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Platinum-based chemotherapeutics exhibit excellent antitumor properties. However, these drugs cause severe side effects including toxicity, drug resistance, and lack of tumor selectivity. Tumor-targeted drug delivery has demonstrated great potential to overcome these drawbacks. Herein, we aimed to design radioactive bisphosphonate-functionalized platinum (195mPt-BP) complexes to confirm preferential accumulation of these Pt-based drugs in metabolically active bone. In vitro NMR studies revealed that release of Pt from Pt BP complexes increased with decreasing pH. Upon systemic administration to mice, Pt-BP exhibited a 4.5-fold higher affinity to bone compared to platinum complexes lacking the bone-seeking bisphosphonate moiety. These Pt-BP complexes formed less Pt-DNA adducts compared to bisphosphonate-free platinum complexes, indicating that in vivo release of Pt from Pt-BP complexes proceeded relatively slow. Subsequently, radioactive 195mPt-BP complexes were synthesized using 195mPt(NO3)2(en) as precursor and injected intravenously into mice. Specific accumulation of 195mPt-BP was observed at skeletal sites with high metabolic activity using micro-SPECT/CT imaging. Furthermore, laser ablation-ICP-MS imaging of proximal tibia sections confirmed that 195mPt BP co-localized with calcium in the trabeculae of mice tibia.

Contains fulltext : 172605.pdf (Publisher’s version ) (Closed access) Gelatin nanoparticles can be tuned with respect to their drug loading efficiency, degradation rate, and release kinetics, which renders these drug carriers highly suitable for a wide variety of biomedical applications. The ease of functionalization has rendered gelatin an interesting candidate material to introduce specific motifs for selective targeting to specific organs, but gelatin nanoparticles have not yet been modified to increase their affinity to mineralized tissue. By means of conjugating bone-targeting alendronate to biocompatible gelatin nanoparticles, a simple method is developed for the preparation of gelatin nanoparticles which exhibit strong affinity to mineralized surfaces. It has been shown that the degree of alendronate functionalization can be tuned by controlling the glutaraldehyde crosslinking density, the molar ratio between alendronate and glutaraldehyde, as well as the pH of the conjugation reaction. Moreover, it has been shown that the affinity of gelatin nanoparticles to calcium phosphate increases considerably upon functionalization with alendronate. In summary, gelatin nanoparticles have been developed, which exhibit great potential for use in bone-specific drug delivery and regenerative medicine.

Injectable composite colloidal gels are developed for regeneration of osteoporotic bone defects through a bottom-up assembly from bisphosphonate-functionalized gelatin and bioactive glass particles. Upon bisphosphonate functionalization, gelatin nanoparticles show superior adhesion toward bioactive glass particles, resulting in elastic composite gels. By tuning their composition, these composite colloidal gels combine mechanical robustness with self-healing ability. The composite colloidal gels support cell proliferation and differentiation in vitro without requiring any osteogenic supplement. In vivo evaluation of the composite colloidal gels reveals their capacity to support the regeneration of osteoporotic bone defects. Furthermore, the bisphosphonate modification of gelatin induces a therapeutic effect on the peri-implantation region by enhancing the bone density of the osteoporotic bone tissue. Consequently, these composite colloidal gels offer new therapeutic opportunities for treatment of osteoporotic bone defects.

Contains fulltext : 172557.PDF (Publisher’s version ) (Open Access) Artificial 3-dimensional (3D) cell culture systems, which mimic the extracellular matrix (ECM), hold great potential as models to study cellular processes under controlled conditions. The natural ECM is a 3D structure composed of a fibrous hydrogel that provides both mechanical and biochemical cues to instruct cell behavior. Here we present an ECM-mimicking genetically engineered protein-based hydrogel as a 3D cell culture system that combines several key features: (1) Mild and straightforward encapsulation meters (1) ease of ut I am not so sure.encapsulation of the cells, without the need of an external crosslinker. (2) Supramolecular assembly resulting in a fibrous architecture that recapitulates some of the unique mechanical characteristics of the ECM, i.e. strain-stiffening and self-healing behavior. (3) A modular approach allowing controlled incorporation of the biochemical cue density (integrin binding RGD domains). We tested the gels by encapsulating MG-63 osteoblastic cells and found that encapsulated cells not only respond to higher RGD density, but also to overall gel concentration. Cells in 1% and 2% (weight fraction) protein gels showed spreading and proliferation, provided a relative RGD density of at least 50%. In contrast, in 4% gels very little spreading and proliferation occurred, even for a relative RGD density of 100%. The independent control over both mechanical and biochemical cues obtained in this modular approach renders our hydrogels suitable to study cellular responses under highly defined conditions.

Item does not contain fulltext Herein, we present a method to release chemotherapeutic platinum-bisphosphonate (Pt-BP) complexes from apatitic calcium phosphate cements (CPCs). Pt-BP-loaded hydroxyapatite nanoparticles (HA NPs) were added at different ratios to the powder phase of the cements, which contained poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres as porogens to accelerate their degradation. In vitro release kinetics of Pt-BP complexes revealed that the release rate of Pt species can be tuned by varying the amount of drug-loaded HA NPs as well as modifying the chemical structure of the Pt-BP complex to tailor its affinity with HA NPs. In addition, the incorporation of PLGA microspheres into the CPCs increased the degradation rate of the materials without affecting the release rate of Pt species. Finally, the antiproliferative activity of the free Pt-BP complexes and Pt-BP-loaded CPCs was evaluated using both human osteosarcoma cancer cells (MG-63) and human bone marrow-derived mesenchymal stromal cells (h-BMMSCs). This study demonstrated that both free Pt-BP complexes and the releasates from the CPCs were antiproliferative in a dose-dependent manner. Moreover, their antiproliferative activity was higher on MG-63 cells compared to h-BMMSC primary cells. In summary, it was shown that injectable CPCs can be rendered chemotherapeutically active by incorporation of HA NPs loaded with HA-binding Pt-BP complexes.

In order to improve the efficacy of therapeutic systems to treat bone tumours, novel drug delivery vehicles should be developed that have strong and specific affinity to mineralised tissue and at the same time are able to release anticancer molecules locally in a controlled and sustained manner. Recently, we developed mineral-binding gelatine nanoparticles with enhanced affinity to calcium phosphate by conjugating alendronate (ALN) molecules onto their surface. Herein, we have enhanced the functionality of these nanoparticles by rendering them potentially therapeutically active via covalent linking of an anticancer platinum–bisphosphonate (Pt–BP) complex. Different functionalisation schemes and molar ratios between reactants were screened and the effective functionalisation of gelatine nanoparticles with Pt–BP (or with both Pt–BP and ALN) was assessed. Our results revealed that the degree of functionalisation could be tailored by varying the molar ratio of Pt–BP and ALN relative to glutaraldehyde used as crosslinker. A sustained and tunable release of platinum as a function of the initial Pt–BP/ALN/glutaraldehyde molar ratio was achieved for both Pt–BP- and dual-functionalised gelatine nanoparticles. Moreover, dual-functionalised gelatine nanoparticles also displayed a high affinity to hydroxyapatite-coated surfaces thanks to the presence of ALN. Summarising, it was demonstrated that mineral-binding gelatine nanoparticles can be loaded with tailored amounts of anticancer molecules, which may benefit the development of bone-seeking carriers for targeted delivery of drugs to treat bone tumours.

Item does not contain fulltext Mimicking the nanostructure of bone and understanding the interactions between the nanoscale inorganic and organic components of the extracellular bone matrix are crucial for the design of biomaterials with structural properties and a functionality similar to the natural bone tissue. Generally, these interactions involve anionic and/or cationic functional groups as present in the organic matrix, which exhibit a strong affinity for either calcium or phosphate ions from the mineral phase of bone. This study reviews the interactions between the mineral and organic extracellular matrix components in bone tissue as a source of inspiration for the design of novel nanocomposites. After providing a brief description of the various structural levels of bone and its main constituents, a concise overview is presented on the process of bone mineralization as well as the interactions between calcium phosphate (CaP) nanocrystals and the organic matrix of bone tissue. Bioinspired synthetic approaches for obtaining nanocomposites are subsequently addressed, with specific focus on chemical groups that have affinity for CaPs or are involved in stimulating and controlling mineral formation, that is, anionic functional groups, including carboxyl, phosphate, sulfate, hydroxyl, and catechol groups.

Item does not contain fulltext Colloidal gels are a particularly attractive class of hydrogels for applications in regenerative medicine, and allow for a "bottom-up" fabrication of multi-functional biomaterials by employing micro- or nanoscale particles as building blocks to assemble into shape-specific bulk scaffolds. So far, however, the synthesis of colloidal composite gels composed of both organic and inorganic particles has hardly been investigated. The current study has focused on the development of injectable colloidal organic-inorganic composite gels using calcium phosphate (CaP) nanoparticles and gelatin (Gel) nanospheres as building blocks. These novel Gel-CaP colloidal composite gels exhibited a strongly enhanced gel elasticity, shear-thinning and self-healing behavior, and gel stability at high ionic strengths, while chemical - potentially cytotoxic - functionalizations were not necessary to introduce sufficiently strong cohesive interactions. Moreover, it was shown in vitro that osteoconductive CaP nanoparticles can be used as an additional tool to reduce the degradation rate of otherwise fast-degradable gelatin nanospheres and fine-tune the control over the release of growth factors. Finally, it was shown that these colloidal composite gels support attachment, spreading and proliferation of cultured stem cells. Based on these results, it can be concluded that proof-of-principle has been obtained for the design of novel advanced composite materials made of nanoscale particulate building blocks which exhibit great potential for use in regenerative medicine.