In contrast to small molar mass compounds, detailed structural investigations of inorganic coreorganic ligand shell hybrid nanoparticles remain challenging. Assessment of batch reaction induced heterogeneities of surface chemical properties and their correlation with particle size has been a particularly long-standing issue. Applying a combination of high performance liquid chromatography (HPLC) and gel permeation chromatography (GPC) to ultrasmall (< 10 nm diameter) poly(ethylene glycol) coated (PEGylated) fluorescent core-shell silica nanoparticles, here we elucidate previously unknown surface heterogeneities resulting from varying dye conjugation to nanoparticle silica cores and surfaces. Heterogeneities are predominantly governed by dye charge as corroborated by molecular dynamics simulations. We demonstrate that this insight enables development of synthesis protocols to achieve PEGylated and targeting ligand functionalized PEGylated silica nanoparticles with dramatically improved surface chemical homogeneity as evidenced by single peak HPLC chromatograms. Since surface chemical properties are key to all nanoparticle interactions, we expect these methods and fundamental insights to become relevant to a number of systems for applications including bioimaging and nanomedicine.
Small-angle X-ray scattering (SAXS) was performed on dispersions of ultrasmall (d < 10 nm) fluorescent organic-inorganic hybrid core-shell silica nanoparticles synthesized in aqueous solutions (C′ dots) by using an oscillating flow cell to overcome beam induced particle degradation. Form factor analysis and fitting was used to determine the size and size dispersity of the internal silica core containing covalently encapsulated fluorophores. The structure of the organic poly(ethylene glycol) (PEG) shell was modelled as a monodisperse corona containing concentrated and semi-dilute regimes of decaying density and as a simple polydisperse shell to determine the bounds of dispersity in the overall hybrid particle. C′ dots containing single growth step silica cores have dispersities of 0.19-0.21; growth of additional silica shells onto the core produces a thin, dense silica layer, and increases the dispersity to 0.22-0.23. Comparison to FCS and DLS measures of size shows good agreement with SAXS measured and modelled sizes and size dispersities. Finally, comparison of a set of same sized and purified particles demonstrates that SAXS is sensitive to the skewness of the gel permeation chromatography elugrams of the original as-made materials. These and other insights provided by quantitative SAXS assessments may become useful for generation of robust nanoparticle design criteria necessary for their successful and safe use, for example in nanomedicine and oncology applications.
Antibody−drug conjugates (ADCs) have recently demonstrated impressive successes in targeted drug delivery. Ultrasmall (<10 nm) nanoparticle−drug conjugates (NDCs) share many similarities with ADCs, while their unique physicochemical properties can be further molecularly engineered to overcome the limitations of ADCs presented by tumor heterogeneity. Key challenges in NDC development include linkage chemistry design between nanoparticle carriers and cytotoxic drugs, as well as meeting the stringent criteria for manufacturing controls, stability, and drug release to enable successful clinical translation. Here, we report a robust chemical approach to covalently link both chemotherapeutic drugs and targeting moieties to a poly(ethylene glycol) (PEG)-coated (PEGylated) ultrasmall silica nanoparticle platform via precisely tailoring the particle surface chemistry. This approach employs the interstitial space between PEG chains on the particle surface to load drugs, enabling the significantly enhanced drug loading capacity as compared to ADCs while the favorable biodistribution and pharmacokinetics profiles are maintained. To achieve both high plasma stability and effective drug release in cancer, cyclopentadiene silane molecules are first inserted into the PEG layer of the particles and condensed with silanol groups on the silica core surface. Via the Diels−Alder reaction, the cyclopentadiene groups are then functionalized with groups enabling click chemistry, and cytotoxic payloads are finally clicked onto the particles via cleavable linkers for drug release within the cancer tissue. The targeted NDC resulting from the systematic screening strategy described here has recently advanced to a phase 1/2 human clinical trial.
To address the key challenges in the development of next-generation drug delivery systems (DDS) with desired physicochemical properties to overcome limitations regarding safety, in vivo efficacy, and solid tumor penetration, an ultrasmall folate receptor alpha (FRα) targeted silica nanoparticle (C’Dot) drug conjugate (CDC; or folic acid CDC) was developed. A broad array of methods was employed to screen a panel of CDCs and identify a lead folic acid CDC for clinical development. These included comparing the performance against antibody–drug conjugates (ADCs) in three-dimensional tumor spheroid penetration ability, assessing in vitro/ex vivo cytotoxic efficacy, as well as in vivo therapeutic outcome in multiple cell-line-derived and patient-derived xenograft models. An ultrasmall folic acid CDC, EC112002, was identified as the lead candidate out of >500 folic acid CDC formulations evaluated. Systematic studies demonstrated that the lead formulation, EC112002, exhibited highly specific FRα targeting, multivalent binding properties that would mediate the ability to outcompete endogenous folate in vivo, enzymatic responsive payload cleavage, stability in human plasma, rapid in vivo clearance, and minimal normal organ retention organ distribution in non-tumor-bearing mice. When compared with an anti-FRα-DM4 ADC, EC112002 demonstrated deeper penetration into 3D cell-line-derived tumor spheroids and superior specific cytotoxicity in a panel of 3D patient-derived tumor spheroids, as well as enhanced efficacy in cell-line-derived and patient-derived in vivo tumor xenograft models expressing a range of low to high levels of FRα. With the growing interest in developing clinically translatable, safe, and efficacious DDSs, EC112002 has the potential to address some of the critical limitations of the current systemic drug delivery for cancer management.
Ultrasmall (diameter below 10 nm) fluorescent core–shell silica nanoparticles have garnered increasing attention in recent years as a result of their high brightness and favorable biodistribution properties important for applications including bioimaging and nanomedicine. Here, we present an in-depth study that provides new insights into the physical parameters that govern full covalent fluorescent dye encapsulation within the silica core of poly(ethylene glycol)-coated core–shell silica nanoparticles referred to as Cornell prime dots (C′ dots). We use a combination of high-performance liquid chromatography (HPLC), gel-permeation chromatography, and fluorescence correlation spectroscopy to monitor the result of ammonia concentration in the synthesis of C′ dots from negatively and positively charged versions of near-infrared dyes Cy5 and Cy5.5. HPLC, in particular, allows the distinction between cases of full versus partial dye encapsulation in the silica particle core leading to surface chemical heterogeneities in the form of hydrophobic surface patches, which, in turn, modulate biological response in ferroptotic cell death experiments. Our results demonstrate that there is a complex interplay between dye–dye and dye–silica cluster interactions originally formed in the sol–gel synthesis governing optimal dye encapsulation. We expect that the reduced surface chemical heterogeneities will make the resulting nanoparticles attractive for a number of applications in biology and medicine.
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