Nano-formulation and controlled delivery of low solubility anticancer drugs.

摘要

Optimal drug delivery and reduction of systemic adverse effects have been age old problems in chemotherapeutics in all types of human cancer. During chemotherapy, using water insoluble drugs like paclitaxel and tamoxifen, it has been realized that better formulations are needed for more specific and controlled drug delivery of these agents. In a novel approach to form high content stable nanocolloids of these drugs with controllable release rate, a sonicated layer-by-layer (LbL) polyelectrolyte coating technology is suggested. The desired features of pharmaceutical carriers for intravenous administration include their small size and biodegradability, good loading capacity for a given drug, high content of a drug in a final preparation, prolonged circulation in the blood, and ability to gradually concentrate in required areas (targeting) via passive accumulation. While these requirements are reasonably well met by a variety of drug carriers (liposomes, microcapsules, nanoparticles) developed for water-soluble drugs, the development of nanoparticulate drug carriers displaying all of these properties for the delivery of poorly soluble pharmaceuticals still represents a challenge.;Intravenous administration of these intrinsically hydrophobic agents is frequently associated with serious problems. One of these problems is that the diameter of blood capillaries is only a few micrometers or less, and intravenous administration of aggregates of undissolved material that form in an aqueous media would cause embolization before reaching and penetrating a target, such as tumor. Additionally, the low solubility of hydrophobic drugs in combination with excretion and metabolic degradation often does not allow for achieving therapeutically significant systemic concentrations. As a result, many promising drug candidates never enter further development because of solubility problems.;Currently, the most popular approach to dissolve poorly soluble drugs and prepare their dosage forms with sufficiently high bioavailability is the use of micellar drug carriers, specifically polymeric micelles.;In this study LbL coating technology is proposed to make stable aqueous colloids of poorly soluble drugs with high stability, controllable release (faster or slower than bulk drug powders), and a very high content of the active drug. To achieve this, aqueous suspensions of poorly soluble drugs with micron range particles are subjected to a powerful ultrasonic treatment in order to decrease the size of individual drug particles to the nano level (between 100 and 200 nm), and while still keeping the obtained nanoparticles under sonication to prevent their fast agglomeration, they are stabilized in solution by applying the LbL technology (alternating addition of polycations and polyanions to the system) and assembling a thin polyelectrolyte coating on their surface. In the process of assembly, the highly charged polymeric layers are always present on the drug particle surface thus preventing particle aggregation after stopping the sonication. At the end of the process, stable nanocolloidal dispersions are formed. After the first polycation layer is deposited on the surface of a drug nanoparticle, it is stabilized by the addition of following oppositely charged polyanion. They form a stable electrostatic complex resulting in the appearance of a very thin but stable polymeric shell around each drug nanoparticle. This polyelectrolyte multilayer shell prevents particle aggregation, and can be easily and reproducibly formed on the surface of any drug particle. By varying the charge density on each polymer or the number of coating cycles, particles with a different surface charge and different composition of the polymeric coating can be prepared. This provides a way to control drug release from such particles by designing the shell architecture at the nanometer level. The use of a polymer containing reactive groups (such as amino or carboxy-groups) for the last "outer" surface coating allow for the attachment of specific ligands, or reporter groups, or other moieties of interest to the nanoparticle surface.;By nanoencapsulation of such anticancer drugs as tamoxifen, paclitaxel, and camptothecin, we demonstrate the general applicability of this approach. The final content of the drug in the preparation as well as its release rate from the preparation can be controlled by the multilayer composition of the shell. The process key point is the deposition of the first polycation layer during the powerful sonication of the drug dispersion. In this process, dispersed by the ultrasound fine drug nanoparticles are immediately coated with a polyelectrolyte monolayer providing a high surface charge, which prevents the aggregation. Such drug nanocolloids remain stable in aqueous solutions after switching off the sonication.