| This thesis describes the design and evaluation of novel lipid nanoparticle (LN) and liposome formulations, with an emphasis on those targeting the folate receptor (FR), which is overexpressed in wide variety of human cancers.; First, methods to extend the shelf life of liposomal formulations via lyophilization were investigated. Incorporation of the cryoprotectants sucrose and glucose into liposomal doxorubicin, daunorubicin, or vincristine effectively maintained the liposomes size distribution upon reconstitution. Drug retention was relatively low (50%), but improved (>88%) when the internal-to-external pH gradient was maintained during lyophilization and reconstitution. These methodologies produced lyophilized products that could be stored and reconstituted without significant changes to critical formulation properties.; Second, FR-targeted LN formulations of paclitaxel and a novel paclitaxel prodrug, paclitaxel-2'-carbonyl-cholesterol (Tax-Chol) were synthesized and evaluated both in vitro and in vivo. Both displayed greater cellular uptake and cytotoxicity in the FR (+) KB and M109 cells than non-targeted LNs, but not in receptor negative cell lines. In addition, FR-targeted LNs of Tax-Chol showed greater tumor growth inhibition and an increase in time of survival when compared with paclitaxel in Cremophor EL in an M109 BALB/c syngraft tumor model.; Third, LNs formulations containing a novel photosensitizing agent hematoporphyrin-stearylamine (HpSA) were prepared and evaluated for cellular uptake and photocytotoxicity. HpSA retained the photosensitizing properties of the parent compound hematoporphyrin. Greater than 95% of HpSA could be incorporated into the LNs at a drug-to-lipid ratio of 1:20. FR targeted LNs of HpSA displayed greater cellular uptake and photocytotoxicity in KB cells than non-targeted LNs.; Finally, novel formulations for three boronated agents, Na3(B 20H17NH3), N5-2OH nucleoside analog and Na 2B12H10(SH)2 (bis-BSH) were evaluated. While liposomal loading of Na3(B20H17NH 3) by passive encapsulation was low (∼3%), the nucleoside analog N5-2OH was efficiently incorporated in LNs (∼95%). A cationic liposome formulation of bis-BSH had a moderate loading efficiency (26%).; In summary, a number of novel liposome and LN formulations of several classes of therapeutic agents were evaluated. Results obtained from the FR-targeted formulations generally indicated efficient tumor cell targeting in vitro. Preliminary studies in vivo indicated significant therapeutic potential for some of the formulations. Further investigation of these formulations is warranted. |
