Abstract
Doxorubicin, an anthracycline cytostatic antibiotic, is widely used in cancer chemotherapy. It has one of the widest anticancer spectrums, especially effective in the treatments of soft tissue and bone sarcomas. However, like other potent chemotherapeutic agents, doxorubicin is a very toxic drug and has a narrow therapeutic index. The clinical usefulness of this drug is limited by its cumulative and dose-related cardiotoxicity. Although a variety of drug delivery systems for doxorubicin have been developed, their use in the treatment of bone sarcomas is limited. The problems associated with the conventional intravenous administration route of doxorubicin for the treatment of bone cancer are: (i) systemic cardiac toxicity caused by the high levels of doxorubicin; (ii) the drug concentration at cancerous site is likely to be low because bone is a moderately perfused organ; and (iii) the narrow therapeutic range of doxorubicin does not permit substantial increases in the dose administered. Therefore, the localized and targeted delivery system for doxorubicin is a logical choice and effective means of minimizing these problems in the treatment of bone sarcomas.|The aim of this study was to develop an implantable and biodegradable drug delivery system containing doxorubicin for the treatment of bone cancer. We evaluated the usage of crosslinked gelatin as a biodegradable matrix material in the design of drug delivery system for doxorubicin. A suitable crosslinking agent (glutaraldehyde) was identified and utilized to control the release characteristics of doxorubicin from the gelatin matrix as well as to maintain the mechanical strength of the implant. The effect of crosslinker (50%, w/w, aqueous solution and sodium bisulfite addition compound) concentration on the rate and extent of doxorubicin release from the implant was also evaluated. An inverse relationship was observed between crosslinker concentration and the rate of doxorubicin release from these implants. A possible crosslinking of glutaraldehyde with the free amino group of doxorubicin has also been postulated.|During the in vitro release study, we observed a color reaction between glutaraldehyde and Tris buffer used as a dissolution medium. Based on this reaction, a visible spectrophotometric method was developed and validated for the determination of glutaraldehyde in solution. The ?imax for this color reaction was found to be 438 nm. Interestingly, a linear relationship was only observed between concentration and absorbency values transposed to natural log scale.|In conclusion, an implantable delivery system for doxorubicin with biodegradable matrix material (crosslinked gelatin) was developed. This system can be surgically implanted at or near the bony tumor site. Glutaraldehyde can be used as a crosslinking agent in this system in order to maintain the mechanical strength of the implant and to sustain the rate of release of the drug from the implant. Glutaraldehyde also reduces the free doxorubicin concentration in the implants probably due to a crosslinking reaction between the drug and glutaraldehyde. This implantable delivery system for doxorubicin with a non-toxic and biodegradable matrix material (crosslinked gelatin) may offer better promise in the treatment of bone sarcomas.