Investigating the Impact of Nanoparticle Size on Active and Passive Tumor Targeting Efficiency

Understanding the principles governing the design of nanoparticles for tumor targeting is essential for the effective diagnosis and treatment of solid tumors. There is currently a poor understanding of how to rationally engineer nanoparticles for tumor targeting. Here, we engineered different-sized spherical gold nanoparticles to discern the effect of particle diameter on passive (poly(ethylene glycol)-coated) and active (transferrin-coated) targeting of MDA-MB-435 orthotopic tumor xenografts. Tumor accumulation of actively targeted nanoparticles was found to be 5 times faster and approximately 2-fold higher relative to their passive counterparts within the 60 nm diameter range. For 15, 30, and 100 nm, we observed no significant differences. We hypothesize that such enhancements are the result of an increased capacity to penetrate into tumors and preferentially associate with cancer cells. We also use computational modeling to explore the mechanistic parameters that can impact tumor accumulation efficacy. We demonstrate that tumor accumulation can be mediated by high nanoparticle avidity and are weakly dependent on their plasma clearance rate. Such findings suggest that empirical models can be used to rapidly screen novel nanomaterials for relative differences in tumor targeting without the need for animal work. Although our findings are specific to MDA-MB-435 tumor xenografts, our experimental and computational findings help to enrich knowledge of design considerations that will aid in the optimal engineering of spherical gold nanoparticles for cancer applications in the future

Ablation of Hypoxic Tumors with Dose-Equivalent Photothermal, but Not Photodynamic, Therapy Using a Nanostructured Porphyrin Assembly

Tumor hypoxia is increasingly being recognized as a characteristic feature of solid tumors and significantly complicates many treatments based on radio-, chemo-, and phototherapies. While photodynamic therapy (PDT) is based on photosensitizer interactions with diffused oxygen, photothermal therapy (PTT) has emerged as a new phototherapy that is predicted to be independent of oxygen levels within tumors. It has been challenging to meaningfully compare these two modalities due to differences in contrast agents and irradiation parameters, and no comparative <i>in vivo</i> studies have been performed until now. Here, by making use of recently developed nanostructured self-quenched porphysome nanoparticles, we were able to directly compare PDT and PTT using matched light doses and matched porphyrin photosensitizer doses (with the photosensitizer being effective for either PTT or PDT based on the existence of nanostructure or not). Therefore, we demonstrated the nanostructure-driven conversion from the PDT singlet oxygen generating mechanism of porphyrin to a completely thermal mechanism, ideal for PTT enhancement. Using a novel hypoxia tumor model, we determined that nanostructured porphyrin PTT enhancers are advantageous to overcome hypoxic conditions to achieve effective ablation of solid tumors

Self-Sensing Porphysomes for Fluorescence-Guided Photothermal Therapy

Porphysomes are highly quenched unilamellar porphyrin–lipid nanovesicles with structurally dependent photothermal properties. The high packing density of porphyrin molecules in the lipid bilayer enables their application in photothermal therapy, whereas the partial disruption of the porphysome structure over time restores the porphyrin fluorescence and enables the fluorescence-guided photothermal ablation. This conversion is a time-dependent process and cannot be easily followed using existing analytical techniques. Here we present the design of a novel self-sensing porphysome (FRETysomes) capable of fluorescently broadcasting its structural state through Förster resonance energy transfer. By doping in a near-infrared emitting fluorophore, it is possible to divert a small fraction of the absorbed energy toward fluorescence emission which provides information on whether the vesicle is intact or disrupted. Addition of bacteriopheophorbide–lipid into the vesicle bilayer as a fluorescence acceptor (0.5–7.5 mol %) yields a large separation of 100 nm between the absorption and fluorescence bands of the nanoparticle. Furthermore, a progressive increase in FRET efficiency (14.6–72.7%) is observed. Photothermal heating and serum stability in FRETysomes is comparable with the undoped porphysomes. The fluorescence arising from the energy transfer between the donor and acceptor dyes can be clearly visualized <i>in vivo</i> through hyperspectral imaging. By calculating the ratio between the acceptor and donor fluorescence, it is possible to determine the structural fate of the nanovesicles. We observe using this technique that tumor accumulation of structurally intact porphyrin–lipid nanovesicles persists at 24 and 48 h postinjection. The development of FRETysomes offers a unique and critical imaging tool for planning porphysome-enabled fluorescence-guided photothermal treatment, which maximizes light-induced thermal toxicity

Electrophilic <i>N</i>‑Trifluoromethylation of N–H Ketimines

A direct <i>N</i>-trifluoromethylation method has been developed by the use of the <i>in situ</i> generated [ArICF₃]⁺ species as the electrophilic trifluoromethyl source. Upon treatment of N–H ketimines with Ruppert–Prakash reagent in the presence of PhI­(OAc)₂ and KF, or with Togni’s reagent II catalyzed by copper salt, <i>N</i>-trifluoromethylated imine products were obtained in moderate to good yields

Forest plot of the pooled incidence of lymphedema, which was stratified by different procedures.

<p>Forest plot of the pooled incidence of lymphedema, which was stratified by different procedures.</p

The results of subgroup analyses for the outcomes of identification rate and crossover rate during SLNB, respectively.

<p>The results of subgroup analyses for the outcomes of identification rate and crossover rate during SLNB, respectively.</p

Selection of single-nucleotide polymorphisms in disease association data-0

<p><b>Copyright information:</b></p><p>Taken from "Selection of single-nucleotide polymorphisms in disease association data"</p><p></p><p>BMC Genetics 2005;6(Suppl 1):S93-S93.</p><p>Published online 30 Dec 2005</p><p>PMCID:PMC1866686.</p><p></p> SNP markers rs1037475, rs980972, rs1491233 (= 3)*: SNP markers rs1037475, rs980972, rs749407 (= 4): all four marker

Chlorosome-Inspired Synthesis of Templated Metallochlorin-Lipid Nanoassemblies for Biomedical Applications

Chlorosomes are vesicular light-harvesting organelles found in photosynthetic green sulfur bacteria. These organisms thrive in low photon flux environments due to the most efficient light-to-chemical energy conversion, promoted by a protein-less assembly of chlorin pigments. These assemblies possess collective absorption properties and can be adapted for contrast-enhanced bioimaging applications, where maximized light absorption in the near-infrared optical window is desired. Here, we report a strategy for tuning light absorption toward the near-infrared region by engineering a chlorosome-inspired assembly of synthetic metallochlorins in a biocompatible lipid scaffold. In a series of synthesized chlorin analogues, we discovered that lipid conjugation, central coordination of a zinc metal into the chlorin ring, and a 3¹-methoxy substitution were critical for the formation of dye assemblies in lipid nanovesicles. The substitutions result in a specific optical shift, characterized by a bathochromically shifted (72 nm) Q_<i>y</i> absorption band, along with an increase in absorbance and circular dichroism as the ratio of dye-conjugated lipid was increased. These alterations in optical spectra are indicative of the formation of delocalized excitons states across each molecular assembly. This strategy of tuning absorption by mimicking the structures found in photosynthetic organisms may spur new opportunities in the development of biophotonic contrast agents for medical applications

Forest plots of the association between preoperative neoadjuvant chemotherapy, axillary status and the risk of ARM metastasis.

<p>(A) preoperative neoadjuvant chemotherapy; (B) axillary status.</p

Forest plot of the pooled identification rate of ARM nodes or lymphatics during ALND.

<p>Forest plot of the pooled identification rate of ARM nodes or lymphatics during ALND.</p