We propose to use antibody-conjugated liposomes to achieve in vivo localization in animal tumors and thus increase the therapeutic index of encapsulated drugs. Targeting of liposomes to specific cells will be done by conjugating them with immunoglobulins which recognize specific cell-surface antigens. We have already shown that this procedures works very efficiently in vitro. Our strategy for achieveing targeting in vivo involves three stages: 1) optimization of specific binding and cytotoxicity in vitro by varying antibody per liposome ratio, liposome size and composition and type of drug; 2) optimization of in vivo targeting against the same cells in mice by use of specific radiolabelled and electronmicroscopic markers for both liposome lipids and aqueous contents and by examining the effect of route of administration, liposome size, dosage, pre- saturation of the reticulo-endothelial system, and increasing endothelial permeability; and 3) evaluation of anti-tumor effects by observing changes in size of implanted tumors and deaths due to hematogenous metastasis. Our choice of target cells involves a progression from situations where cells are """"""""accessible"""""""" (such as lymphoid tissue) to systems where the cells may be relatively inaccessible (such as implanted tumors). Our strategy of selecting drugs for maximal therapeutic index includes the following: drug derivatives that are not normally transported into cells (lipsome-dependent drugs) in order to decrease systemic toxicity; drugs that become membrane permeable in the low pH environment after endocytosis (lysosomophobic drugs) in order to increase the efficiency of intracellular delivery; and drugs that can be transported into cells after slow release from liposomes simply attached to target cells (localized depot effect).
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