Accumulation Kinetics and Biological Action of Doxorubicin in Rabbit Intervertebral Discs

Area of Science:

• Pharmacology
• Biomedical Engineering
• Orthopedics

Background:

• Doxorubicin (DOX) is a potent chemotherapy agent with known dose-dependent toxicities in normal tissues.
• The intervertebral disc (IVD) is avascular, raising questions about drug penetration and potential side effects from systemic treatments like DOX.

Purpose of the Study:

• To quantify Doxorubicin (DOX) accumulation and clearance in the intervertebral disc (IVD).
• To evaluate the biological effects of DOX on annulus fibrosus (AF) and nucleus pulposus (NP) cells and tissues.

Main Methods:

• Intravenous administration of DOX to rabbits, followed by IVD isolation and drug quantification using LC-HRMS/MS.
• In vitro assessment of DOX effects on IVD cell physiology (viability, redox status, p38 MAPK activation, senescence).
• In vivo histological analysis of IVD tissue quality post-DOX administration.

Main Results:

• DOX accumulation in the IVD was significantly lower than in vascularized skin, decreasing from the outer AF to the inner NP.
• Low DOX concentrations in the IVD had minimal impact on cell viability, redox status, and p38 MAPK activation, without inducing senescence.
• DOX did not negatively affect the extracellular matrix (ECM) integrity, preserving collagen and proteoglycan content.

Conclusions:

• The intervertebral disc (IVD) exhibits limited Doxorubicin (DOX) uptake, suggesting a lower risk of direct toxicity to spinal tissues.
• DOX treatment did not compromise the viability or function of annulus fibrosus (AF) and nucleus pulposus (NP) cells.
• The structural integrity of the IVD extracellular matrix (ECM) remains unaffected by systemic Doxorubicin (DOX) administration.