Recent Advances in the Delivery of Bone Morphogenetic Proteins for Targeting Glioma: An Updated Review

Abstract

Bone Morphogenetic Proteins might be the most prospective in glioma treatment because of the facts that they can differentiate glioma cells, inhibit tumor growth and manage glioma stem cells. Its clinical application is hindered by several challenges, including limited permeability across the blood-brain barrier, which impedes effective delivery to the central nervous system; high susceptibility to enzymatic degradation, which compromises stability and therapeutic efficacy; and nonselective binding, which reduces specificity and may result in unintended off-target effects. This review systematically covers the advanced BMP delivery systems such as nanoparticles, smart carriers, gene therapy, and exosome-based system. Hydrogels, scaffolds, and microspheres' local delivery methods are also discussed as prospective options. The in vitro studies reveal that BMPs are effective and using in vivo glioma models there is also evidence of the effectiveness of BMPs. In addition, new clinical trials reveal concern with safety, tolerability, and therapeutic effects of BMPs, especially their combination with chemotherapy and immunotherapy. BMP specificity and therapeutic performance are further optimized by Personalized medicine and CRISPR/Cas engineering. However, regulatory barriers and product commercialization are challenging issues. This review highlights the need for novel approaches and advanced technologies to address the challenges associated with BMP delivery, aiming to establish BMP-based therapies as an effective treatment strategy for glioma.

Keywords: blood–brain barrier; bone morphogenetic proteins; gene therapy strategies; glioma treatment; nanoparticle-based delivery.

Figure 1

GBM has several characteristic features that can or do contribute to its virile phenotype and that can also be viewed as the targets for therapy. Some of the features of infiltrating cells, genomic alterations, abnormal angiogenesis, immune escape and reprogramming of the stroma outside the tumor cells are observed in most of these tumors. Adapted from Cruz JVR, Batista C, Afonso B, et al. Obstacles to glioblastoma treatment two decades after temozolomide. Cancers. 2022;14(13):3203. Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Figure 2

Signaling pathway of BMP4 as well as activators and inhibitors of BMP4 cellular signaling. BMP4 may interact with preformed complexes (PFCs), in which, BMPR Type I and Type II receptors are bound at the cell surface and with Type I receptors that form BMP4 induced signaling complexes (BISC) in association with Type II receptors. RGMs, DRAGON, and BAMBI can increase BMP4 dimer binding of Type I receptors in both PFCs and BISCs. Signal recognition leads to the phosphorylation of receptor associated SMADs (Smad1/5/8). Signaling activated SMADs merge with co-SMAD4 to affect the nucleus and in mutants with p300 or stat, they act as transcription initiationers which broaden neural and astroglial genes. BMP-1 as well as sulfated polysaccharides act as extracellular activator while Noggin, Chordin and Gremlin interact with BMP4, thus inhibiting the activity of this signal pathway. Pathway activity can be blocked using intracellular inhibitors SMAD6/7, Smurf1/2 and dorsomorphin. BMP4 may also use SMAD-independently signalling pathways for instance MAPK/p38, JNK, Erk etc Pseudo-receptors like BAMBI can bind to BMP4 dimers, however these pseudo-receptor complexes do not transduce signals due to absence of kinase domains on them. Adapted from Xi G, Best B, Mania-Farnell B, James CD, Tomita T. Therapeutic potential for bone morphogenetic protein 4 in human malignant glioma. Neoplasia. 2017;19(4):261–270. Creative Commons license (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Figure 3

BMP Signalling Pathways in Glioma Cells.

Figure 4

Local Delivery Systems for Bone Morphogenetic Proteins in Glioma Treatment.