Guangzhou Novaken Pharmaceutical Co., Ltd.

Cutaneous melanoma is one of the most common malignant skin cancer with high lethality. Chemotherapy and photothermal therapy are important and extensively studied treatment modalities for melanoma. However, these therapies still face some challenges, which severely restrict their further applications, such as unsatisfactory efficacy of monotherapy, nonspecific uptake and release during drug delivery, and unexpected adverse effects from system administration. Recently, the strategies of collaboration, functional modification, stimuli-responsive design, and topical administration all show great prospect for solving above problems. In this research, a multifunctional nanoparticle-integrated dissolving microneedle drug delivery system was constructed, in which the nanoparticles were prepared based on the framework with the incorporation of photothermal agent (CuS) into Zeolitic imidazolate framework-8 and functionalized by hyaluronic acid. This system can co-load multi-modal drugs, improve specific uptake and distribution of targeted tumor, deliver drug locally, and release drug intelligently and spatiotemporally, thereby promising a low-dose administration with high efficiency. The high inhibiting tumor performance and excellent systematic safety were verified both in vitro and in vivo. Together, this smart design overcame the drawbacks of monotherapy and conventional system administration. We believe the nanoparticle-integrated dissolving microneedles will be in prospect of clinical application for more superficial tumors with further delicate optimization. STATEMENT OF SIGNIFICANCE: Melanoma is one of the most common skin cancers with high lethality. Extensively studied chemotherapy and photothermal therapy still face some challenges, such as the limited therapeutic efficacy and the severe system adverse effects. In order to overcome these drawbacks, the multifunctional nanoparticle-integrated dissolving microneedles (DMNs) were designed. Especially, the nanoparticles could co-load multi-modal drugs, improve specific uptake, and release drug intelligently and spatiotemporally. The microneedles could increase the drug accumulation in tumor, thus achieving excellent therapeutic efficacy and reducing side effects. This system paved the way to a less invasive, more focused and efficient therapeutic strategy for melanoma therapy.

The fluorescence dye-loaded nanoparticles are widely used as bioimaging agents in the field of nanotheranostics. However, the nanoparticles for nanotheranostics usually consist of synthetic materials, such as metal, silica, and organic polymers, which are often biologically incompatible and may arouse toxicity issues. Herein, the potential of near-infrared probe DiR-containing solid lipid nanoparticle suspensions (DiR-SLNS) as the bioimaging agent, which was prepared by lipids and surfactants with excellent biocompatibility, was investigated in this study. The nanostructure of DIR-SLNS system and the distribution of DiR were studied by dissipative particle dynamics (DPD) simulations. The stability of physicochemical properties and fluorescence spectra of DIR-SLNS system were investigated using dynamic laser scattering (DLS), nanoparticle tracking analysis (NTA), and fluorescence spectra. The fluorescence intensity-concentration correlation of DIR-SLNS was also evaluated. As a result, DiR-SLNS demonstrated a "core-shell"-like nanostructure and DiR was mainly distributed in the cetyl palmitate (CP) core rather than the surface of SLNS, which was beneficial to its potential applications in bioimaging. DiR-SLNS exhibited remarkable physicochemical stability as the nanoparticles maintained ~ 90% fluorescence intensity during the 10-day storage time. The correlation between fluorescence intensity and concentration was established and validated using a linear regression model. This study proposed a type of promising candidates in nano-scale with higher safety and fluorescence stability for bioimaging.

Microneedle arrays have emerged as an alternative method for transdermal drug delivery. Although micromolding using a centrifugation method is widely used to prepare microneedles in laboratory, few researchers were focused on manufacturing processes capable of facile scale-up. A novel female mold was initially designed in this study, namely double-penetration female mold (DPFM) with the pinpoints covered by waterproof breather membrane which was beneficial to reduce the influence of gas resistance and solution viscosity. In addition, DPFM-based positive-pressure microperfusion technique (PPPT) was proposed for the scale-up fabrication of dissolving microneedle arrays (DMNA). In this method, polymer solution and base solution were poured into the DPFM by pressure difference, followed by drying and demolding. The results of optimal microscopy and SEM revealed that the obtained microneedles were uniformly distributed conical-shaped needles. The skin penetration test showed that DMNA prepared using PPPT were able to penetrate the rat skin with a high penetration rate. To realize the transition of microneedles fabrication from laboratory to industry, an automatic equipment was further designed in this study. Different from micromolding method using centrifugation, the equipment based on PPPT and DPFM has superiorities in the scale-up fabrication of microneedles in a highly effective, controllable, and scalable way.