Systemic Cisplatin Does Not Affect the Bone Regeneration Process in a Critical Size Defect Murine Model.

Osteosarcoma (OS) is the most common primary malignant bone tumor, and the current standard of care for OS includes neoadjuvant chemotherapy, followed by an R0 surgical resection of the primary tumor, and then postsurgical adjuvant chemotherapy. Bone reconstruction following OS resection is particularly challenging due to the size of the bone voids and because patients are treated with adjuvant and neoadjuvant systemic chemotherapy, which theoretically could impact bone formation. We hypothesized that an osteogenic material could be used in order to induce bone regeneration when adjuvant or neoadjuvant chemotherapy is given. We utilized a biomimetic, biodegradable magnesium-doped hydroxyapatite/type I collagen composite material (MHA/Coll) to promote bone regeneration in the presence of systemic chemotherapy in a murine critical size defect model. We found that in the presence of neoadjuvant or adjuvant chemotherapy, MHA/Coll is able to enhance and increase bone formation in a murine critical size defect model (11.16 ± 2.55 or 13.80 ± 3.18 versus 8.70 ± 0.81 mm3) for pre-op cisplatin + MHA/Coll (p-value = 0.1639) and MHA/Coll + post-op cisplatin (p-value = 0.1538), respectively, at 12 weeks. These findings indicate that neoadjuvant and adjuvant chemotherapy will not affect the ability of a biomimetic scaffold to regenerate bone to repair bone voids in OS patients. This preliminary data demonstrates that bone regeneration can occur in the presence of chemotherapy, suggesting that there may not be a necessity to modify the current standard of care concerning neoadjuvant and adjuvant chemotherapy for the treatment of metastatic sites or micrometastases.

Metal-Organic Framework as a New Type of Magnetothermally-Triggered On-Demand Release Carrier.

The development of external stimuli-controlled payload systems has been sought after with increasing interest toward magnetothermally-triggered drug release (MTDR) carriers due to their non-invasive features. However, current MTDR carriers present several limitations, such as poor heating efficiency caused by the aggregation of iron oxide nanoparticles (IONPs) or the presence of antiferromagnetic phases which affect their efficiency. Herein, a novel MTDR carrier is developed using a controlled encapsulation method that fully fixes and confines IONPs of various sizes within the metal-organic frameworks (MOFs). This novel carrier preserves the MOF's morphology, porosity, and IONP segregation, while enhances heating efficiency through the oxidation of antiferromagnetic phases in IONPs during encapsulation. It also features a magnetothermally-responsive nanobrush that is stimulated by an alternating magnetic field to enable on-demand drug release. The novel carrier shows improved heating, which has potential applications as contrast agents and for combined chemo and magnetic hyperthermia therapy. It holds a great promise for magneto-thermally modulated drug dosing at tumor sites, making it an exciting avenue for cancer treatment.

Mimicking the Organic and Inorganic Composition of Anabolic Bone Enhances Human Mesenchymal Stem Cell Osteoinduction and Scaffold Mechanical Properties.

Engineered bone graft designs have been largely inspired by adult bone despite functionally significant differences from the composition of anabolic bone in both the mineralized and non-mineralized fractions. Specifically, anabolic bone contains hydroxyapatite with ionic substitutions that facilitate bone turnover and relatively rare collagens type VI and XII that are important for normal bone development. In this work, human mesenchymal stem cells (hMSCs) were cultured in lyophilized collagen type I scaffolds mineralized with hydroxyapatite containing Mg2+ substitutions, then induced to deposit an extracellular matrix (ECM) containing collagens VI and XII by exposure to GW9662, a PPARγ inhibitor. Delivery of GW9662 was accomplished through either Supplemented Media or via composite microspheres embedded in the scaffolds for localized delivery. Furthermore, hMSCs and scaffolds were cultured in both static and perfuse conditions to investigate the interaction between GW9662 treatment and perfusion and their effects on ECM deposition trends. Perfusion culture enhanced cell infiltration into the scaffold, deposition of collagen VI and XII, as well as osteogenic differentiation, as determined by gene expression of osteopontin, BMP2, and ALP. Furthermore, scaffold mineral density and compressive modulus were increased in response to both GW9662 treatment and perfusion after 3 weeks of culture. Local delivery of GW9662 with drug-eluting microspheres had comparable effects to systemic delivery in the perfusate. Together, these results demonstrate a strategy to create a scaffold mimicking both organic and inorganic characteristics of anabolic bone and its potential as a bone graft.

Bromelain surface modification increases the diffusion of silica nanoparticles in the tumor extracellular matrix.

Tumor extracellular matrix (ECM) represents a major obstacle to the diffusion of therapeutics and drug delivery systems in cancer parenchyma. This biological barrier limits the efficacy of promising therapeutic approaches including the delivery of siRNA or agents intended for thermoablation. After extravasation due to the enhanced penetration and retention effect of tumor vasculature, typical nanotherapeutics are unable to reach the nonvascularized and anoxic regions deep within cancer parenchyma. Here, we developed a simple method to provide mesoporous silica nanoparticles (MSN) with a proteolytic surface. To this extent, we chose to conjugate MSN to Bromelain (Br-MSN), a crude enzymatic complex, purified from pineapple stems, that belongs to the peptidase papain family. This surface modification increased particle uptake in endothelial, macrophage, and cancer cell lines with minimal impact on cellular viability. Most importantly Br-MSN showed an increased ability to digest and diffuse in tumor ECM in vitro and in vivo.