Targeting Hepatic Cancer Cells with PEGylated Dendrimers Displaying <i>N</i>‐Acetylgalactosamine and SP94 Peptide Ligands

Medina, Scott H.; Tiruchinapally, Gopinath; Chevliakov, Maxim V.; Durmaz, Yasemin Yüksel; Stender, Rachell; Ensminger, William D.; Shewach, Donna S.; El-Sayed, Mohamed

doi:10.1002/adhm.201200406

Cited by 35 publications

(36 citation statements)

References 57 publications

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“…For example, Gref et al showed that PEG-coated surfaces can still support protein adsorption via direct interactions with the core material even at high PEG density, poly(lactic acid) (PLA), PLGA and poly(varepsilon-caprolactone) (PCL) nanoparticles coated with the same high density of PEG where shown to adsorb different levels and types of protein on their surfaces [49]. However, it remains possible that at a ultra-high PEG density on carrier surfaces that results in no protein absorption onto carrier surface the negative effect of plasma proteins on PLGA carriers can be eliminated [50]. In our ongoing work, we are exploring whether variation in PEG density and chain length can alter PLGA particle adhesion to the vascular wall in blood.…”

Section: Discussionmentioning

confidence: 99%

Plasma Protein Corona Modulates the Vascular Wall Interaction of Drug Carriers in a Material and Donor Specific Manner

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 99%

Plasma Protein Corona Modulates the Vascular Wall Interaction of Drug Carriers in a Material and Donor Specific Manner

et al. 2014

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“…PAMAMs can be prepared to be nontoxic, with multiple peripheral functional groups, for the conjugation of drugs, targeting, imaging, radioactive, and chelating agents. 2,3,13,21–23 It has been shown that the circulation time, organ biodistribution, and passive tumor targeting depend strongly on the physicochemical properties of the dendrimers, extent of PEGylation, presence of ligands, and dendrimer– protein interactions. 24–30 …”

Section: Introductionmentioning

confidence: 99%

Biodistribution of Fluorescently Labeled PAMAM Dendrimers in Neonatal Rabbits: Effect of Neuroinflammation

Lesniak¹,

Mishra²,

et al. 2013

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Dendrimers are being explored in many preclinical studies as drug, gene, and imaging agent delivery systems. Understanding their detailed organ, tissue, cellular uptake, and retention can provide valuable insights into their effectiveness as delivery vehicles and the associated toxicity. This work explores a fluorescence-quantification based assay that enables simultaneous quantitative biodistribution and imaging of dendrimers with a single agent. We have labeled an ethylenediamine-core generation-4 hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimer using the fluorescent photostable, near-IR cyanine dye (Cy5) and performed quantitative and qualitative biodistribution of the dendrimer-Cy5 conjugates (D-Cy5) in healthy neonatal rabbits and neonatal rabbits with cerebral palsy (CP). The biodistribution of D-Cy5 and free Cy5 dye was evaluated in newborn rabbits, based on the developed quantification methods using fluorescence spectroscopy, high-performance liquid chromatography (HPLC), and size exclusion chromatography (SEC) and supported by microscopic imaging. The uptake was assessed in the brain, heart, liver, lungs, kidneys, blood serum, and urine. Results obtained based on these three independent methods are in good agreement and indicate the fast renal clearance of D-Cy5 and free Cy5 with relatively higher organs accumulation of the D-Cy5 conjugate. Following systemic administration, the D-Cy5 mainly accumulated in kidneys and bladder at 24 h. The quantitative biodistribution is in good agreement with previous studies based on radiolabeling. These methods for dendrimers quantification are easier and more practical, provide excellent sensitivity (reaching 0.1 ng per gram of tissue), and allow for quantification of dendrimers in different organs over longer time periods without concerns for radioactive decay, while also enabling tissue and cellular imaging in the same animal. In kits with fetal-neuroinflammation induced CP, there was a significantly higher uptake of D-Cy5 in the brain, while biodistribution in other organs was similar to that of healthy kits.

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“…Further, the free end of the PEG block can be used to conjugate different types of targeting ligands prior to the formulation of the nanodroplets, which will allow the presentation of a welldefined and tunable number of targeting ligands on the droplets' surface to mediate selective binding to cancer cells. 24 The carboxylic acid groups in the central PAA block are used for covalent cross-linkage of the polymer chains to form a flexible shell that stabilizes the nanodroplets. The fluorinated and hydrophobic P(HDFMA-co-MMA) block is designed to facilitate the encapsulation of PFP in the droplets' core.…”

Section: ■ Introductionmentioning

confidence: 99%

Development of Nanodroplets for Histotripsy-Mediated Cell Ablation

Durmaz

Vlaisavljevich

et al. 2014

Mol. Pharmaceutics

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This report describes the synthesis of amphiphilic copolymers (ABC-1 and ABC-2) composed of a hydrophilic poly(ethylene glycol) (PEG) block, a central poly(acrylic acid) (PAA) block, and a random copolymer of heptadecafluorodecyl methacrylate (HDFMA) and methyl methacrylate (MMA) forming the hydrophobic block, which are used to form nanodroplets for ultrasound-mediated cell ablation. Specifically, the effect of molecular weight of PEG and P(HDFMA-co-MMA) blocks on polymer's ability to self-assemble around a variable amount (0%, 1%, and 2% v/v) of perfluoropentane (PFP) forming nanodroplets is investigated. The ability of different nanodroplets formulations embedded with a monolayer of red blood cells (RBCs) in tissue-mimicking agarose phantoms to initiate and sustain a bubble cloud in response to ultrasound treatments with different acoustic pressures and the associated ablation of RBCs were also investigated. Results show that ABC-1 polymer composed of a 2 kDa PEG block and a 6.7 kDa P(HDFMA-co-MMA) block better encapsulate the PFP core compared to ABC-2 polymer composed of a 5 kDa PEG block and 11.4 kDa P(HDFMA-co-MMA) block. Further, the ablative capacity indicated by the damage area in the RBCs monolayer increased with the increase in PFP content and reached its maximum with the nanodroplets formulated using ABC-1 polymer and encapsulating 2% v/v PFP. The nanodroplets formulated using ABC-1 polymer and loaded with 2% PFP produced the cavitation cloud and exhibited their ablative effect at an acoustic pressure that is 2.5-fold lower than the acoustic pressure needed to generate the same effect using a histotripsy (ultrasound) pulse alone, which indicates the ability of these nanodroplets to achieve targeted and self-limiting fractionation of disease cells while sparing neighboring healthy ones. Results also show that effective nanodroplets maintained their size and concentration upon incubation with bovine serum albumin at 37 °C for 24 h, which indicates their stability in physiologic conditions and their promise for in vivo cancer cell ablation.

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Targeting Hepatic Cancer Cells with PEGylated Dendrimers Displaying N‐Acetylgalactosamine and SP94 Peptide Ligands

Cited by 35 publications

References 57 publications

Plasma Protein Corona Modulates the Vascular Wall Interaction of Drug Carriers in a Material and Donor Specific Manner

Plasma Protein Corona Modulates the Vascular Wall Interaction of Drug Carriers in a Material and Donor Specific Manner

Biodistribution of Fluorescently Labeled PAMAM Dendrimers in Neonatal Rabbits: Effect of Neuroinflammation

Development of Nanodroplets for Histotripsy-Mediated Cell Ablation

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