Short-term effects of mechanical loading on the transdifferentiation of condylar chondrocytes.

INTRODUCTION: Transdifferentiation of chondrocytes into bone cells explains most of the prenatal and early postnatal condylar growth, but its role during later postnatal growth and the mechanisms regulating transdifferentiation remain unknown. This study aimed to quantify the effects of mechanical loading on chondrocyte-derived osteogenesis during late postnatal condylar growth using a short-term mandibular laterotrusion model. METHODS: Thirty 4-week-old Aggrecan-CreERT2, R26RtdTomato, and 2.3Col1a1-GFP compound mice received tamoxifen injections and were divided into control and experimental groups. Appliances were bonded to shift the mandibles of the experimental mice for 5 days, causing protrusion and retrusion of the right and left condyles, respectively. Radiographic, microcomputed tomographic, and histomorphometric analyses were performed. RESULTS: The experimental and control groups showed substantial transdifferentiation of chondrocytes into bone cells. The experimental mice developed asymmetric mandibles, with the protrusive side significantly longer than the retrusive side. The protrusive condyles showed significantly increased chondrogenesis and greater numbers of chondrocyte-derived osteogenic cells, especially in the posterior third. The opposite effects were seen on the retrusive side. CONCLUSIONS: Transdifferentiation of chondrocytes into bone cells occurs during late postnatal condylar growth. Laterotrusion regulates condylar chondrogenesis and chondrocyte transdifferentiation, which alters the amount and direction of condylar growth. Our study demonstrated that chondrocytes are key players in condylar bone formation and should be the focus of studies to control and further understand condylar growth.

Polyethylene glycol-b-poly(lactic acid) polymersomes as vehicles for enzyme replacement therapy.

AIM: Polymersomes are created to deliver an enzyme-based therapy to the brain in lysosomal storage disease patients. MATERIALS & METHODS: Polymersomes are formed via the injection method using poly(ethylene glycol)-b-poly(lactic acid) (PEGPLA) and bound to apolipoprotein E, to create a brain-targeted delivery vehicle. RESULTS: Polymersomes have a smallest average diameter of 145 ± 21 nm and encapsulate ß-galactosidase at 72.0 ± 12.2% efficiency. PEGPLA polymersomes demonstrate limited release at physiologic pH (7.4), with a burst release at the acidic pH (4.8) of the lysosome. PEGPLA polymersomes facilitate delivery of active ß-galactosidase to an in vitro model of GM1 gangliosidosis. CONCLUSION: The foundation has been laid for testing of PEGPLA polymersomes to deliver enzymatic treatments to the brain in lysosomal storage disorders for the first time.

Promiscuous tumor targeting phage proteins.

Cancer cell-specific targeting ligands against numerous cancer cell lines have been selected previously and used as ligands for cell-specific delivery of chemotherapies and various nanomedicines. However, tumor heterogeneity is one recognized problem hampering clinical translation of targeted anti-cancer medicines. Therefore, a novel class of targeting ligands is required that recognize receptors expressed between a variety of cancer phenotypes, identified here as 'promiscuous' ligands. In this work, promiscuous phage fusion proteins were first identified by a novel selection scheme to enrich for pan-cancer cell binding abilities, as indicated by conserved structural motifs identified previously in other cancer types. Additionally, peptide sequences containing a combination of motifs were identified to modulate binding. A panel of phage fusion proteins was studied for their specificity and selectivity for lung and pancreatic cancer cells. Phage displaying the fusion peptides GSLEEVSTL or GEFDELMTM, the two predominate clones with greatest binding ability, were used to modify preformed, doxorubicin-loaded, liposomes. These modified liposomes increased cytotoxicity up to 8.1-fold in several cancer cell lines when compared with unmodified liposomal doxorubicin. Taken together, these data indicate that promiscuous phage proteins, selected against different cancer cell lines, can be used as targeting ligands for treatment of heterogeneous tumor populations.