Nanoparticle-macrophage interactions: A balance between clearance and cell-specific targeting.

The surface properties of nanoparticles (NPs) are a major factor that influences how these nanomaterials interact with biological systems. Interactions between NPs and macrophages of the reticuloendothelial system (RES) can reduce the efficacy of NP diagnostics and therapeutics. Traditionally, to limit NP clearance by the RES system, the NP surface is neutralized with molecules like poly(ethylene glycol) (PEG) which are known to resist protein adsorption and RES clearance. Unfortunately, PEG modification is not without drawbacks including difficulties with the synthesis and associations with immune reactions. To overcome some of these obstacles, we neutralized the NP surface by acetylation and compared this modification to PEGylation for RES clearance and tumor-specific targeting. We found that acetylation was comparable to PEGylation in reducing RES clearance. Additionally, we found that dendrimer acetylation did not impact folic acid (FA)-mediated targeting of tumor cells whereas PEG surface modification reduced the targeting ability of the NP. These results clarify the impact of different NP surface modifications on RES clearance and cell-specific targeting and provide insights into the design of more effective NPs.

Hydrolytic charge-reversal of PEGylated polyplexes enhances intracellular un-packaging and activity of siRNA.

Hydrolytically degrading nano-polyplexes (HDG-NPs) that reverse charge through conversion of tertiary amines to carboxylic acids were investigated to improve intracellular un-packaging of siRNA and target gene silencing compared to a non-degradable analog (non-HDG-NPs). Both NP types comprised reversible addition-fragmentation chain-transfer (RAFT) synthesized diblock copolymers of a poly(ethylene glycol) (PEG) corona-forming block and a cationic block for nucleic acid packaging that incorporated butyl methacrylate (BMA) and either dimethylaminoethyl methacrylate (DMAEMA, non-HDG-NPs) or dimethylaminoethyl acrylate (DMAEA, HDG-NPs). HDG-NPs decreased significantly in size and released significantly more siRNA (∼40%) than non-HDG-NPs after 24 h in aqueous solution. While both HDG-NPs and non-HDG-NPs had comparable uptake and cytotoxicity up to 150 nM siRNA doses, HDG-NPs achieved significantly higher target gene silencing of the model gene luciferase in vitro. High resolution FRET confocal microscopy was used to monitor the intracellular un-packaging of siRNA. Non-HDG-NPs had significantly higher FRET efficiency than HDG-NPs, indicating that siRNA delivered from HDG-NPs was more fully un-packaged and therefore had improved intracellular bioavailability.

A strategy for combating melanoma with oncogenic c-Myc inhibitors and targeted nanotherapy.

AIMS: The activity of the transcription factor c-Myc is dependent upon heterodimerization with Max to control target gene transcription. Small-molecule inhibitors of c-Myc-Max have exhibited low potency and poor water solubility and are therefore unsuitable for in vivo application. We hypothesized that a nanomedicine approach incorporating a cryptic c-Myc inhibitor prodrug could be delivered and enzymatically released in order to effectively inhibit melanoma. MATERIALS & METHODS: An Sn-2 lipase-labile Myc inhibitor prodrug was synthesized and included in two αvß3-targeted nanoparticle platforms (20 and 200 nm). The inherent antiproliferate potency was compared with the lipid-free compound using human and mouse melanoma cell lines. RESULTS & CONCLUSION: These data demonstrate for the first time a successful nanodelivery of c-Myc inhibitors and their potential use to prevent melanoma.

Surface passivation of carbon nanoparticles with branched macromolecules influences near infrared bioimaging.

A superior and commercially exploitable 'green synthesis' of optically active carbon nanoparticle (OCN) is revealed in this work. The naked carbon particles (<20 nm) were derived from commercial food grade honey. The fluorescence properties of these particles were significantly enhanced by utilizing hyberbranched polymer for surface passivation. A dramatic increase in near infrared emission was achieved compared to a linear polymer (PEG) coated carbon nanoparticles. Interestingly, as passivating agent becomes more extensively branched (pseudo generation 2 to 4), the average radiant efficiency amplifies considerably as a direct result of the increasing surface area available for light passivation. The particles showed negligible loss of cell viability in presence of endothelial cells in vitro. Preliminary in vivo experiment showed high contrast enhancement in auxiliary lymphnode in a mouse model. The exceptionally rapid lymphatic transport of these particles suggests that such an approach may offer greater convenience and reduced procedural expense, as well as improved surgical advantage as the patient is positioned on the table for easier resection.