Liposomes in the treatment of malignancy: a clinical perspective

Abstract

Technological advances in liposomal preparation and efficient drug entrapment, along with supportive preclinical studies, have led to a number of recent clinical trials utilizing liposomes as drug carriers in the treatment of human malignancy. Although the results of these trials must be considered preliminary, it is clear that liposomal delivery of chemotherapeutic agents is safe at the doses administered. Aside from minor constitutional symptoms, virtually all toxicity could be attributed to release of the incorporated drug. Myelosuppression tends to be the dose-limiting toxicity with free drug, whereas constitutional symptoms are more likely to occur with encapsulated biologic therapy. Prior to human trials, there was fear that intravenous injecttion of liposomes could result in pulmonary emboli. No cases of pulmonary embolism secondary to liposome therapy have been recorded. The objective response rate in the patients studied appears to be minimal. This is not surprising, since the overwhelming majority of patients studied had disease that was advanced and previously shown to be refractory to therapy. Subgroups of patients that appear to benefic most include those with breast cancer who were treated with liposomal doxorubicin and those with advanced melanoma treated with liposomal tumor vaccines. Additional phase II and III clinical trials will better define the effectiveness of treatment modalities incorporating liposomes. VI-A. Future directions One of the earliest applications of liposomes may be in the amelioration of drug toxicity. Although not yet proven, the clinical studies reviewed suggest that liposomal delivery of doxorubicin reduces cardiotoxicity without sacrificing antitumor effect. Although similar claims have been made in support of continuous infusion doxorubicin [11], one can avoid unnecessary hospitalization or the bulk and expense of portable infusion devices by a single administration of the liposomal preparation. Liposome encapsulation can markedly alter the biodistribution and pharmacokinetics of well-known chemotherapeutic agents. The effectiveness of liposomal drug delivery in human trials thus far has probably been more closely related to altered pharmacokinetics rather than enhanced drug delivery to tumor or increased tumor responsiveness. As demonstrated by Gabizon [19], increased liposome circulating time in the murine model can be achieved by using small unilamellar vesicles containing a phosphati-dylcholine of high phase-transition temperature and a small molar fraction of monosialoganglioside or hydrogenated phosphatidylinositol. More recently, Klibinov [48], Mori [49] and Allen [50] have shown that the addition of a 2000 Da (polyethylene)glycol molecule to the liposome surface markedly prolongs circulation time. Sophisticated vesicles that can avoid the RES and specifically target tumor via ligands such as antitumor monoclonal antibodies have proven effective in animal models and hold promise for future clinical trials. Watanabe et al. were able to demonstrate an antitumor response in nude Mice inoculated with a human melanoma cell line, using an anti-human melanoma antibody (A375) conjugated to liposomes containing macrophage-activating factor [21]. Hashimoto et al. designed immunoconjugates encapsulating actinomycin D with a surface antibody specific for mouse mammary tumors. These immunoconjugates demonstrated antitumor activity in vivo [22]. Similarly, Watanabe et al. have successfully used sodium butyrate laden liposomes conjugated with anti-CD19 to treat a murine lymphoma model [23]. In addition to altering the biodistribution of drugs, liposomal encapsulation appears to alter mechanisms of drug uptake and metabolism. Lovo cells known to be resistant to free cisplatin have demonstrated sensitivity to L-NDDP. Thus, liposomal delivery may be effective in overcoming mechanisms of cellular resistance and allow the use of encapsulated antitumor agents after resistance develops to the free drug. By overcoming cellular resistance, tumors inherently refractory to a specific agent may become sensitive. Therefore, liposomal encapsulation may increase the spectrum of well-known agents. As mentioned earlier, there is a rationale for combining liposomal immunotherapy with biological response modifiers. Immunomodulators, such as γ-interferon or interleukin-2 (IL-2), have the potential to augment the effectiveness of liposomal MTP-PE by increasing the antitumor response directly or by allowing vascular leaks such that vesicles have access to the tumor bed. Lautersztain et al. have treated 33 patients afflicted with a variety of metastatic solid tumors refractory to chemotherapy with a combination of gamma-interferon and L-MTP-PE [45]. They demonstrated a clinical response in two patients. The major side effects noted were chills, fever, anorexia, fatigue and reversible leukopenia. Further trials of liposomes in conjunction with biologic response modifiers are under way. Liposomal delivery of antitumor therapy is in its infancy and the optimal liposome/drug formulation has not yet been determined. However, the clinical implications of objective responses to LED in patients with advanced breast cancer and to L-TAA in patients with metastatic melanoma are significant. Other preparations, such as L-NDDP and L-MTP-PE, which have been well tolerated in phase I studies, require further clinical evaluation. Based on the results of early clinical trials, phase II and III studies are indicated to determine the role of liposome-encapsulated drugs in the treatment of human malignancy.