Abstract
Surface PEGylation, biological camouflage, shape and stiffness modulation of nanoparticles as well as liver blockade and macrophage depletion have all improved the blood longevity of nanomedicines. Yet, the mononuclear phagocytic system still recognizes, sequesters, and processes the majority of blood borne particles. Here, the natural fatty acid methyl palmitate is combined with endogenous blood components – albumin – realizing ∼200 nm stable, spherical nanoparticles (MPN) capable of inducing a transient and reversible state of dormancy into macrophages. In primary bone marrow derived monocytes (BMDM), the rate of internalization of 5 different particles, ranging in size from 200 up to 2000 nm, with spherical and discoidal shapes, and made out of lipids and polymers, was almost totally inhibited after an overnight pre-treatment with 0.5 mM MPN. Microscopy analyses revealed that MPN reversibly reduced the extension and branching complexity of the microtubule network in BMDM, thus altering membrane bulging and motility. In immunocompetent mice, a 4 h pre-treatment with MPN was sufficient to redirect 2000 nm rigid particles from the liver to the lungs realizing a lung-to-liver accumulation ratio larger than 2. Also, in mice bearing U87-MG tumor masses, a 4 h pre-treatment with MPN enhanced the therapeutic efficacy of docetaxel-loaded nanoparticles significantly inhibiting tumor growth. The natural liver sequestering function was fully recovered overnight. This data would suggest that MPN pre-treatment could transiently and reversibly inhibit non-specific particle sequestration, thus redirecting nanomedicines towards their specific target tissue while boosting their anti-cancer efficacy and imaging capacity.
Highlights
The therapeutic and imaging capabilities of nanomedicines could be boosted by properly negotiating their interactions with multiple biological barriers, which are sequentially distributed from the site of injection up to the sub-cellular biological target.[1,2,3] It is well accepted that the first and, perhaps, the major impediment to the effective delivery of therapeutic and imaging cargos via systemically injected nanomedicines is represented by the Mononuclear Phagocytic System (MPS).[2,4] This collects cells of the immune system, primarily circulating monocytes and resident macrophages, whose function is to sequester and process any object that is not recognized as self
methyl palmitate nanoparticles (MPN) were self-assembled by mixing a methyl palmitate ethanol solution to an aqueous solution of Bovine Serum Albumin (BSA) or Fetal Bovine Serum (FBS)
The pre-administration of MPN was shown to change the fate of systemically injected nanomedicines boosting their specific tissue accumulation and therapeutic performance
Summary
The therapeutic and imaging capabilities of nanomedicines could be boosted by properly negotiating their interactions with multiple biological barriers, which are sequentially distributed from the site of injection up to the sub-cellular biological target.[1,2,3] It is well accepted that the first and, perhaps, the major impediment to the effective delivery of therapeutic and imaging cargos via systemically injected nanomedicines is represented by the Mononuclear Phagocytic System (MPS).[2,4] This collects cells of the immune system, primarily circulating monocytes and resident macrophages, whose function is to sequester and process any object that is not recognized as self.
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