Publications

We have published several scientific articles related to the work in Moroxite. Please find selected publications below or contact us at info@moroxite.net for full list.

Efficient systemic pharmacological treatment of solid tumors is hampered by inadequate tumor concentration of cytostatics necessitating development of smart local drug delivery systems. To overcome this, we demonstrate that Doxorubicin (DOX), a cornerstone drug used for osteosarcoma treatment, shows reversible accretion to hydroxyapatite (HA) of both nano (nHA) and micro (mHA) size. nHA particles functionalized with DOX get engulfed in the lysosome of osteosarcoma cells where the acidic microenvironment causes a disruption of the binding between DOX and HA. The released DOX then accumulates in the mitochondria causing cell starvation, reduced migration and apoptosis. The HA + DOX delivery system was also tested in-vivo on osteosarcoma bearing mice. Locally delivered DOX via the HA particles had a stronger tumor eradication effect compared to the controls as seen by PET-CT and immunohistochemical staining of proliferation and apoptosis markers. These results indicate that in addition to systemic chemotherapy, an adjuvant nHA could be used as a carrier for intracellular delivery of DOX for prevention of tumor recurrence after surgical resection in an osteosarcoma. Furthermore, we demonstrate that nHA particles are pivotal in this approach but a combination of nHA with mHA could increase the safety associated with particulate nanomaterials while maintaining similar therapeutic potential.

Doxorubicin (DOX) is a cornerstone drug in the treatment of osteosarcoma. However, achieving sufficient concentration in the tumor tissue after systemic administration with few side effects has been a challenge. Even with the most advanced nanotechnology approaches, less than 5% of the total administered drug gets delivered to the target site. Alternatives to increase the local concentration of DOX within the tumor using improved drug delivery methods are needed. In this study, we evaluate a clinically approved calcium sulfate/hydroxyapatite (CaS/HA) carrier, both in-vitro and in-vivo, for local, sustained and controlled delivery of DOX to improve osteosarcoma treatment. In-vitro drug release studies indicated that nearly 28% and 36% of the loaded drug was released over a period of 4-weeks at physiological pH (7.4) and acidic pH (5), respectively. About 63% of the drug had been released after 4-weeks in-vivo. The efficacy of the released drug from the CaS/HA material was verified on two human osteosarcoma cell lines MG-63 and 143B. It was demonstrated that the released drug fractions functioned the same way as the free drug without impacting its efficacy. Finally, the carrier system with DOX was assessed using two clinically relevant human osteosarcoma xenograft models. Compared to no treatment or the clinical standard of care with systemic DOX administration, the delivery of DOX using a CaS/HA biomaterial could significantly hinder tumor progression by inhibiting angiogenesis and cell proliferation. Our results indicate that a clinically approved CaS/HA biomaterial containing cytostatics could potentially be used for the local treatment of osteosarcoma.

Doxorubicin (Dox), an anthracyclin agent, is widely used as a chemotherapy agent for different kinds of malignancies. However, even when entrapped in liposomes, Dox has a terminal half-life in plasma of 69.3 h compared to 17.3 h with free doxorubicin (Rahman et al1 ). And only a small fraction (<5%) of the total administered liposomal formulation is actually delivered to the target site2 . Alternatives to improve efficient and contained delivery of Dox locally within the tissue are needed. Zoledronic acid (ZA) is a new-generation bisphosphonate, and widely used as an adjuvant treatment for bone metastasis, to reduce tumor-related pain and skeletal-related events3 . It could also increase bone formation and enhance repair of large bone defects4 . Furthermore, locally delivered ZA can stay at the target site for up to 6 months due to its affinity to hydroxyapatite (HA) (manuscript in progress). Local dual delivery of Dox and ZA acts synergistically to achieve strong and long-term anti-tumor effect, as well as bone regeneration at the eradicated tumor site. Tumor recurrences and simultaneously an enhanced repair of the bone defect can be achieved. The aim of the present study was to characterize the release kinetics of Dox and ZA from an injectable FDA and CE approved calcium sulfate/hydroxyapatite (CaS/HA) carrier and evaluate the effect on human osteosarcoma cells MG-63. 

List of publications

  1. Yang L.et al., Bone mineral: A trojan horse for bone cancers efficient mitochondria targeted delivery and tumor eradication with nano hydroxyapatite containing doxorubicin. Materials Today Bio  https://doi.org/10.1016/j.mtbio.2022.100227
  2. Yang L. et al., Sustained and controlled delivery of doxorubicin from an in-situ setting hydroxyapatite carrier for local treatment of osteosarcoma. Acta Biomaterialia 2021. https://www.sciencedirect.com/science/article/pii/S1742706121004475
  3. Yang L. et al., Nano-/micro- sized hydroxyapatite moiety improves doxorubicin delivery and tumor eradication., 2021
  4. Yang L. et al., Dual delivery of doxorubicin and zoledronic acid from an injectable calcium sulphate/hydroxyapatite carrier.ORS 2020 Annual Meeting. Phoenix, Arizona. February 8 – 11, 2020. Abstract number 551.
  5. Yang L. et al., Sequential and sustained release of doxorubicin and paclitaxel from a calcium sulfate/hydroxyapatite carrier.27th Annual meeting of European Orthopedic Research Society (EORS 2019). Maastricht, Netherlands