Current status of silica-based nanoparticles as therapeutics and its potential as therapies against viruses.

In the past decade, interest in nanoparticles for clinical indications has been steadily gaining traction. Most recently, Lipid Nanoparticles (LNP) have been used successfully to construct the SARS-CoV-2 mRNA vaccines for rapid pandemic response. Similarly, silica is another nanomaterial which holds much potential to create nanomedicines against pathogens of interest. One major advantage of silica-based nanoparticles is its crystalline and highly ordered structure, which can be specifically tuned to achieve the desired properties needed for clinical applications. Increasingly, clinical research has shown the potential of silica nanoparticles not only as an antiviral, but also its ability as a delivery system for antiviral small molecules and vaccines against viruses. Silica has an excellent biosafety profile and has been tested in several early phase clinical trials since 2012, demonstrating good tolerability and minimal reported side effects. In this review, we discuss the clinical development of silica nanoparticles to date and identify the gaps and potential pitfalls in its path to clinical translation.

Amplified parallel antigen rapid test for point-of-care salivary detection of SARS-CoV-2 with improved sensitivity.

In the ongoing COVID-19 pandemic, simple, rapid, point-of-care tests not requiring trained personnel for primary care testing are essential. Saliva-based antigen rapid tests (ARTs) can fulfil this need, but these tests require overnight-fasted samples; without which independent studies have demonstrated sensitivities of only 11.7 to 23.1%. Herein, we report an Amplified Parallel ART (AP-ART) with sensitivity above 90%, even with non-fasted samples. The virus was captured multimodally, using both anti-spike protein antibodies and Angiotensin Converting Enzyme 2 (ACE2) protein. It also featured two parallel flow channels. The first contained spike protein binding gold nanoparticles which produced a visible red line upon encountering the virus. The second contained signal amplifying nanoparticles that complex with the former and amplify the signal without any linker. Compared to existing dual gold amplification techniques, a limit of detection of one order of magnitude lower was achieved (0.0064 ng·mL-1). AP-ART performance in detecting SARS-CoV-2 in saliva of COVID-19 patients was investigated using a case-control study (139 participants enrolled and 162 saliva samples tested). Unlike commercially available ARTs, the sensitivity of AP-ART was maintained even when non-fasting saliva was used. Compared to the gold standard reverse transcription-polymerase chain reaction testing on nasopharyngeal samples, non-fasting saliva tested on AP-ART showed a sensitivity of 97.0% (95% CI: 84.7-99.8); without amplification, the sensitivity was 72.7% (95% CI: 83.7-94.8). Thus, AP-ART has the potential to be developed for point-of-care testing, which may be particularly important in resource-limited settings, and for early diagnosis to initiate newly approved therapies to reduce COVID-19 severity.

Comparing Semiconductor Nanocrystal Toxicity in Pregnant Mice and Non-Human Primates.

Rationale: Despite growing use of engineered nanomaterials (ENM) in applications from electronics to medicine, the potential risk to human health remains a critical concern within clinical use. ENM exposure during pregnancy can potentially cause reproductive toxicity even at levels that produce no measurable harm to animals in normal conditions. Methods: Phospholipid micelle-encapsulated CdSe/CdS/ZnS semiconductor nanocrystals with an average hydrodynamic diameter of 60 nm were intravenously injected during pregnancy in both rodent and nonhuman primate animal models. Cadmium concentration levels and maternal haematological and biochemical markers were determined, along with histopathological examination of major organs. Results: Nanocrystals were found to have crossed the placenta from mother to fetus in both rodents and nonhuman primates. However, the animal models display different responses with respect to reproductive toxicity. In the rodent model, toxicity symptoms are absent in treated subjects, with no observed gestational or fetal abnormalities and complications. A significantly higher miscarriage rate of 60% is recorded for macaques after prenatal nanoparticle administration. There was a miscarriage rate of 15% in the general population despite only ~0.16% of the initial cadmium dose present in the fetus. Blood and biochemical markers of treated macaques indicate acute hepatocellular injury within a week after nanoparticle administration. Histology of major organs of the miscarried macaque fetuses show no abnormalities. Conclusion: The potential of nanomaterials to cross the placenta and impact fetal survival in primates suggest the necessity of precautionary measures to prevent gestational exposure of ENMs.

A Self-Powered Implantable Drug-Delivery System Using Biokinetic Energy.

The first triboelectric-nanogenerator (TENG)-based self-powered implantable drug-delivery system is presented. Pumping flow rates from 5.3 to 40 µL min-1 under different rotating speeds of the TENG are realized. The implantable drug-delivery system can be powered with a TENG device rotated by human hand motion. Ex vivo trans-sclera drug delivery in porcine eyes is demonstrated by utilizing the biokinetic energies of human hands.

Synthesis and characterization of multifunctional hybrid-polymeric nanoparticles for drug delivery and multimodal imaging of cancer.

In this study, multifunctional hybrid-polymeric nanoparticles were prepared for the treatment of cultured multicellular tumor spheroids (MCTS) of the PANC-1 and MIA PaCa-2 pancreatic carcinoma cell lines. To synthesize the hybrid-polymeric nanoparticles, the poly lactic-co-glycolic acid core of the particles was loaded with Rhodamine 6G dye and the chemotherapeutic agent, Paclitaxel, was incorporated into the outer phospholipid layer. The surface of the nanoparticles was coated with gadolinium chelates for magnetic resonance imaging applications. This engineered nanoparticle formulation was found to be suitable for use in guided imaging therapy. Specifically, we investigated the size-dependent therapeutic response and the uptake of nanoparticles that were 65 nm, 85 nm, and 110 nm in size in the MCTS of the two pancreatic cancer cell lines used. After 24 hours of treatment, the MCTS of both PANC-1 and MIA PaCa-2 cell lines showed an average increase in the uptake of 18.4% for both 65 nm and 85 nm nanoparticles and 24.8% for 110 nm nanoparticles. Furthermore, the studies on therapeutic effects showed that particle size had a slight influence on the overall effectiveness of the formulation. In the MCTS of the MIA PaCa-2 cell line, 65 nm nanoparticles were found to produce the greatest therapeutic effect, whereas 12.8% of cells were apoptotic of which 11.4% of cells were apoptotic for 85 nm nanoparticles and 9.79% for 110 nm nanoparticles. Finally, the study conducted in vivo revealed the importance of nanoparticle size selection for the effective delivery of drug formulations to the tumors. In agreement with our in vitro results, excellent uptake and retention were found in the tumors of MIA PaCa-2 tumor-bearing mice treated with 110 nm nanoparticles.

An in-vivo evaluation of a MEMS drug delivery device using Kunming mice model.

The use of MEMS implantable drug delivery pump device enables one to program the desired drug delivery profile in the device for individualized medicine treatment to patients. In this study, a MEMS drug delivery device is prepared and employed for in vivo applications. 12 devices are implanted subcutaneously into Kunming mice for evaluating their long term biocompatibility and drug-delivery efficiency in vivo. All the mice survived after device implantation surgery procedures. Histological analysis result reveals a normal wound healing progression within the tissues-to-device contact areas. Serum analysis shows that all measured factors are within normal ranges and do not indicate any adverse responses associated with the implanted device. Phenylephrine formulation is chosen and delivered to the abdominal cavity of the mice by using either the implanted MEMS device (experimental group) or the syringe injection method (control group). Both groups show that they are able to precisely control and manipulate the increment rate of blood pressure in the small animals. Our result strongly suggests that the developed refillable implantable MEMS devices will serve as a viable option for future individualized medicine applications such as glaucoma, HIV-dementia and diabetes therapy.

Standalone Lab-on-a-Chip Systems toward the Evaluation of Therapeutic Biomaterials in Individualized Disease Treatment.

As each tumor is unique, treatments should be individualized in terms of their drug formulation and time dependent dosing. In vitro lab-on-a-chip (LOC) drug testing is a viable avenue to individualize treatments. A drug testing platform in the form of a customizable standalone LOC system is proposed for treatment individualization in vitro. The platform was used to individualize the treatment of pancreatic cancer by using PANC-1 and MIA PaCa-2 cell lines cultured on-chip. Using on-chip drug uptake, growth, and migration inhibition assays, the therapeutic effect of various treatment combinations was analyzed. Thereafter, optimized treatments were devised for each cell line. The individualized dosage for MIA PaCa-2 cell line was found to be between 0.05-0.1 µg/µL of doxorubicin (DOX), where the greatest growth and migration inhibition effects were observed. As the PANC-1 cell line showed resistance to DOX only formulations, a multidrug approach was used for individualized treatment. Compared to the DOX only formulations, the individualized treatment produced the same degree of migration inhibition but with 5-10 times lower concentration of DOX, potentially minimizing the side-effects of the treatment. Furthermore, the individualized treatment had an average of 672.4% higher rate of growth inhibition. Finally, a preliminary study showed how a tested formulation from the LOC system can be translated for use by employing a nanoparticle system for controlled delivery, producing similar therapeutic effects. The use of such systems in clinical practice could potentially revolutionize treatment formulation by maximizing the therapeutic effects of existing treatments while minimizing their potential side effects through individualization of treatment.

High reliability nanosandwiched Pt/Ti multilayer electrode actuators for on-chip biomedical applications.

Microactuators provide the main driving force for fluid pumping in microfluidic devices and thus play an important role in on-chip biomedical applications. Interdigitated electrode based electrochemical actuators have provided a viable choice for effective actuation with advantages of flexible controllability, biocompatibility and ease of fabrication. However, the current feature size of a typical electrode structure is around 100 µm, which is relatively large for device miniaturization and integration. Further decrease in the feature size will lead to dramatic decrease in the reliability and lifetime of the actuators, caused by metal delamination. In this work, we propose a novel design of electrodes to fabricate a new type of microactuator with high reliability. To prevent the occurrence of delamination, a nanosandwiched multilayer structure of titanium/platinum is used to construct the conductive metal layer for the interdigitated electrodes. The feature size of the electrodes is greatly reduced to 20 µm where we have reduced the size by 80% of the similar structures reported previously. At the same time, the lifetime of the new electrodes has been dramatically increased to over 400% as compared to the conventional design. With these remarkable improvements in the electrode design, we have fabricated a prototype microfluidic device integrating the new microactuator for drug tests in cancer therapy, demonstrating its usefulness for on-chip biomedical applications.

An electrochemically actuated MEMS device for individualized drug delivery: an in vitro study.

Individualized disease treatment is a promising branch for future medicine. In this work, we introduce an implantable microelectromechanical system (MEMS) based drug delivery device for programmable drug delivery. An in vitro study on cancer cell treatment has been conducted to demonstrate a proof-of-concept that the engineered device is suitable for individualized disease treatment. This is the first study to demonstrate that MEMS drug delivery devices can influence the outcome of cancer drug treatment through the use of individualized disease treatment regimes, where the strategy for drug dosages is tailored according to different individuals. The presented device is electrochemically actuated through a diaphragm membrane and made of polydimethylsiloxane (PDMS) for biocompatibility using simple and cost-effective microfabrication techniques. Individualized disease treatment was investigated using the in vitro programmed delivery of a chemotherapy drug, doxorubicin, to pancreatic cancer cell cultures. Cultured cell colonies of two pancreatic cancer cell lines (Panc-1 and MiaPaCa-2) were treated with three programmed schedules and monitored for 7 days. The result shows that the colony growth has been successfully inhibited for both cell lines among all the three treatment schedules. Also, the different observations between the two cell lines under different schedules reveal that MiaPaCa-2 cells are more sensitive to the drug applied. These results demonstrate that further development on the device will provide a promising novel platform for individualized disease treatment in future medicine as well as for automatic in vitro assays in drug development industry.