Review and analysis of FDA approved drugs using lipid-based formulations.

Lipid-based drug delivery systems (LBDDS) are one of the most studied bioavailability enhancement technologies and are utilized in a number of U.S. Food and Drug Administration (FDA) approved drugs. While researchers have used several general rules of thumb to predict which compounds are likely to benefit from LBDDS, formulation of lipid systems is primarily an empiric endeavor. One of the challenges is that these rules of thumb focus in different areas and are used independently of each other. The Developability Classification System attempts to link physicochemical characteristics with possible formulation strategies. Although it provides a starting point, the formulator still has to empirically develop the formulation. This article provides a review and quantitative analysis of the molecular properties of these approved drugs formulated as lipid systems and starts to build an approach that provides more directed guidance on which type of lipid system is likely to be the best for a particular drug molecule.

Liposomes loaded with histone deacetylase inhibitors for breast cancer therapy.

Histone deacetylase (HDAC) inhibitors (HDACi) of the class I trichostatin A (TSA), CG1521 (CG), and PXD101 (PXD) were incorporated at a high rate (approximately 1mM) in liposomes made of egg phosphatidylcholine/cholesterol/distearoylphosphoethanolamine-polyethylenglycol(2000) (64:30:6). Physicochemical parameters (size, zeta potential, loading, stability, release kinetics) of these HDACi-loaded pegylated liposomes were optimized and their cytotoxicity (MTT test) was measured in MCF-7, T47-D, MDA-MB-231 and SkBr3 breast cancer cell lines. In MCF-7 cells, TSA and PXD were efficient inducers of proteasome-mediated estradiol receptor alpha degradation and they both affected estradiol-induced transcription (TSA>PXD) contrary to CG. Moreover, TSA most efficiently altered breast cancer cell viability as compared to the free drug, CG-liposomes being the weakest, while unloaded liposomes had nearly no cytotoxicity. Pegylated liposomes loaded with TSA or PXD remained stable in size, charge and biological activity for one month when stored at 4 degrees C. All HDACi-loaded liposomes released slowly the encapsulated drug in vitro, CG-loaded liposomes showed the slowest release kinetic. These formulations could improve the efficacy of HDACi not only in breast cancers but also in other solid tumors because most of these drugs are poor water soluble and unstable in vivo, and their administration remains a challenge.

Therapeutic potential of new 4-hydroxy-tamoxifen-loaded pH-gradient liposomes in a multiple myeloma experimental model.

PURPOSE: To determine the better liposomal formulation incorporating the active metabolite of tamoxifen, 4-hydroxy-tamoxifen (4HT) and the biological impact of 4HT-pH-gradient liposomes on response to in vivo treatment. METHODS: Several pegylated liposomes were formulated by varying the composition of lipids, increasing external pH from 7.4 to 9.0 and doubling the lipid concentration. Dipalmitoylphosphatidylcholine / cholesterol / distearoylphosphoethanolamine poly(ethylene)glycol liposomes (DL-9 liposomes) were chosen for their physico-chemical properties. Toxicity and release kinetics were assessed in breast cancer MCF-7 as well as in multiple myeloma (MM) cells. In vivo antitumor activity and bio-distribution were measured in the RPMI8226 MM model. RESULTS: Compared to conventional non-pH-gradient liposomes, 4HT-DL-9 liposomes resulted in concentration of up to 1 mM 4HT, greater stability, relative toxicity and slow 4HT release. Intravenous injections of 4HT-DL-9 liposomes at 4 mg/kg/week blocked MM tumor growth. Ki67 and CD34 labeling decreased in treated tumors, concomitantly with increase of activated caspase-3 supporting a cell proliferation arrest, a decrease of tumor vasculature and the induction of tumor cell death. CONCLUSION: This antitumor effect was assumed to be the result of a modified biodistribution of 4HT once trapped in DL-9 liposomes. Such 4HT-containing pH-gradient Stealth nanocarriers could be helpful for MM treatment.