The nanoscale plasma protein interaction with intravenously injected particulate carrier systems is known to modulate their organ distribution and clearance from the bloodstream. However, the role of this plasma protein interaction in prescribing the adhesion of carriers to the vascular wall remains relatively unknown. Here, we show that the adhesion of vascular-targeted poly(lactide-co-glycolic-acid) (PLGA) spheres to endothelial cells is significantly inhibited in human blood flow, with up to 90% reduction in adhesion observed relative to adhesion in simple buffer flow, depending on the particle size and the magnitude and pattern of blood flow. This reduced PLGA adhesion in blood flow is linked to the adsorption of certain high molecular weight plasma proteins on PLGA and is donor specific, where large reductions in particle adhesion in blood flow (>80% relative to buffer) is seen with ∼60% of unique donor bloods while others exhibit moderate to no reductions. The depletion of high molecular weight immunoglobulins from plasma is shown to successfully restore PLGA vascular wall adhesion. The observed plasma protein effect on PLGA is likely due to material characteristics since the effect is not replicated with polystyrene or silica spheres. These particles effectively adhere to the endothelium at a higher level in blood over buffer flow. Overall, understanding how distinct plasma proteins modulate the vascular wall interaction of vascular-targeted carriers of different material characteristics would allow for the design of highly functional delivery vehicles for the treatment of many serious human diseases.
Vascular-targeted drug delivery systems could provide more efficient and effective pharmaceutical interventions for treating a variety of diseases including cardiovascular, pulmonary, inflammatory, and malignant disorders. However, several factors must be taken into account when designing these systems. The diverse blood hemodynamics and rheology, and the natural clearance process that tend to decrease the circulation time of foreign particles all lessen the probability of successful carrier interaction with the vascular wall. An effective vascular-targeted drug delivery system must be able to navigate through the bloodstream while avoiding immune clearance, attach to the vascular wall, and release its therapeutic cargo at the intended location. This review will summarize and analyze current literature reporting on (1) nanocarrier fabrication methods and materials that allow for optimum therapeutic encapsulation, protection, and release; (2) localization and binding dynamics of nanocarriers as influenced by hemodynamics and blood rheology in medium-to-large vessels; (3) blood cells' responses to various types of nanocarrier compositions and its effects on particle circulation time; and (4) properties that affect nanocarrier internalization at the target site.
Long-acting or extended release parenteral dosage forms have attracted extensive attention due to their ability to maintain therapeutic drug concentrations over long periods of time and reduce administration frequency, thus improving patient compliance. It is essential to have an in vitro release (IVR) testing method that can be used to assure product quality during routine production as well as predict and understand the in vivo performance of a formulation. The purpose of this work was to develop a discriminatory in vitro release method to guide formulation and process development of long-acting parenteral (LAP) nanosuspension formulations composed of poorly water-soluble drugs (BCS class II). Injectable nanosuspension formulations were developed to serve as test articles for method development. Several different IVR methods were evaluated for their application to the formulation screening and process development including (1) USP apparatus 2, (2) dialysis and reverse dialysis sac, and (3) continuous flow-through cell (USP apparatus 4). Preliminary data shows the promising results to support the utilization of USP 4 over more widely accepted USP 2 and dialysis methods. A combination of more representative in vivo hydrodynamics and ease of maintaining sink conditions yields the USP 4 flow-through cell method a more suitable in vitro release method for nanosuspension-based LAP formulations of poorly water-soluble compounds, such as compounds A and B.
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