The role of drug-lipid interactions in biodistribution and therapeutic effects for drugs incorporated into liposomes
Bethune, Claudette R., 1967-
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While a number of drugs formulated in liposomes or lipid vesicles are approved for human use, many are formulated empirically, without a full or complete understanding the role of drug-lipid interactions. Hence, the primary goal of this thesis is to study the role of drug-lipid interactions in modulating biodistribution and therapeutic effects when drugs are formulated in liposomes.We first investigated drug-lipid interactions by studying the interactions of a series of opioids with varying hydrophobicity to associate to and release. from liposomes. While highly lipophilic sufentanil associated completely with liposomes, the hydrophilic agent morphine sulfate had low association (30%). The dissociation rate of morphine from liposomes was significantly lower (37-fold) than for sufentanil in the presence of CSF. Studies with a catheterized pig model equipped with microdialysis probes confirmed that in vitro results parallel the in vivo drug release profiles of respective liposome-associated drugs. Our results also suggest that drug incorporation into the aqueous compartment of liposomes and the degree of insertion to lipid membranes, all may modulate a drugs association and dissociation in vitro and in vivo.With this knowledge of drug-lipid interactions, we chose to determine whether the antitumor agent 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) incorporated liposomes may increase the stability of this highly volatile agent. Our results showed that lipid association increased CCNU's stability and efficacy against tumor cell lines. In rats, liposome-formulated CCNU enhanced total drug exposure in plasma with significant decreases in behavioral neurotoxicities. Mechanistic studies in rats suggested that intact drug-liposome complexes, rather than free-drug molecules dissociated from liposomes in systemic circulation, accumulated in tumors. Liposome-associated CCNU reduced plasma free fractions of CCNU by one-half as compared to free drug. It is probable that a combination of increased drug accumulation in tumors and reduced plasma free fractions contributed to the enhanced tumor-growth suppression of lipid-associated CCNU.In conclusion, a systematic study to understand drug-lipid interactions improves our ability to design and optimize drug formulations that use liposomes to improve the therapeutic index of highly potent drugs.
- Pharmaceutics