Surface Modification to Alter Biodistribution

The potential of injectable polymeric drug carriers (nanoparticles) is compromised by their accumulation in the tissues of the mononuclear phagocytic system (MPS). Thus, the therapeutic efficacy of the drugs associated with the nanoparticles is limited to the treatment of several liver diseases.90,91 Long-circulating nanoparticles can be obtained by their surface modification with dysopsonic polymers such as PEG.92,93 Indeed, these hydrophilic and flexible polymers can prevent the opsonin-nanoparticle interaction, which is the first step of the recognition by the immune system. In the tumor-bearing animal models, these long-circulating nanoparticles would be able to extravasate thorough the endothelium, allowing drugs to concentrate in the tumors.94 Recently, it was shown that the synthesis of amphiphilic PEGylated polymers allows the direct preparation of PEG-coated nanoparticles, ensuring the stability of the PEG coating layer because the PEG chains remain chemically linked to the nanoparticle core.95-97 Otherwise, a PEG coating layer simply adsorbed onto preformed nanoparticles is desorbed in vivo.78 Peracchia et al.98 synthesized a novel MePEGcyanoacrylate-hexadecylcyanoacrylate (PEG-PHDCA) copolymer, and the presence of a PEG layer on the nanoparticle surface was confirmed by surface chemical analysis.99 Poly(alkyl cyanoacrylate) nanoparticles are rapidly biodegradable and hence could be able to release the associated drug into the bloodstream in a controlled manner before liver capture could occur. For solid tumors, extravasation could be followed by a rapid degradation of the polymer, leading to a rapid drug release.100 The cytotoxicity of PHDCA polymer was decreased after its PEGylation in the mouse macrophage cell line J774.101 This is due to the lower extent of the particle/cell interaction, because of the steric repulsion effect of PEG chains. Biodistribution studies with the above MePEGcyanoacrylate-hexadecylcyanoacrylate copolymer nanoparticles revealed that the nanoparticles exhibited long-circulating properties.102 No effect of the degree of PEGylation on the plasma retention was observed because increasing the copolymer from 1:5 to 1:2 did not improve the nanoparticle circulation time. The 1:5 PEG-PHDCA copolymer probably already exhibited a PEG content that was able to determine a brush PEG configuration103 and, thus, an optimal PEG density at the particle surface for the steric repulsion to occur efficiently. Together, the nanoparticles showed low liver accumulation and high spleen uptake, representing the possibility of targeting drugs to this tissue. More recently, a rapidly biodegradable copolymer poly(methoxyethy-lene glycol-cyanoacrylate-co-n-hexadecylcyanoacrylate) has been developed for the preparation of stealth nanoparticles.102,104 Similarly, Ping et al.105 synthesized poly(methoxyethyleneglycol cyanoacrylate-co-n-hexadecyl cyanoacrylate) (PEGylated PHDCA) nanoparticles loaded with an antitumor agent salvicine. The nanoparticles showed a significant initial burst of salvicine followed by a sustained release in 7.4 pH phosphate-buffered saline, thus suggesting its usefulness in tumor therapy.

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