The Implications of Stochastic Synthesis for the Conjugation of Functional Groups to Nanoparticles

Mullen, Douglas G.; Desai, Ankur; Waddell, Jack N.; Cheng, Xue-Min; Kelly, Christopher V.; McNerny, Daniel Q.; Majoros, István J.; Baker, James R.; Sander, Leonard M.; Orr, Bradford G.; Holl, Mark M. Banaszak

doi:10.1021/bc8002106

Cited by 46 publications

(102 citation statements)

References 29 publications

(32 reference statements)

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“…Percentage (%) of the nanoconjugate loading with Morpholino AON, mAb or mPEG 5000 was calculated by using the formula % = 100 × ( μmol ligand)/(μmol malic acid). Note that the % loading is an average value of variations referring to polydispersity of the polymer preparation and stochastic nature of conjugation chemistry [34]. …”

Section: Methodsmentioning

confidence: 99%

Toxicity and efficacy evaluation of multiple targeted polymalic acid conjugates for triple-negative breast cancer treatment

Ljubimova

Portilla-Arias²,

Patil³

et al. 2013

Journal of Drug Targeting

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Engineered nanoparticles are widely used for delivery of drugs but frequently lack proof of safety for cancer patient's treatment. All-in-one covalent nanodrugs of the third generation have been synthesized based on a poly(β-L-malic acid) (PMLA) platform, targeting human triple-negative breast cancer (TNBC). They significantly inhibited tumor growth in nude mice by blocking synthesis of epidermal growth factor receptor, and α4 and β1 chains of laminin-411, the tumor vascular wall protein and angiogenesis marker. PMLA and nanodrug biocompatibility and toxicity at low and high dosages were evaluated in vitro and in vivo. The dual-action nanodrug and single-action precursor nanoconjugates were assessed under in vitro conditions and in vivo with multiple treatment regimens (6 and 12 treatments). The monitoring of TNBC treatment in vivo with different drugs included blood hematologic and immunologic analysis after multiple intravenous administrations. The present study demonstrates that the dual-action nanoconju-gate is highly effective in preclinical TNBC treatment without side effects, supported by hematologic and immunologic assays data. PMLA-based nanodrugs of the Polycefin™ family passed multiple toxicity and efficacy tests in vitro and in vivo on preclinical level and may prove to be optimized and efficacious for the treatment of cancer patients in the future.

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Section: Methodsmentioning

confidence: 99%

Toxicity and efficacy evaluation of multiple targeted polymalic acid conjugates for triple-negative breast cancer treatment

Ljubimova

Portilla-Arias²,

Patil³

et al. 2013

Journal of Drug Targeting

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“…Figure 4a shows GPC light scattering signals for four of these ligand-dendrimer samples. 11 The samples had mean ligand/dendrimer ratios between 0.4 and 1.5 (measured by NMR). Although all four samples elute as single peaks with similar peak shapes and retention times, the material was shown to have significantly different distributions.…”

Section: Distributions In Ligand-nanoparticle Systems: Present But Ofmentioning

confidence: 99%

Heterogeneous Ligand–Nanoparticle Distributions: A Major Obstacle to Scientific Understanding and Commercial Translation

2011

Self Cite

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CONSPECTUS Nanoparticles conjugated with functional ligands are expected to have a major impact in medicine, photonics, sensing, and nanoarchitecture design. One major obstacle to realizing the promise of these materials, however, is the difficulty in controlling the ligand/nanoparticle ratio. This obstacle can be segmented into three key areas: First, many system designs have failed to account for the true heterogeneity of ligand/nanoparticle ratios that compose each material. Second, the field's accepted level of characterization of ligand-nanoparticle materials is deficient as it does not provide an accurate definition of material composition that is necessary to both understand the material-property relationships as well as to monitor the consistency of the material. In particular, many characterization assays only determine the mean ligand/nanoparticle ratio and do not provide the number and relative amount of the different ligand/nanoparticle ratios that compose a material. Third, some synthetic approaches that are presently in use may not produce consistent material as they are sensitive to reaction kinetics, and the synthetic history of the nanoparticle. In this account we describe the recent advances that we have made in understanding the material composition of ligand-nanoparticle systems. Our work has been enabled by a model system using poly(amidoamine) dendrimers and two small molecule ligands. Using reverse phase high-pressure liquid chromatography (HPLC) we have successfully resolved and quantified the relative amount of each ligand/dendrimer ratio present. This type of information is rare for the entire field of ligand-nanoparticle materials because most analytical techniques have been unable to identify the components in the distribution. Our experimental data indicates that the actual distribution of ligand-nanoparticle components is much more heterogeneous than commonly assumed. The mean ligand/nanoparticle ratio that is so often the only information known about a material is insufficient. This is because the mean does not provide information on the diversity of components in the material and often does not describe the most common component (the mode). Additionally, our experimental data has provided examples of material batches with the same mean ligand/nanoparticle ratio and very different distributions. This discrepancy indicates that the mean cannot be used as the sole metric to assess the reproducibility of a system. We further found that distribution profiles can be highly sensitive to the synthetic history of the starting material as well as slight changes in reaction conditions. We have incorporated the lessons from our experimental data into new systems designs to provide improved control over the ligand/nanoparticle ratios.

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“…Theoretical models have been devised to predict the approximate heterogeneity of a given GNP-ligand solution. 36 Since the melting temperature (T m ) of GNP-DNA conjugates is size-dependent, they can be separated based on size from a heterogenous solution via serialized centrifugation at successively lower temperatures. 37 GNPs can also be characterized by size according to their electron dynamics in response to photoexcitation where absorption of light can cause the "bleaching" of surface plasmon interband transitions.…”

Section: Characterizationmentioning

confidence: 99%

Functionalized gold nanoparticles for the binding, stabilization, and delivery of therapeutic DNA, RNA, and other biological macromolecules

DeLong¹,

Wanekaya²,

Reynolds³

et al. 2010

NSA

180

102

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Nanotechnology has virtually exploded in the last few years with seemingly limitless opportunity across all segments of our society. If gene and RNA therapy are to ever realize their full potential, there is a great need for nanomaterials that can bind, stabilize, and deliver these macromolecular nucleic acids into human cells and tissues. Many researchers have turned to gold nanomaterials, as gold is thought to be relatively well tolerated in humans and provides an inert material upon which nucleic acids can attach. Here, we review the various strategies for associating macromolecular nucleic acids to the surface of gold nanoparticles (GNPs), the characterization chemistries involved, and the potential advantages of GNPs in terms of stabilization and delivery.

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The Implications of Stochastic Synthesis for the Conjugation of Functional Groups to Nanoparticles

Cited by 46 publications

References 29 publications

Toxicity and efficacy evaluation of multiple targeted polymalic acid conjugates for triple-negative breast cancer treatment

Toxicity and efficacy evaluation of multiple targeted polymalic acid conjugates for triple-negative breast cancer treatment

Heterogeneous Ligand–Nanoparticle Distributions: A Major Obstacle to Scientific Understanding and Commercial Translation

Functionalized gold nanoparticles for the binding, stabilization, and delivery of therapeutic DNA, RNA, and other biological macromolecules

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