Development of Natural-Based Bone Cement for a Controlled Doxorubicin-Drug Release

Abstract

Osteosarcoma (OS) accounts for 60% of all global bone cancer diagnoses. Intravenous administration of Doxorubicin Hydrochloride (DOXO) is the current form of OS treatment, however, systemic delivery has been linked to the onset of DOXO induced cardiomyopathy. Biomaterials including calcium phosphate cements (CPCs) and nanoparticles (NPs) have been tested as localized drug delivery scaffolds for OS cells. However, the tumor microenvironment is critical in cancer progression, with mesenchymal stem cells (MSCs) thought to promote OS metastasis and drug resistance. The extent of MSC assisted survival of OS cells in response to DOXO delivered by CPCs is unknown. In this study, we aimed at investigating the effect of DOXO release from a new formulation of calcium phosphate-based bone cement on the viability of OS cells cocultured with hMSC in vitro. NPs made of PLGA were loaded with DOXO and incorporated in the formulated bone cement to achieve local drug release. The inclusion of PLGA-DOXO NPs into CPCs was also proven to increase the levels of cytotoxicity of U2OS cells in mono-and coculture after 24 and 72 h. Our results demonstrate that a more effective localized DOXO delivery can be achieved via the use of CPCs loaded with PLGA-DOXO NPs compared to CPCs loaded with DOXO, by an observed reduction in metabolic activity of U2OS cells in indirect coculture with hMSCs. The presence of hMSCs offer a degree of DOXO resistance in U2OS cells cultured on PLGA-DOXO NP bone cements. The consideration of the tumor microenvironment via the indirect inclusion of hMSCs in this study can act as a starting point for future direct coculture and in vivo investigations.

Designing Multifunctional Devices for Regenerative Pharmacology Based on 3D Scaffolds, Drug-Loaded Nanoparticles, and Thermosensitive Hydrogels: A Proof-of-Concept Study

“…Besides the possibility to directly integrate active molecules into 3D frameworks, therapeutic agents can also be loaded into scaffolds or hydrogels upon previous encapsulation into ad hoc designed nano- or micro-carriers, such as polymeric or inorganic particles [ 22 , 23 ]. This approach has the advantage of protecting the payload from fast degradation/deactivation and enhances control over its release kinetics.…”

“…In the same year, Ferreira et al demonstrated the possibility to incorporate similar polymeric particles into PLA scaffolds fabricated via thermally induced phase separation with the aim to develop biomimetic constructs for wound healing and soft tissue regeneration [ 32 ]. Very recently, PLGA particles encapsulating doxorubicin hydrochloride were added to a calcium phosphate bone cement, resulting in a more effective and localized delivery of the cargo compared to direct drug loading into the cement as such [ 23 ].…”

Nature-Inspired Unconventional Approaches to Develop 3D Bioceramic Scaffolds with Enhanced Regenerative Ability

“…Typically, the porosity of CPCs is in the range of 30–55% and is dependent on the liquid/powder ratio: higher ratios are related to an increase in porosity and vice versa [ 71 ]. Furthermore, the presence of a specific level of porosity makes this product also an excellent carrier for a controlled drug delivery system [ 72 , 73 , 74 ]. In this respect, the porosity of CPCs can be enhanced through the introduction of solid porogens, such as inorganic substances and polymers, or by the use of foaming agents [ 75 ].…”

Fabrication of Multifunctional Drug Loaded Magnetic Phase Supported Calcium Phosphate Nanoparticle for Local Hyperthermia Combined Drug Delivery and Antibacterial Activity

“…Among the various modes of hyperthermia, magnetic hyperthermia is an exciting modality to kill cancer cells selectively by applying an external time varying magnetic field using a magnetic specimen as a hyperthermia agent. − Magnetic hyperthermia can be accomplished via magnetic thermoseed or selective internalization of magnetic nanoparticles within cells as an invasive or noninvasive approach. However, thermoseed may be a suitable approach for bone cancer treatment as the bone fillers or substitute material employed can be made both magnetic hyperthermia and chemotherapeutic agents by combining magnetic nanoparticles and appropriate drugs along with the filler materials. − Furthermore, unlike the other modes of hyperthermia treatment for cancers, in the local magnetic hyperthermia where the thermoseed is placed and removed surgically before and after treatment, in the case of bone cancer treatment, there is no need for a second surgery to remove the thermoseed as it acts as a bone filler material or tissue engineering scaffold. , …”