Highly Efficient Near-IR Photothermal Microneedles with Flame-Made Plasmonic Nanoaggregates for Reduced Intradermal Nanoparticle Deposition
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PROVIDER: S-EPMC7615098 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
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Project description:Owing to their biocompatibility, gold nanoparticles have many applications in healthcare, notably for targeted drug delivery and the photothermal therapy of tumors. The addition of a silica shell to the nanoparticles can help to minimize the aggregation of the nanoparticles upon exposure to harsh environments and protect any Raman reporters adsorbed onto the metal surface. Here, we report the effects of the addition of a silica shell on the photothermal properties of a series of gold nanostructures, including gold nanoparticle aggregates. The presence of a Raman reporter at the surface of the gold nanoparticles also allows the structures to be evaluated by surface-enhanced Raman scattering (SERS). In this work, we explore the relationship between the degree of aggregation and the position and the extinction of the near-infrared plasmon on the observed SERS intensity and in the increase in bulk temperature upon near-infrared excitation. By tailoring the concentration of the silane and the thickness of the silica shell, it is possible to improve the photothermal heating capabilities of the structures without sacrificing the SERS intensity or changing the optical properties of the gold nanoparticle aggregates.
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Project description:Photothermal microneedle (MN) arrays have the potential to improve the treatment of various skin conditions such as bacterial skin infections. However, the fabrication of photothermal MN arrays relies on time-consuming and potentially expensive microfabrication and molding techniques, which limits their size and translation to clinical application. Furthermore, the traditional mold-and-casting method is often limited in terms of the size customizability of the photothermal array. To overcome these challenges, we fabricated photothermal MN arrays directly via 3D-printing using plasmonic Ag/SiO2 (2 wt % SiO2) nanoaggregates dispersed in ultraviolet photocurable resin on a commercial low-cost liquid crystal display stereolithography printer. We successfully printed MN arrays in a single print with a translucent, nanoparticle-free support layer and photothermal MNs incorporating plasmonic nanoaggregates in a selective fashion. The photothermal MN arrays showed sufficient mechanical strength and heating efficiency to increase the intradermal temperature to clinically relevant temperatures. Finally, we explored the potential of photothermal MN arrays to improve antibacterial therapy by killing two bacterial species commonly found in skin infections. To the best of our knowledge, this is the first time describing the printing of photothermal MNs in a single step. The process introduced here allows for the translatable fabrication of photothermal MN arrays with customizable dimensions that can be applied to the treatment of various skin conditions such as bacterial infections.
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Project description:Intradermal (ID) immunization is of increasing interest due to the easy accessibility and excellent immunogenic properties of the skin. Among ID immunization methods, dissolving microneedles (MNs) have appeared as an alternative to traditional hypodermic immunization, offering many advantages, such as being an easily administered method, with no need for health personnel, painless, and avoiding the use of needles and sharp wastage. In this study, an affordable and easy-to-produce MNs method was developed based on aqueous blends of 30% w/w poly (methyl vinyl ether-co-maleic anhydride). As an antigen model, a subunit vaccine candidate based on outer membrane vesicles from Shigella flexneri was used. Both unloaded and antigen-loaded MNs were synthetized and characterized. The MNs were successfully validated in an in vitro Parafilm M® skin model and in a pig skin ex vivo model. Biodistribution studies were performed in BALB/c mice using 99mTcO4- radiolabeled samples. Results indicated that the vesicle vaccine was successfully released from the MNs and targeted gastrointestinal tract after 6 h post-administration. In vivo immunization and protection studies were performed in BALB/c mice. Mice were intradermally immunized through ear skin with one single dose of 200 g antigenic complex, eliciting the production of specific systemic IgG and mucosal IgA. Moreover, MNs were able to protect mice from an experimental infection with 1×106 CFU/mouse of S. flexneri four weeks after immunization. This work demonstrates for the first time the potential of outer membrane vesicle-loaded dissolving MNs for ID vaccination against enteropathogens like Shigella.
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Project description:Tumor associated macrophages (TAM) are key pathogenic factors in neoplastic diseases. They are known to have plasticity and can polarize into two opposing phenotypes, including the tumoricidal M1 and the protumoral M2 phenotypes with high prevalence of M2-phentoypes in patients with poor prognosis. Strategies for targeting M2-TAM may consequently increase the efficacy of therapeutic strategies for cancer treatment. Gold nanorod-assisted plasmonic photothermal therapy (PPTT) has emerged as a promising treatment for cancer but the effects of macrophage polarization parameters in the performance of this new treatment modality is still unknown. Herein, human monocytic THP-1 cells were polarized into two opposite phenotypic macrophages (M1-TAM and M2-TAM) and their response to PPTT was examined. M2-TAM exhibits a three-fold increase in AuNP uptake compared to M1-TAM. Laser irradiation results in selective killing of pro-tumoral M2-TAM after treatment with AuNPs with limited effects on anti-tumoral M1-TAM. A positive correlation between the expression of CD206 marker and the AuNP uptake may indicate the role of CD206 in facilitating AuNP uptake. Our findings also suggest that the differences in AuNP avidity and uptake between the M1-TAM and M2-TAM phenotypes may be the rationale behind the effectiveness of PPTT in the treatment of solid tumors.
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Project description:Induced hyperthermia has been demonstrated as an effective oncological treatment due to the reduced heat tolerance of most malignant tissues; however, most techniques for heat generation within a target volume are insufficiently selective, inducing heating and unintended damage to surrounding healthy tissues. Plasmonic photothermal therapy (PPTT) utilizes light in the near-infrared (NIR) region to induce highly localized heating in gold nanoparticles, acting as exogenous chromophores, while minimizing heat generation in nearby tissues. However, optimization of treatment parameters requires extensive in vitro and in vivo studies for each new type of pathology and tissue targeted for treatment, a process that can be substantially reduced by implementing computational modeling. Herein, we describe the development of an innovative model based on the finite element method (FEM) that unites photothermal heating physics at the nanoscale with the micron scale to predict the heat generation of both single and arrays of gold nanoparticles. Plasmonic heating from laser illumination is computed for gold nanoparticles with three different morphologies: nanobipyramids, nanorods, and nanospheres. Model predictions based on laser illumination of nanorods at a visible wavelength (655 nm) are validated through experiments, which demonstrate a temperature increase of 5 °C in the viscinity of the nanorod array when illuminated by a 150 mW red laser. We also present a predictive model of the heating effect induced at 810 nm, wherein the heating efficiencies of the various morphologies sharing this excitation peak are compared. Our model shows that the nanorod is the most effective at heat generation in the isolated scenario, and arrays of 91 nm long nanorods reached hyperthermic levels (an increase of at least 5 °C) within a volume of over 20 μm3.
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Project description:Hollow microneedles are an emerging technology for delivering drugs and therapeutics, such as vaccines and insulin, into the skin. Although the benefits of intradermal drug delivery have been known for decades, our understanding of fluid absorption by skin tissue has been limited due to the difficulties in imaging a highly scattering biological material such as skin. Here, we report the first real-time imaging of skin tissue at the microscale during intradermal injections through hollow microneedles, using optical coherence tomography. We show that skin tissue behaves like a deformable porous medium and absorbs fluid by locally expanding rather than rupturing to form a single fluid filled cavity. We measure the strain distribution in a cross section of the tissue to quantify local tissue deformation, and find that the amount of volumetric expansion of the tissue corresponds closely to the volume of fluid injected. Mechanically restricting tissue expansion limits fluid absorption into the tissue. Our experimental findings can provide insights to optimize the delivery of drugs into skin for different therapeutic applications, and to better model fluid flow into biological tissue.
| S-EPMC6137045 | biostudies-literature
Project description:Hyperactivity of signal transducer and activity of transcription 3 (STAT3) plays a crucial role in melanoma invasion and metastasis. Gene therapy applying siRNA targeting STAT3 is a potential therapeutic strategy for melanoma. In this article, we first fabricated safe and novel dissolving microneedles (MNs) for topical application of STAT3 siRNA to enhance the skin penetration of siRNA and used polyethylenimine (PEI, 25 kDa) as carrier to improve cellular uptake of siRNA. The results showed that MNs can effectively penetrate skin and rapidly dissolve in the skin. In vitro B16F10 cell experiments presented that STAT3 siRNA PEI complex can enhance cellular uptake and transfection of siRNA, correspondingly enhance gene silencing efficiency and inhibit tumor cells growth. In vivo experiments indicated that topical application of STAT3 siRNA PEI complex delivered by dissolving MNs into skin can effectively suppress the development of melanoma through silencing STAT3 gene, and the inhibition effect is dose-dependent. STAT3 siRNA delivery via dissolving MNs is a promising approach for skin melanoma treatment with targeting inhibition efficacy and minimal adverse effects.
| S-EPMC5773564 | biostudies-literature
Project description:Topical retinoid treatments stimulate biological activities in the skin. The main physical barrier, which limits the efficacy of transdermal drug delivery, is the stratum corneum. Proretinal nanoparticles (PRN) have already been proven to efficiently deliver retinal into the epidermis. In the present study, two transdermal drug delivery systems, microneedles (MN) and PRN, were combined to directly target the dermis. The microchannels induced by the MN, the PRN localization in the microchannels and the skin closure kinetics were investigated by non-invasive imaging techniques, such as dermoscopy, optical coherence tomography and multiphoton tomography. Additionally, the amount of retinal in the epidermis and dermis after application in three different forms (PRN-Loaded microneedles, PRN suspension or conventional retinal solution) was compared. All imaging techniques confirmed the formation of microchannels in the skin, which were partly still detectable after 24 h. Multiphoton tomography showed the release of PRN from the MN within the microchannels. The recovered retinal concentration in the dermis was significantly higher when applied via PRN-loaded microneedles. We hypothesized that this platform of PRN-loaded microneedles can provide a rapid and efficient administration of retinal in the dermis and could be of benefit in some skin conditions such as atrophic scar or photo-aged skin.
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Project description:PurposeA dissolving microneedle array (dMNA) is a vaccine delivery device with several advantages over conventional needles. By incorporating particulate adjuvants in the form of poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) into the dMNA, the immune response against the antigen might be enhanced. This study aimed to prepare PLGA-NP-loaded dMNA and to compare T-cell responses induced by either intradermally injected aqueous-PLGA-NP formulation or PLGA-NP-loaded dMNA in mice.MethodsPLGA NPs were prepared with microfluidics, and their physicochemical characteristics with regard to encapsulation efficiencies of ovalbumin (OVA) and CpG oligonucleotide (CpG), zeta potentials, polydispersity indexes, and sizes were analysed. PLGA NPs incorporated dMNA was produced with three different dMNA formulations by using the centrifugation method, and the integrity of PLGA NPs in dMNAs was evaluated. The immunogenicity was evaluated in mice by comparing the T-cell responses induced by dMNA and aqueous formulations containing ovalbumin and CpG (OVA/CpG) with and without PLGA NP.ResultsPrepared PLGA NPs had a size of around 100 nm. The dMNA formulations affected the particle integrity, and the dMNA with poly(vinyl alcohol) (PVA) showed almost no aggregation of PLGA NPs. The PLGA:PVA weight ratio of 1:9 resulted in 100% of penetration efficiency and the fastest dissolution in ex-vivo human skin (< 30 min). The aqueous formulation with soluble OVA/CpG and the aqueous-PLGA-NP formulation with OVA/CpG induced the highest CD4 + T-cell responses in blood and spleen cells.ConclusionsPLGA NPs incorporated dMNA was successfully fabricated and the aqueous formulation containing PLGA NPs induce superior CD4+ and CD8+ T-cell responses.
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Project description:The strong immunogenicity induction is the powerful weapon to prevent the virus infections. This study demonstrated that one-step synthesis of DNA polyplex vaccine in microneedle (MN) patches can induce high immunogenicity through intradermal vaccination and increase the vaccine stability for storage outside the cold chain. More negative charged DNA vaccine was entrapped into the needle region of MNs followed by DNA polyplex formation with branched polyethylenimine (bPEI) pre-coated in the cavities of polydimethylsiloxane (PDMS) molds that can deliver more DNA vaccine to immune-cell rich epidermis with high transfection efficiency. Our data in this study support the safety and immunogenicity of the MN-based vaccine; the MN patch delivery system induced an immune response 3.5-fold as strong as seen with conventional intramuscular administration; the DNA polyplex formulation provided excellent vaccine stability at high temperature (could be stored at 45ºC for at least 4 months); the DNA vaccine is expected to be manufactured at low cost and not generate sharps waste. We think this study is significant to public health because there is a pressing need for an effective vaccination in developing countries.
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