The design and development of DaunoXome(R) for solid tumor targeting in vivo

This article reviews the formulation development and characterization of the tumor-targeting daunorubicin liposome preparation, DaunoXome(R). The identification of liposome formulations capable of delivering their contents to solid tumors in vivo was contingent upon the development of an active loading technique for entrapping the gamma emitter, In-111. Using (111)labeled liposomes, various formulations were screened for their ability to deliver entrapped materials to solid tumors selectively. With this In-111 labeling approach, a wide range of compositions and physical characteristics (size, phase transition temperature, surface charge, etc.) were evaluated for their abilities to remain intact in the circulation for prolonged periods as well as to deliver and release their entrapped contents selectively within solid tumors in vivo. We identified as particularly effective, a formulation of distearolyphosphatidylcholine (DSPC) and cholesterol in a 2:1 mole ratio with diameters less than 100 nm. In clinical studies involving nearly 400 patients, these liposomes imaged a wide variety of primary cancers and their metastases. Classes of tumors successfully imaged include: breast, prostate, colon, kidney, cervix, thyroid, larynx, lung (small cell and non-small cell), lymphomas (malignant and Hodgkin's), sarcomas (soft tissue and Kaposi's). This basic formulation served as a model for development of a liposome delivery system to target antineoplastic agents to solid tumors in vivo. It had been know for some time that the formulation of anthracyclines. into liposomes could be particularly advantageous for improving the therapeutic benefits of this drug class. For reasons discussed below, we selected daunorubicin over other anthracyclines for liposome development. The resulting daunorubicin liposome product, (DaunoXome(R)) is a formulation of daunorubicin in small unilamellar vesicles (SUVs) composed of highly pure distearoylphosphatidylcholine (DSPC) and cholesterol in a 2:1 mole ratio. Several countries, including the United States, have approved DaunoXome(R) for use in for treating Kaposi's sarcoma (KS) in HIV-positive patients. As with the In-111 tumor imaging liposomes, we believe that DaunoXome(R) extravasates selectively into solid tumors through discontinuities in the capillary beads arising in tumor neovasculature. Preclinical investigations have indicated that DaunoXome(R) increases in vivo daunorubicin tumor delivery by about 10-fold over conventional drug, yielding a comparable increase in therapeutic efficacy. Investigations on the modes of delivery and of action indicate that DaunoXome(R) arrives at and accumulates within tumor cells primarily in an intact form. Once within the tumor cells, the liposomes release drug over a prolonged period (36 h or more), providing sustained, high levels of cytotoxic material within tumor cells. HIV-positive patients tolerate DaunoXome(R) well and their responses to it compare favorably with the typical therapy of ABV (doxorubicin, bleomycin, vincristine), demonstrating reduced toxicity while retaining comparable to improved antitumor activity. In this review, we report on issues of DaunoXome(R)'s formulation development and it's preclinical and clinical investigations.