BMP‐6 Loaded Polyelectrolyte Complex Nanoparticles Inducing Osteogenic Differentiation and Apoptosis of Malignant Plasma Cells for Local Treatment of Multiple Myeloma

Abstract

In the malignant plasma cell disease multiple myeloma (MM), bone lesions and resulting fractures caused by MM cell (MMC) accumulation represent a major cause of morbidity and mortality. Despite recent advantages in systemic treatment, residual MMCs remain, especially in bone lesions. Therefore an interfacial delivery system for local treatment of MM and induced bone disease based on polyelectrolyte complex nanoparticles (PEC NP) loaded with bone morphogenetic protein 6 (BMP‐6) inducing de‐novo bone formation and MMC apoptosis is presented herein. BMP‐6 loaded PEC NP are fabricated by defined mixing bio‐related cationic and anionic polysaccharides and BMP‐6 according to molar ratio of BMP‐6/PEC‐NP of 1/3. BMP‐6/PEC NP bound to a model substrate releases 10% BMP‐6 sustainably within two weeks as accessed by infrared spectroscopy. BMP‐6 loaded PEC NP adheres to cell membranes of MMCs and MSCs and activated phosphorylation of Smad 1/5. Osteogenic differentiation (ALP‐concentration) is enhanced in MSCs (p < 0.05). All patient samples (10/10) of MMCs show significant induction of apoptosis (median 84%, p < 0.05). Finally, BMP‐6/PEC NP are successfully integrated in a commercial hyaluronic acid based hydrogel material revealing MMC death as principal proof for the local treatment of MM induced bone lesions.

Driving Osteocytogenesis from Mesenchymal Stem Cells in Osteon-like Biomimetic Nanofibrous Scaffolds

“…β-Gly supports bone formation by providing a phosphate source for hydroxyapatite formation and by promoting the phosphorylation of ERK1/2 . In terms of growth factors, Bone Morphogenic Proteins (BMPs), multifunctional growth factors within the transforming growth factor β (TGF-β) superfamily, are most frequently used due to their unique osteoinductive potential and crucial roles in skeletal development and maintenance. − The canonical BMP signaling cascade initiates when BMPs associate with type I and type II BMP receptors to form a multimeric receptor ligand complex, followed by phosphorylation of BMP-specific Smads, including Smad 1, 5 and 8, to regulate the expression of the targeted genes, including Runx 2 and ALP. , Of the known BMP variants, BMP2, BMP6 and BMP9 have been shown to be the most potent inducers of osteoblast differentiation from MSCs. ,,− Of these, although BMP2 has received FDA approval for clinical use, , BMP6 has been shown to be more potent (both in vitro and in vivo ). , Regardless, despite the remarkable potential of BMPs for bone regeneration and repair, broader clinical application is often hindered by their random folding, short half-life, high prices and immunogenicity. ,,, A viable alternative is a short peptide of the active domains of the protein capable of replicating the signaling cascades induced by the full length protein. Studies have shown that the biological activity of BMP-derived peptides is highly influenced by their carriers and that carriers designed to sustain the bioactivity and release of BMPp can lead to reduced effective dose sizes and reduced occurrence of side effects compared to full length proteins , …”

Driving Osteocytogenesis from Mesenchymal Stem Cells in Osteon-like Biomimetic Nanofibrous Scaffolds

“…The canonical BMP signaling cascade initiates when BMPs associate with type I and type II BMP receptors to form a multimeric receptor ligand complex, followed by phosphorylation of BMP-specific Smads, including Smad 1, 5 and 8, to regulate the expression of the targeted genes, including Runx 2 and ALP [7c, 8] . Of the known BMP variants, BMP2, BMP6 and BMP9 have been shown to be the most potent inducers of osteoblast differentiation from MSCs [7e, 9] . Of these, although BMP2 has received FDA approval for clinical use [10] , BMP6 has been shown to be more potent (both in vitro and in vivo ) [11] .…”