis and Osteosarcoma genesis. (A) Initiation of osteogenic differentiation from mesenchymal stem cells (MSCs). MSCs are multipotent bone marrow cells that are capable of differentiating to bone (osteoblast/osteocyte), fat (adipocyte), and cartilage (chondrocyte) tissues. (B) Defects in osteogenesis lead to osteosarcoma genesis. Genetic alterations probably interfere with the normal osteogenic process, resulting in incompletely differentiated osteoblasts or osteocytes in bone. These defects disrupt the balance between proliferation and differentiation, and may cause a group of cells to display uncontrolled cell proliferation. Osteosarcoma progenitors may arise from these cells and expand to form osteosarcoma. This figure was created with BioRender.com.

Figure 2

Antibody-Drug Conjugate Mechanism of Action. A chemodrug is coupled to an antibody that specifically targets a certain OS antigen. Antibodies attach themselves to the antigens on the surface of cancerous cells. The biochemical reaction between the antibody and the target protein (antigen) triggers a signal in the OS cell, which then inhibits OS cell growth, or internalizes the antibody together with the linked chemo drug and eliminates the OS cell. This figure was created with BioRender.com.

Figure 3

Targeted delivery systems of OS. Different delivery systems have ideal properties for chemodrugs transport and delivery. Targeting ligands may be attached to the surface allowing an active targeting strategy and an increase in efficiency of the therapeutic payloads in OS therapy. After internalization, dissociation occurs at a proper microenvironment due to different stimuli (enzyme, redox, etc.), drug payloads are released into the cytosol of cancer cells. This figure was created with BioRender.com.

Figure 4

3D Printing guided advanced OS therapy. 3D printing scaffold and various types of carbon sources or nanocariers that may be incorporated. The nanocarriers and carbon sources are included in a 3D printed scaffold. The scaffold is then implanted into the critical defect site in the tibial due to OS resection to present bone regeneration, photothermal therapy, and local chemo release. This figure was created with BioRender.com.