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Abstract
In our previous work we showed that taxanes (paclitaxel (Ptx) and docetaxel(Dtx)) can be spontaneously loaded into monosialoganglioside (GM1) nanomicelles, increasing their water solubility about 6,000 times, to render stable water soluble formulations that could be used as a novel strategy to deliver drugs in cancer. Here, we describe the hydrophobic interaction of Human Serum Albumin (HSA) with GM1 micelles loaded with Ptx, as a strategy that could improve tumour drug accumulation. This interaction is regulated by conditions such pH and temperature and generates ternary complexes GM1/Ptx/HSA with sizes around 19 to 24 nm and hydrodynamic radius equivalent to a globular protein of 140-180 kDa. These mixed micelles were stable in solution for at least 40 days and also upon freeze-thawing or lyophilization-solubilization cycles. The results of in vitro assays showed that the nano-structures developed are taken up by cell cultures with an antimitotic activity of Ptx on tumoral and nontumoral cell lines that was similar to that observed with the free drug in DMSO solution.
Highlights
Several hydrophobic drugs, especially those used in oncological treatments, appear with poor or limited water solubility, rapid phagocytic and renal clearance, and elevated systemic toxicity which represent the major barriers that limit the therapeutic use
The results reported in our previous work show that micelle forming monosialogangliosides (i.e., GM1 and GM2), with critical micellar concentrations (CMCs) in the order of 10-8 M, spontaneously interact with Ptx and docetaxel (Dtx) forming water soluble structures that are relatively insensitive to dilution and allow their aqueous delivery and antimitotic activity [10]
Several attempts have been performed in recent years to formulate taxanes associated to albumin [17-19]
Summary
Especially those used in oncological treatments, appear with poor or limited water solubility, rapid phagocytic and renal clearance, and elevated systemic toxicity which represent the major barriers that limit the therapeutic use. Many laboratories have developed strategies to avoid systemic toxicity and to increase the low water solubility of hydrophobic drugs such as Ptx. Liposomes composed of a phospholipid bilayer are capable of encapsulating the active drug [4,5]. Other strategy to improve the systemic delivery of water-insoluble drugs is the use of micelles. The results reported in our previous work show that micelle forming monosialogangliosides (i.e., GM1 and GM2), with critical micellar concentrations (CMCs) in the order of 10-8 M, spontaneously interact with Ptx and docetaxel (Dtx) forming water soluble structures that are relatively insensitive to dilution and allow their aqueous delivery and antimitotic activity [10]. As albumin binding could improve tumor targeting, in this work we characterized the events involved in the interaction between HSA and GM1/Ptx mixed micelles
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