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The rate-limiting step for diagnostics development is the discovery and validation of biomarker analytes. We describe a new analyte-agnostic and label-free approach based on colorimetric reactions involving type I polymerization photoinitiators. We demonstrate that a chemically diverse array of hydrogels embedded with cleaved type I photoinitiators could act as microreactors, undergoing colorimetric reactions with bound analytes. The colorimetric signatures produced were visually distinctive and readable with a flatbed document scanner. Signatures of a broad range of sample types were accurately differentiated by unsupervised clustering without knowledge of any analytes bound to the array. The principles described have the potential to enable scalable and cost-effective analysis of complex samples.

Drug delivery to tumors suffers from poor solubility, specificity, diffusion through the tumor micro-environment and nonoptimal interactions with components of the extracellular matrix and cell surface receptors. Nanoparticles and drug-polymer complexes address many of these problems. However, large size exasperates the problem of slow diffusion through the tumor. Three-dimensional tumor spheroids are good models to evaluate approaches to mitigate these difficulties and aid in design strategies to improve the delivery of drugs to treat cancer effectively. Diffusion of drug carriers is highly dependent on cell uptake rate parameters (association/dissociation) and temperature. Hyperthermia increases molecular transport and is known to act synergistically with chemotherapy to improve treatment. This study presents a new inverse estimation approach based on Bayesian probability for estimating nanoparticle cell uptake rates from experiments. The parameters were combined with a finite element computational model of nanoparticle transport under hyperthermia conditions to explore its effect on tumor porosity, diffusion and particle binding (association and dissociation) at cell surfaces. Carboxy-PEG-silane (cPEGSi) nanoparticles showed higher cell uptake compared to methoxy-PEG-silane (mPEGSi) nanoparticles. Simulations were consistent with experimental results from Skov-3 ovarian cancer spheroids. Amorphous silica (cPEGSi) nanoparticles (58 nm) concentrated at the periphery of the tumor spheroids at 37°C but mild hyperthermia (43°C) increased nanoparticle penetration. Thus, hyperthermia may enhance cancer treatment by improving blood delivery to tumors, enhancing extravasation and penetration into tumors, trigger release of drug from the carrier at the tumor site and possibly lead to synergistic anti-cancer activity with the drug.

Wireless and precise stimulation of deep brain structures could have important applications to study intact brain circuits and treat neurological disorders. Herein, we report that magnetoelectric nanoparticles (MENs) can be guided to a targeted brain region to stimulate brain activity with a magnetic field. We demonstrated the nanoparticles’ capability to reliably evoke fast neuronal responses in cortical slices ex vivo. After fluorescently labeled MENs were intravenously injected and delivered to a targeted brain region by applying a magnetic field gradient, a magnetic field of low intensity (350–450 Oe) applied to the mouse head reliably evoked cortical activities, as revealed by two-photon and mesoscopic imaging of calcium signals and by an increased number of c-Fos expressing cells after stimulation. Neither brain delivery of MENs nor the magnetic stimulation caused significant increases in astrocytes and microglia. Thus, MENs could enable a non-invasive and contactless deep brain stimulation without the need of genetic manipulation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01071-0.

Aim: We studied externally controlled anticancer effects of binding tumor growth inhibiting synthetic peptides to magnetoelectric nanoparticles (MENs) on treatment of glioblastomas. Methods: Hydrothermally synthesized 30-nm MENs had the core–shell composition of CoFe2O4@BaTiO3. Molecules of growth hormone-releasing hormone antagonist of the MIA class (MIA690) were chemically bound to MENs. In vitro experiments utilized human glioblastoma cells (U-87MG) and human brain microvascular endothelial cells. Results: The studies demonstrated externally controlled high-efficacy binding of MIA690 to MENs, targeted specificity to glioblastoma cells and on-demand release of the peptide by application of d.c. and a.c. magnetic fields, respectively. Conclusion: The results support the use of MENs as an effective drug delivery carrier for growth hormone-releasing hormone antagonists in the treatment of human glioblastomas.

We report a novel system of organically modified silica nanoparticles (Ormosil) capable of near infrared fluorescence and chemotherapy with adjuvant hyperthermia for image guided cancer therapy. Ormosil nanoparticles were loaded with a chemotherapeutic, Doxorubicin (DOX) and cyanine dye, IR820. Ormosil particles had a mean diameter of 51.2±2.4 nanometers and surface charge of -40.5±0.8mV. DOX was loaded onto Ormosil particles via physical adsorption (FDSIR820) or covalent linkage (CDSIR820) to the silanol groups on the Ormosil surface. Both formulations retained DOX and IR820 over a period of 2 days in aqueous buffer, though CDSIR820 retained more DOX (93.2%) compared to FDSIR820 (77.0%) nanoparticles. Exposure to near infrared laser triggered DOX release from CDSIR820. Uptake of nanoparticles was determined by deconvolution microscopy in ovarian carcinoma cells (Skov-3). CDSIR820 localized in the cell lysosomes whereas cells incubated with FDSIR820 showed DOX fluorescence from the nucleus indicating leakage of DOX from the nanoparticle matrix. FDSIR820 nanoparticles showed severe toxicity in Skov-3 cells whereas CDSIR820 particles had the same cytotoxicity profile as bare (No DOX and IR820) Ormosil particles. Furthermore, exposure of CDSIR820 nanoparticles to Near Infrared laser at 808 nanometers resulted in generation of heat (to 43°C from 37°C) and resulted in enhanced cell killing compared to Free DOX treatment. Bio-distribution studies showed that CDSIR820 nanoparticles were primarily present in the organs of Reticuloendothelial (RES) system.

Aim: The biodistribution and clearance of magnetoelectric nanoparticles (MENs) in a mouse model was studied through electron energy dispersive spectroscopy. Materials & methods: This approach allows for detection of nanoparticles (NPs) in tissues with the spatial resolution of scanning electron microscopy, does not require any tissue-sensitive staining and is not limited to MENs. Results: The size-dependent biodistribution of intravenously administrated MENs was measured in vital organs such as the kidneys, liver, spleen, lungs and brain at four different postinjection times including 1 day, 1 week, 4 and 8 weeks, respectively. Conclusion: The smallest NPs, 10-nm MENs, were cleared relatively rapidly and uniformly across the organs, while the clearance of the larger NPs, 100- and 600-nm MENs, was highly nonlinear with time and nonuniform across the organs.

Magnetoelectric (ME) nanoparticles (MENs) intrinsically couple magnetic and electric fields. Using them as nuclear magnetic resonance (NMR) sensitive nanoprobes adds another dimension for NMR detection of biological cells based on the cell type and corresponding particle association with the cell. Based on ME property, for the first time we show that MENs can distinguish different cancer cells among themselves as well as from their normal counterparts. The core-shell nanoparticles are 30 nm in size and were not superparamagnetic. Due to presence of the ME effect, these nanoparticles can significantly enhance the electric field configuration on the cell membrane which serves as a signature characteristic depending on the cancer cell type and progression stage. This was clearly observed by a significant change in the NMR absorption spectra of cells incubated with MENs. In contrast, conventional cobalt ferrite magnetic nanoparticles (MNPs) did not show any change in the NMR absorption spectra. We conclude that different membrane properties of cells which result in distinct MEN organization and the minimization of electrical energy due to particle binding to the cells contribute to the NMR signal. The nanoprobe based NMR spectroscopy has the potential to enable rapid screening of cancers and impact next-generation cancer diagnostic exams.

A novel pegylated multifunctional probe of Ormosil nanoparticles (PEGCDSIR820) loaded with Near Infrared dye (NIR; IR820) and a chemotherapeutic drug, Doxorubicin (DOX) was developed for cancer theranostic applications. PEGCDSIR820 nanoparticles had an average diameter of 58.2 ± 3.1 nm, zeta potential of − 6.9 ± 0.1 mV in cell culture media and stability against aggregation in physiological buffers. The encapsulation efficiency of DOX was 65.0 ± 3.0%, and that of IR820 was 76.0 ± 2.1%. PEGCDSIR820 showed no cytotoxicity in ovarian cancer cells (Skov-3). The cytotoxicity markedly increased when Skov-3 cells incubated with PEGCDSIR820 particles were exposed to 808 nm laser due to the combination of adjuvant hyperthermia (43 °C) and enhanced DOX release. Exposure to laser enhanced the release of DOX, 45% of DOX release was observed in 3 h compared to 23% without laser exposure. Confocal imaging in Skov-3 cells showed that the combination of hyperthermia due to NIR exposure and release of DOX caused cell necrosis. Furthermore, in spheroids exposed to NIR laser penetration of DOX was deeper compared to the absence of laser exposure. Skov-3 spheroids incubated with pegylated nanoparticles for 24 h and exposed to laser showed 94% reduction in cell viability. Encapsulation of IR820 in PEGCDSIR820 increased the in-vivo elimination half-life to 41.0 ± 7.2 h from 30.5 ± 0.5 h of free IR820.

The purpose of this study was to compare the cellular uptake and cytotoxicity of targeted and nontargeted doxorubicin (DOX)-loaded poly(d,l-lactide co-glycolide) (PLGA) nanoparticle (NP) drug delivery systems in drug-resistant ovarian (SKOV-3) and uterine (MES-SA/Dx5) cancer cell lines. The cellular uptakes of DOX from nonconjugated DOX-loaded NPs (DNPs) and from HER-2 antibody-conjugated DOX-loaded NPs (ADNPs) in MES-SA/Dx5 cancer cells were higher compared to free DOX. Results also showed higher uptake of DOX from ADNPs in SKOV-3 cells compared with both free DOX and DNPs treatment. Cytotoxicity results at 10 μM extracellular DOX concentration were consistent with the cellular uptake results. Our study concludes that cellular uptake and cytotoxicity of DOX can be improved in MES-SA/Dx5 cells by loading DOX into PLGA NPs. DNPs targeted to membrane receptors may enhance cellular uptake and cytotoxicity in SKOV-3 cells.The authors of this study compare the cellular uptake and cytotoxicity of targeted and nontargeted doxorubicin loaded PLGA nanoparticle delivery systems in drug-resistant ovarian and uterine cancer cell lines, concluding that cellular uptake and cytotoxicity of doxorubicin can be improved by the proposed methods.

We report a novel system of organically modified silica nanoparticles (Ormosil) capable of near infrared fluorescence and chemotherapy with adjuvant hyperthermia for image guided cancer therapy. Ormosil np’s were loaded with a chemotherapeutic, Doxorubicin (DOX) and cyanine dye, IR820. Ormosil particles had a mean diameter of 51.2 ± 2.4 nanometers and surface charge of −40.5±0.8 millivolts. DOX was loaded onto Ormosil particles via physical adsorption (FDSIR820) or covalent linkage (CDSIR820) to the silanol groups on Ormosil surface. Both formulations retained DOX and IR820 over period of 2 days in aqueous buffer, though CDSIR820 retained more DOX (93.2%) compared to FDSIR820 (77.0 %) nanoparticles. Exposure to near infrared laser triggered DOX release from CDSIR820. Uptake of nanoparticles was determined by deconvolution microscopy in ovarian carcinoma cells (Skov-3). CDSIR820 localized in the cell lysosomes whereas, cells incubated with FDSIR820 showed DOX fluorescence from the nucleus indicating leakage of DOX from the nanoparticle matrix. FDSIR820 nanoparticles showed severe toxicity in Skov-3 cells whereas, CDSIR820 particles had the same cytotoxicity profile as Bare (No DOX and IR820) Ormosil particles. Furthermore, exposure of CDSIR820 nanoparticles to Near Infrared laser at 808 nanometers resulted in generation of heat (to 43°C from 37°C) and resulted in enhanced cell killing compared to Free DOX treatment. Bio-distribution studies showed that CDSIR820 nanoparticles were primarily present in the organs of Reticuloendothelial (RES) system.

To test the effectiveness of a dual–agent-loaded PLGA nanoparticulate drug delivery system containing doxorubicin (DOX) and indocyanine green (ICG) in a DOX-sensitive cell line and two resistant cell lines that have different resistance mechanisms. The DOX-sensitive MES-SA uterine sarcoma cell line was used as a negative control. The two resistant cell lines were uterine sarcoma MES-SA/Dx5, which overexpresses the multidrug resistance exporter P-glycoprotein, and ovarian carcinoma SKOV-3, which is less sensitive to doxorubicin due to a p53 gene mutation. The cellular uptake, subcellular localization and cytotoxicity of the two agents when delivered via nanoparticles (NPs) were compared to their free-form administration. The cellular uptake and cytotoxicity of DOX delivered by NPs were comparable to the free form in MES-SA and SKOV-3, but much higher in MES-SA/Dx5, indicating the capability of the NPs to overcome P-glycoprotein resistance mechanisms. NP-encapsulated ICG showed slightly different subcellular localization, but similar fluorescence intensity when compared to free ICG, and retained the ability to generate heat for hyperthermia delivery. The dual-agent-loaded system allowed for the simultaneous delivery of hyperthermia and chemotherapy, and this combinational treatment greatly improved cytotoxicity in MES-SA/Dx5 cells and to a lesser extent in SKOV-3 cells.

In regard to cancer therapy, magnetoelectric nanoparticles (MENs) have proven to be in a class of its own when compared to any other nanoparticle type. Like conventional magnetic nanoparticles, they can be used for externally controlled drug delivery via application of a magnetic field gradient and image-guided delivery. However, unlike conventional nanoparticles, due to the presence of a non-zero magnetoelectric effect, MENs provide a unique mix of important properties to address key challenges in modern cancer therapy: (i) a targeting mechanism driven by a physical force rather than antibody matching, (ii) a high-specificity delivery to enhance the cellular uptake of therapeutic drugs across the cancer cell membranes only, while sparing normal cells, (iii) an externally controlled mechanism to release drugs on demand, and (iv) a capability for image guided precision medicine. These properties separate MEN-based targeted delivery from traditional biotechnology approaches and lay a foundation for the comp...

The purpose of this study was to prepare targeted Poly lactide-co-glycolide (PLGA) nanoparticles with simultaneous entrapment of indocyanine green (ICG) and doxorubicin (DOX) by surface decorating them with tumor specific monoclonal antibodies in order to achieve simultaneous therapy and imaging. ICG was chosen as an imaging and hyperthermia agent and DOX was used as a chemotherapeutic agent. ICG and DOX were incorporated into PLGA nanoparticles using the oil-in-water emulsion solvent evaporation technique. These nanoparticles were further surface decorated with antibodies against Human Epithelial Receptor-2 (HER-2) using carbodiimide chemistry. The uptake of antibody conjugated ICG-DOX-PLGA nanoparticles (AIDNP) was enhanced in SKOV-3 (HER-2 overexpressing cell lines) compared to their non-conjugated counterparts (ICG–DOX–PLGA nanoparticles (IDNP)). The uptake of antibody conjugated ICG–DOX–PLGA nanoparticles, however, was similar in MES-SA and MES-SA/Dx5 cancer cells (HER-2 negative cell lines), which were used as negative controls. The cytotoxicity results after laser treatment (808 nm, 6.7 W/cm 2 ) showed an enhanced toxicity in treatment of SKOV-3. The negative controls exhibited comparable cytotoxicity with or without exposure to the laser. Thus, this study showed that these antibody conjugated ICG–DOX–PLGA nanoparticles have potential for combinatorial chemotherapy and hyperthermia.

The objective of this study was to develop biodegradable poly(DL-lactide-co-glycolic acid) (PLGA) nanoparticles simultaneously loaded with indocyanine green (ICG) and doxorubicin (DOX). The modified oil in water single emulsion solvent evaporation method was used. To enhance the incorporation of both agents and control particle size, four independent processing parameters including amount of polymer, initial ICG content, initial DOX content, and concentration of poly-vinyl alcohol (PVA) were investigated. The ICG and DOX entrapment in nanoparticles as well as the nanoparticle size were determined. The nanoparticles produced by standardized formulation were in the range of 171+/-2 nm (n=3) with low polydispersity index (0.040+/-0.014, n=3). The entrapment efficiency was determined by spectrofluorometer measurements. The efficiency was 44.4+/-1.6% for ICG and 74.3+/-1.9% for DOX. Drug loading was 0.015+/-0.001%, w/w, for ICG and 0.022+/-0.001%, w/w, for DOX (n=3). The release pattern was biphasic. ICG and DOX loaded-nanoparticle preparation was standardized based on the following parameters: PLGA concentration, PVA concentration and initial drug content.

Nanoparticulate drug delivery systems have the potential to allow delivery of diagnostic and therapeutic agents to tumor sites in a targeted manner. The objective of this study was to develop biodegradable poly(DL-lactide-co-glycolic acid) (PLGA) nanoparticles loaded with an imaging/hyperthermia agent and a chemotherapy agent to allow for simultaneous diagnostics and treatment. Indocyanine Green (ICG) was selected as the imaging/hyperthermia agent, and doxorubicin (DOX) as the chemotherapy agent. The modified oil in water emulsion solvent evaporation method was used for PLGA nanoparticle preparation. To achieve an optimal degree of incorporation and particle size, we systematically assessed four independent processing variables including amount of PLGA, initial ICG amount, initial DOX amount, and PVA concentration. For every combination, we measured the nanoparticle size and the percent entrapment of ICG and DOX into the PLGA nanoparticles. The nanoparticles produced by optimal formulation had sizes of 171± 2 nm, (n=3) with a low polydispersity index (0.040 ± 0.014, n=3). We determined the entrapment efficiency (by fluorescence measurements using DMSO burst release) as 44.4 ± 1.6 % for ICG and 74.3 ± 1.9 % for DOX. Drug loading was 0.015 ± 0.001 % w/w for ICG and 0.022 ± 0.001% w/w for DOX (n=3). The release pattern was biphasic.