Potential of biosurfactant as green pharmaceutical excipients for coating of microneedles: A mini review.

Microneedles, a novel transdermal delivery system, were designed to improve drug delivery and address the challenges typically encountered with traditional injection practices. Discovering new and safe excipients for microneedle coating to replace existing chemical surfactants is advantageous to minimize their side effect on viable tissues. However, some side effects have also been observed for this application. The vast majority of studies suggest that using synthetic surfactants in microneedle formulations may result in skin irritation among other adverse effects. Hence, increasing knowledge about these components and their potential impacts on skin paves the way for finding preventive strategies to improve their application safety and potential efficacy. Biosurfactants, which are naturally produced surface active microbial products, are proposed as an alternative to synthetic surfactants with reduced side effects. The current review sheds light on potential and regulatory aspects of biosurfactants as safe excipients in the coating of microneedles.

Dual Adjuvant-Loaded Peptide Antigen Self-Assembly Potentiates Dendritic Cell-Mediated Tumor Immunotherapy.

Clinical translation of current cancer vaccine research has been hampered by limited antitumor immune responses due to inefficient antigen delivery and presentation, suboptimal DC and T cell activation. Biomaterial-based nanovaccine offers targeted antigen delivery, protection from degradation in vivo, and prolonged tumor therapeutic efficacy. This study introduces a lipid-coated deoxycholic acid-survivin nanoassembly (DA-L-DSA). Survivin, overexpressed in several cancer cells and involved in cancer cell growth and immune evasion, is selected as a tumor-associated antigen. An major histocompatibility complex class I binding epitope of survivin is engineered into the nanoassembly. R848, TLR 7/8 agonist, and SD-208, TGF-beta receptor1 kinase inhibitor, are coencapsulated into the nanoassembly as potent adjuvants to boost DC maturation and enhance antigen presentation. The DA-L-DSA effectively stimulates the maturation of dendritic cells, migrates into lymph nodes, and enhances T-cell activation and Th1 response. A substantial influx of cytotoxic T lymphocytes into primary tumors is observed in a murine melanoma model and demonstrates anti-metastatic effects in a spontaneous breast cancer metastasis model. Furthermore, DA-L-DSA exhibits a remarkable synergistic effect in the combination therapy with immune checkpoint inhibitors alleviating immunosuppressive tumor microenvironment. Taken together, these findings suggest DA-L-DSA as a promising immuno-therapeutic platform that could be applicable to diverse intractable cancers.

Self-Assembled Oligopeptoplex-Loaded Dissolving Microneedles for Adipocyte-Targeted Anti-Obesity Gene Therapy.

Advancements in gene delivery systems are pivotal for gene-based therapeutics in oncological, inflammatory, and infectious diseases. This study delineates the design of a self-assembled oligopeptoplex (SA-OP) optimized for shRNA delivery to adipocytes, targeting obesity and associated metabolic syndromes. Conventional systems face challenges, including instability due to electrostatic interactions between genetic materials and cationic oligopeptides. Additionally, repeated injections induce discomfort and compromise patient well-being. To circumvent these issues, a dissolvable hyaluronic acid-based, self-locking microneedle (LMN) patch is developed, with improved micro-dose efficiency, for precise SA-OP delivery. This platform offers pain-free administration and improved SA-OP storage stability. In vitro studies in 3T3-L1 cells demonstrated improvements in SA-OP preservation and gene silencing efficacy. In vivo evaluation in a mice model of diet-induced type 2 diabetes yielded significant gene silencing in adipose tissue and a 21.92 ± 2.51% reduction in body weight with minimum relapse risk at 6-weeks post-treatment, representing a superior therapeutic efficacy in a truncated timeframe relative to the GLP-1 analogues currently available on the market. Additionally, SA-OP (LMN) mitigated insulin resistance, inflammation, and hepatic steatosis. These findings establish SA-OP (LMN) as a robust, minimally invasive transdermal gene delivery platform with prolonged storage stability for treating obesity and its metabolic comorbidities.

Engineering TGF-ß inhibitor-encapsulated macrophage-inspired multi-functional nanoparticles for combination cancer immunotherapy.

BACKGROUND: The emergence of cancer immunotherapies, notably immune checkpoint inhibitors, has revolutionized anti-cancer treatments. These treatments, however, have been reported to be effective in a limited range of cancers and cause immune-related adverse effects. Thus, for a broader applicability and enhanced responsiveness to solid tumor immunotherapy, immunomodulation of the tumor microenvironment is crucial. Transforming growth factor-ß (TGF-ß) has been implicated in reducing immunotherapy responsiveness by promoting M2-type differentiation of macrophages and facilitating cancer cell metastasis. METHODS: In this study, we developed macrophage membrane-coated nanoparticles loaded with a TGF-ßR1 kinase inhibitor, SD-208 (M[Formula: see text]-SDNP). Inhibitions of M2 macrophage polarization and epithelial-to-mesenchymal transition (EMT) of cancer cells were comprehensively evaluated through in vitro and in vivo experiments. Bio-distribution study and in vivo therapeutic effects of M[Formula: see text]-SDNP were investigated in orthotopic breast cancer model and intraveneously injected metastasis model. RESULTS: M[Formula: see text]-SDNPs effectively inhibited cancer metastasis and converted the immunosuppressive tumor microenvironment (cold tumor) into an immunostimulatory tumor microenvironment (hot tumor), through specific tumor targeting and blockade of M2-type macrophage differentiation. Administration of M[Formula: see text]-SDNPs considerably augmented the population of cytotoxic T lymphocytes (CTLs) in the tumor tissue, thereby significantly enhancing responsiveness to immune checkpoint inhibitors, which demonstrates a robust anti-cancer effect in conjunction with anti-PD-1 antibodies. CONCLUSION: Collectively, responsiveness to immune checkpoint inhibitors was considerably enhanced and a robust anti-cancer effect was demonstrated with the combination treatment of M[Formula: see text]-SDNPs and anti-PD-1 antibody. This suggests a promising direction for future therapeutic strategies, utilizing bio-inspired nanotechnology to improve the efficacy of cancer immunotherapy.

Rapidly Separable Micropillar Integrated Dissolving Microneedles.

Dissolving microneedle (DMN) patches were developed as efficient and patient-friendly transdermal delivery systems for biopharmaceuticals. However, recent studies have confirmed that the efficiency of DMNs to deliver biopharmaceuticals is highly reduced because of incomplete insertion caused by the stiffness and elastic properties of the skin. Therefore, micropillar integrated DMNs were developed to overcome the insertion limitations of DMN patches. Although micropillars were designed as integrated applicators to implant DMNs across the skin, they can also become inserted into the skin, leading to skin injury and inflammation. Herein, we have developed a separable micropillar integrated DMN (SPDMN) capable of inserting DMNs across the skin with high efficiency while minimizing skin injury risk through the introduction of a safety ring feature. Unlike previously developed systems, the SPDMN does not require continuous skin attachment and can be detached immediately post-application, leaving DMNs implanted inside the skin. Altogether, the findings of this study lead to the development of a quick, safe, and efficient DMN-based drug delivery platform.

Dissolving Microneedles for Rapid and Painless Local Anesthesia.

Microneedles are emerging drug delivery methods for painless treatment. The current study tested dissolving microneedles containing lidocaine (Li-DMN) for use in local anesthesia. An Li-DMN patch was fabricated by centrifugal lithography with carboxymethyl cellulose as a structural polymer and assessed for physical properties by optical microscopy and a fracture force analyzer. The biocompatibility was evaluated by a histology section in vitro and by ear thickness in vivo. The efficacy of the Li-DMN patch was assessed by electrophysiological recordings in primary cultured sensory neurons in vitro and a von Frey test on rats' hind paws in vivo. The physical properties of the microneedle showed enough rigidity for transdermal penetration. The maximal capacity of lidocaine-HCl in the Li-DMN patch was 331.20 ± 6.30 µg. The cytotoxicity of the dissolving microneedle to neuronal cells was negligible under an effective dose of lidocaine for 18 h. Electrophysiological recordings verified the inhibitory effect of the voltage-gated sodium channel current by the Li-DMN patch in vitro. A skin reaction to the edema test and histologic analysis of the rats' ears after application of the Li-DMN patch were negligible. Also, the application of the Li-DMN patch reduced the nocifensive behavior of the rats almost immediately. In conclusion, the dissolving microneedle patch with carboxymethyl cellulose is a promising candidate method for the painless delivery of lidocaine-HCl.

Scalp Micro-Pigmentation via Transcutaneous Implantation of Flexible Tissue Interlocking Biodegradable Microneedles.

Alopecia, characterized by hair follicle blockage and hair loss, disrupts the normal cycle of hair growth. Although not a life-threatening condition, a growing body of evidence suggests that the psychological state of individuals experiencing alopecia can be highly influenced. Despite considerable research on hair loss treatment, interest in micro-pigmentation has increased in recent decades. Micropigmentation is an effective method to camouflage the visual contrast between the scalp and hair strands. However, the localization, intensity and dimension of microdots depend highly upon the physician performing the implantation. Incorrectly localized microdots within the skin may lead to patchy or faded micropigmentation. To overcome the limitations of conventional micro-pigmentation, we aimed to develop micro-pigment-encapsulated biodegradable microneedles (PBMs), capable of accurately implanting pigments below the epithelial-dermal junction of the scalp in a minimally invasive manner. A tissue interlocking microneedle technique was utilized to fabricate double-layered PBMs over a biodegradable flexible sheet, which could be washed off post-implantation. We confirmed that the intensity, dimension and insertion depth of 1,000 µm-long PBMs was maintained on pig cadaver skin over time. This study suggested that the developed PBMs would serve as an attractive platform for scalp micro-pigmentation in the future.

Innovative polymeric system (IPS) for solvent-free lipophilic drug transdermal delivery via dissolving microneedles.

Lipophilic drugs are potential drug candidates during drug development. However, due to the need for hazardous organic solvents for their solubilization, these drugs often fail to reach the pharmaceutical market, and in doing so highlight the importance of solvent free systems. Although transdermal drug delivery systems (TDDSs) are considered prospective safe drug delivery routes, a system involving lipophilic drugs in solvent free or powder form has not yet been described. Here, we report, for the first time, a novel approach for the delivery of every kind of lipophilic drug in powder form based on an innovative polymeric system (IPS). The phase transition of powder form of lipophilic drugs due to interior chemical bonds between drugs and biodegradable polymers and formation of nano-sized colloidal structures allowed the fabrication of dissolving microneedles (DMNs) to generate a powerful TDDS. We showed that IPS based DMN with powder capsaicin enhances the therapeutic effect for treatment of the rheumatic arthritis in a DBA/1 mouse model compared to a solvent-based system, indicating the promising potential of this new solvent-free platform for lipophilic drug delivery.