In Vitro and In Vivo Evaluation of PEGylated Layer‐by‐Layer Polyelectrolyte‐Coated Paclitaxel Nanocrystals

Abstract

Drug nanocrystals (NCs) are colloidal dispersions composed almost entirely of drug. As such, there is substantial interest in targeting them to diseased tissues, where they can locally deliver high doses of the therapeutic. However, because of their uncontrolled dissolution characteristics in vivo and uptake by the monomolecular phagocyte system, achieving tumor accumulation is challenging. To address these issues, a layer-by-layer approach is adopted to coat paclitaxel NCs with alternating layers of oppositely charged polyelectrolytes, using a PEGylated copolymer as the top layer. The coating successfully slows down dissolution in comparison to the noncoated NCs and to Abraxane (an approved paclitaxel nanoformulation), provides colloidal stability in physiologically relevant media, and has no intrinsic effect on cell viability at the concentrations tested. Nevertheless, their pharmacokinetic and biodistribution profile indicates that the NCs are rapidly cleared from the bloodstream followed by accumulation in the mononuclear phagocyte system organs (i.e., liver and spleen). This is hypothesized to be a consequence of the shedding of the PEGylated polyelectrolyte from the NCs' surface. While therapeutic efficacy was not investigated (due to poor tumor accumulation), overall, this work questions whether approaches that rely solely on electrostatic interactions for retaining coatings on the surfaces of NCs are appropriate for use in vivo.

A Comparative In Vivo Study of Albumin‐Coated Paclitaxel Nanocrystals and Abraxane

“…The plasma PTX concentration‐time profiles indicated higher PTX concentrations with Cim‐F‐alb than with Abraxane, especially at later time points (beyond 6 h post‐injection). The terminal t 1/2 in plasma following the dosing of Abraxane was 3.7 h, comparable to the values reported in other studies with mouse models and similar analytical methods . The t 1/2 of Cim‐F‐alb was 5.6 h, ≈1.5 times longer than that of Abraxane.…”

“…With this expectation, several groups have developed NC formulations of PTX and evaluated their PK/BD profiles . PTX NCs were prepared with an average size ranging from 150 to 250 nm by various methods such as high‐pressure homogenization or antisolvent precipitation .…”

“…With no surface protection, these NCs however showed rather unfavorable PK/BD profiles, such as a shorter plasma t 1/2 , less systemic exposure, greater accumulation in the mononuclear phagocytic system (MPS) organs, and lower tumor accumulation than PTX injectable solutions . Surface stabilizers such as polymeric surfactants or proteins were used to protect the NCs from opsonin adsorption and MPS recognition and/or to increase target specificity, but the outcomes have been equivocal. PTX NCs stabilized with Pluronic F127 and docusate sodium did not enhance the systemic exposure of PTX but rather increased the liver and spleen accumulation .…”

“…PTX NCs stabilized with Pluronic F127 and docusate sodium did not enhance the systemic exposure of PTX but rather increased the liver and spleen accumulation . PTX NCs with a layer‐by‐layer polyelectrolyte assembly and polyethylene glycol (PEG) layer on the surface showed higher accumulation in the MPS organs and lower tumor accumulation than Abraxane, due to the premature loss of PEG surface and subsequent opsonization …”

“…With this expectation, several groups have developed NC formulations of PTX and evaluated their PK/BD profiles. [11][12][13][14][15] PTX NCs were prepared with an average size ranging from 150 to 250 nm by various methods such as high-pressure homogenization or antisolvent precipitation. [12,14] With no surface protection, these NCs however showed rather unfavorable PK/BD profiles, such as a shorter plasma t 1/2 , less systemic exposure, greater accumulation in the mononuclear phagocytic system (MPS) organs, [15] and lower tumor accumulation than PTX injectable solutions.…”