Drug Delivery and Translational Research最新文献

Microneedle patches, which are minimally invasive and have high patient compliance, offer a potential alternative for transdermal drug delivery, particularly in chronic diseases such as osteoporosis, which require consistent long-term therapy. Genistein is an osteoprotective plant-derived isoflavone that suffers from poor aqueous solubility and low bioavailability, thereby limiting its medicinal value. In this study, a genistein-loaded solid lipid nanoparticles integrated with dissolving microneedles was developed for the management of osteoporosis. SLNs were prepared using glyceryl monostearate and Tween 80, and optimized by using a Box-Behnken design. The optimised formulation of SLNs (F3) was incorporated into dissolving microneedles. The developed dissolving microneedles were studied for various characterisations, and they featured uniform geometry, sharp, pointed edges, a drug delivery profile of 69.218 ± 3.64% at 8 h. Its anti-osteoporotic studies were carried out on 6 groups of Wistar albino rats, and studies showed that significant decrease in the creatinine level and osteoclast cells; on the other hand, a substantial increase in total protein, bone weight, hardness, thickness, and trabecular composition. A skin irritation test, which was performed, manifested the biocompatible, dermatologically safe quality of the developed dissolving microneedles. This microneedle platform, coupled with an optimised SLNs carrier, ensures a non-invasive controlled transdermal delivery, maximising genistein's osteogenic potency for the effective management of osteoporosis.

With nearly half of all pregnancies occurring unintended, effective and acceptable contraceptive options remain a global necessity. Though contraceptives with extended durations of action reduce the need for strict daily adherence, thus enhancing compliance and reliability, only one of these methods - the copper intrauterine device (IUD) - prevents pregnancy without administering exogenous hormones. Herein, we demonstrate co-delivery of two nonhormonal contraceptive agents, lactic acid (LA) and glycerol monolaurate (GML), using a next-generation 3D-printed intravaginal ring (IVR). Through alterations in ring properties and drug loading, a range of LA and GML release rates were achieved in vitro, demonstrating the flexibility of the platform technology. Rings elicited sustained release of LA and GML at target release rates over 30 days or longer. Additionally, these studies explored how drugs with different physiochemical properties interact within the IVR matrix and further elucidated IVR drug loading and release mechanisms.

Human microbiota is now recognized as a fundamental organ of the body. In its healthy state, it fulfills essential local and systemic functions, whereas dysbiosis disrupts these roles and can contribute to disease. Although numerous studies have examined the relationship between microbiota and cancer, often revealing conflicting mechanisms and outcomes, this work has focused almost exclusively on the gut, leaving the lung microbiota largely unexplored. In this project, a ferrocifen compound was selected as an anticancer agent for lung cancer therapy. We found that lung microbiota actively degraded the ferrocifen. To prevent this degradation, the antibacterial peptide buforin II was synthesized, purified, and characterized. After confirming its antimicrobial activity, it was covalently conjugated to the ferrocifen, yielding an amphiphilic bioconjugate. This prodrug was subsequently formulated into self-assembled structures to enhance ferrocifen solubility and bioavailability. The resulting self-assemblies were evaluated in an orthotopic murine model of lung cancer and administered via nebulization to assess their therapeutic efficacy. A significant reduction in tumor progression and an improved predicted survival in mice were obtained. Together, these findings highlight the capacity of the lung microbiota to interfere with anticancer therapies and underscore the importance of considering this flora when designing treatment strategies for lung cancer.

Leveraging the intrinsic platelet-cancer cell crosstalk through platelet membrane-coated nanosystems offers a promising avenue for targeted drug delivery, particularly against triple-negative breast cancer, the most aggressive highly metastatic breast cancer subtype. In parallel, repurposing the antiparasitic ivermectin (Ivm) for anticancer applications is hindered by poor solubility and high toxicity, restricting its parenteral administration. In this study, ivermectin nanocrystals (Ivm-NC) were first developed to enhance drug solubility and systemic delivery. Afterwards, platelet-membrane was employed for realizing platelet-mimetic-camouflaged PMV/Ivm-NC for active-targeted tumor homing, immune evasion and higher biocompatibility. The innovative PMV/Ivm-NC presented optimum particle-size and zeta-potential, while exhibiting a sustained release pattern. Successful coating and retention of platelet membrane proteins was confirmed by SDS-PAGE profiling and immunocytochemistry for the platelet-membrane-protein P-selectin. In vitro studies for PMV/Ivm-NC demonstrated higher selective-cytotoxicity (IC₅₀ 2.89 ± 0.38 µg/mL) and anti-migratory potential on MDA-MB-231 cells, and cytocompatibility on normal human fibroblasts vs. uncoated Ivm-NC. In 4T1-tumor-bearing BALB/c mice, PMV-functionalization fostered preferential tumor-homing and reduced off-target distribution, compared to uncoated-NC. In addition, PMV/Ivm-NC secured pronounced tumor-growth inhibition, down-regulation of oncogenic markers (VEGF and cyclin D1), upregulation of pro-apoptotic Bax and caspase-3, and enhanced immune-infiltration of CD4⁺ and CD8⁺ T-cells, suggesting Ivm-induced immunogenic cell death. Histological evaluation confirmed higher tumor-necrosis and lower mitotic-count, as well as a notable lung-antimetastatic activity. Serum biochemistry and histopathology confirmed favorable biocompatibility. Together, our findings highlight PMV/Ivm-NC as a promising biomimetic-camouflaged nanoplatform for harnessing Ivm repurposed anticancer immunotherapy and reducing possible toxicity with selective, active targeting of triple negative breast cancer.

Intraoperatively applied local drug delivery systems (LDDS) offer a means of overcoming blood-brain barrier (BBB) impermeability. However, there is a paucity of LDDS development for paediatric tumours arising in the posterior fossa. Here we demonstrate applicability of an LDDS against medulloblastoma group 3 (G3 MB) and atypical teratoid/rhabdoid tumours (AT/RT), neoplasms associated with poor prognoses. A poly(ethyleneglycol)-poly(caprolactone)-poly(ethyleneglycol) (PECE) hydrogel loaded with chemotherapeutics identified as effective against primary G3 MB and AT/RT in vitro, was prepared as an injectable, biodegradable formulation. CHIR99021 (glycogen synthase kinase-3 inhibitor), ribavirin (guanosine analogue) and PG545 (heparanase inhibitor) were chosen based upon an inability to traverse the BBB. The hydrogel alone was well-tolerated, and drug-loaded hydrogel achieved > 1-month therapeutic release. Orthotopic xenograft studies against G3 MB and AT/RT indicated good tolerability to combined CHIR99021 and PG545 or combined CHIR99021 and ribavirin loaded loaded LDDS respectively. Median survival of AT/RT arms receiving XRT alone was comparable to CHIR99021- and ribavirin-loaded LDDS, with long-term survivors observed only in the latter arm, demonstrating a significant survival benefit. LDDS against cerebellar tumours using PECE offers a promising therapeutic alternative and the possibility of circumventing radiation-induced adverse effects for children impacted by these diseases.

Mucosal vaccination generates protective immune responses directly at the primary site of STI infection. However, the delivery of nanoparticles is hindered by the mucus barrier at these mucosal surfaces. Due to this interference, research on mucosal administration of self-amplifying (sa)-mRNA encapsulated in lipid nanoparticles (LNP) is currently limited and inconsistent. Some progress has been reported for nasal mRNA vaccination. However, for STIs, protective immune responses are required at the urogenital tract, which is achieved through intravaginal or intranasal administration. Therefore, in this research, we aimed to determine whether an sa-mRNA-LNP reporter vaccine could be effectively administered mucosally, evaluating its potential as a novel platform for STI vaccination. The sa-mRNA luciferase construct was encapsulated in two LNP formulations. In vitro studies demonstrated that these formulations maintained their potency after being sprayed with different sprayers and exposed to different mucus solutions, except for a human cervicovaginal simulant. Next, pigs received 15 µg of the sa-mRNA intravaginally and intranasally through a mucosal spray or injection. The mucosal spray resulted in expression and uptake only at the vaginal mucosa, whereas injection of the formulations resulted in expression at both mucosal sites. However, expression after spraying in the vaginal mucosa disappeared by day 4 post-administration. No differences were observed between both LNP formulations. These findings demonstrate that sa-mRNA can be used for mucosal administration, and expression can be achieved in a more relevant animal model. However, additional research is needed to develop more suitable particles for these complex environments.

Neurodegenerative diseases are increasingly significant causes of mortality and morbidity worldwide, particularly among the elderly. Despite their widespread prevalence, effective treatment options remain inadequate. A significant challenge contributing to this therapeutic gap is the impermeability of the blood-brain barrier to many drugs. Thus, developing new strategies to bypass this barrier and deliver therapeutic agents to the central nervous system (CNS) is crucial. The intranasal (IN) route has emerged as a promising approach in animal models of neurodegenerative diseases. This method of administration is gaining attention as a viable alternative for delivering various pharmacological agents, including proteins, miRNA, and oligonucleotides, to the CNS. It offers advantages over oral and intravenous routes. However, translating IN formulations from preclinical models to clinical practice presents several challenges. Assessing the adequacy of current clinical trials in evaluating IN delivery efficacy is crucial. Furthermore, the introduction of novel formulations such as nanoparticles sparks excitement for enhancing the effectiveness of IN drug administration compared to traditional free drug solutions. This review summarizes recent advancements in delivering therapeutic molecules to the CNS to treat neurodegenerative diseases. We explore critical strategies to overcome the blood-brain barrier obstacle, focusing on recent progress using the IN route as a potential avenue for effective neurodegenerative disease therapies. Additionally, we will delve into the preclinical studies that have provided the basis for the clinical trials conducted.

There are several types of breast cancer where the breast's cells proliferate uncontrollably. A selective oestrogen receptor modulator called Tamoxifen citrate (TAM) is used to treat and prevent breast cancer in both men and women. TAM is classified as class II under the biopharmaceutical categorization system (BCS) of medications. It exhibits low plasma levels, which can result in therapeutic failure due to its poor water solubility. To improve its chemotherapeutic efficiency and drug targeting, nanotechnology was exploited. In this article, TAM-loaded SLNs were prepared, characterized, and radiolabelled with Technetium-99m ([^99mTc]Tc) using stannous salts followed by the assessment of their radiochemical efficiency and in vivo biodistribution compared to the radiolabelled free TAM ([^99mTc]Tc-TAM). The results showed that the concentration of lipid had a highly prominent effect on the particle size and encapsulation efficiency of the drug, where the best selected formula showed spherical, non-aggregated morphology with a 134.6 ± 0.3 nm size and 83.9 ± 2.5% drug encapsulation. The radiolabelling purity was more than 97.4%, and it was stable for at least 6 h. In solid tumor-bearing mice, [^99mTc]Tc-TAM-SLNs exhibited around 3 times more uptake than [^99mTc]Tc-TAM solution. Accordingly, [^99mTc]Tc-TAM-SLNs can be suggested as a useful targeted delivery strategy for chemotherapy drugs.

Until recently, approved handheld auto-injectors (AIs) have been limited to volumes ≤ 2 mL. A prototype rapid high-volume AI (HVAI) that can deliver 10 mL in 30 s was developed to administer therapeutics co-formulated with a proprietary recombinant human hyaluronidase PH20 (rHuPH20). This phase I, open-label study assessed the tolerability of subcutaneous (SC) injections of 10% (100 mg/mL) immunoglobulin G (IgG) solution co-administered with 4000 U/mL rHuPH20, delivered using a syringe pump at a target rate of 5 or 10 mL/30 seconds or the prototype HVAI at a target rate of 10 mL/30 seconds in healthy human subjects. Subjects received 5 mL (Cohort A, n = 12) or 10 mL (Cohort B, n = 12) of test solution via syringe pump (injection visit 1), and 10 mL of test solution via HVAI (Cohorts A & B; injection visit 2). Primary endpoints were tolerability and safety outcomes. Secondary endpoints included HVAI injection duration. All 24 subjects completed visit 1; 23/24 completed visit 2. All injections were tolerated, with no serious adverse events (AEs). Following syringe pump administration, 6/24 subjects (25%) reported eight treatment-emergent AEs (TEAEs); after HVAI administration, 4/23 (17%) reported four TEAEs, all mild in severity. Mean (± SEM) injection duration via HVAI was 27.9 ± 0.8 s. Most subjects (91%, 21/23) experienced no or mild injection-site pain following HVAI administration, and 96% (22/23) said they would be willing to have the HVAI injection again. SC injection of a 10% IgG solution in combination with rHuPH20 was well tolerated at an injection rate of 10 mL/~30 s using the prototype HVAI.

Contraceptive options for men are limited to either condom use or surgical vasectomy. Ongoing scientific efforts seek to expand existing male contraceptive options to include reversible options with high efficacy and reliability. Herein, we formulated EP055, a novel non-hormonal compound with reversible contraceptive effect, into an in-situ forming implant (ISFI) to demonstrate potential of male contraception with a long-acting injectable. Over a dozen ISFI formulations were studied, though release durations were limited due to the hydrophilic nature of EP055. An optimized EP055-ISFI formulation (F.04) elicited sustained release in vitro over 35 days and was further investigated in vivo for safety, pharmacokinetics (PK), and efficacy in male BALB/c mice. Plasma EP055 concentrations elicited high burst release in the first 24 h followed by first order-like release kinetics up to day 14 and sustained release between day 14-28. EP055 ISFI removal resulted in a rapid decline of EP055 plasma concentration, which fell below the limit of quantification. A reduction in sperm motility and an increase in premature acrosomal membrane degradation were observed with sperm samples collected at day 3 post EP055-ISFI administration, indicating contraceptive efficacy. Furthermore, EP055 was well-tolerated with no signs of systemic inflammation. Collectively, these results support future development of EPPIN-targeting molecules and in-situ forming implants for male contraception.