Carriers For Delivery Research Articles

A DFT study on antimonene as a drug delivery vehicle for carmustine, lomustine and nitrosourea anticancer drugs

We used antimonene (Sb) as a delivery vehicle for transporting drugs like Carmustine (CMT), Lomustine (LOMU) and Nitrosourea (NU) in both gaseous and liquid states. The Sb nanosheet structure is stable, and its potential for drug adsorption has been investigated in both parallel and perpendicular directions. The parallel configuration is most stable with a higher adsorption energy of −1.18 eV, −0.63 eV and −1.14 eV for LOMU, CMT and NU respectively. We investigated structural parameters, electronic properties, work function and chemical reactivity. Only NU alters the Sb’s semiconductor behaviour to metallic and has the shortest recovery time in the parallel direction. Hirshfield charge analysis revealed that nanosheet displays electron accepting properties, whereas drugs act as electron donors. The decreased work function for CMT and LOMU enhances substrate activity, indicating stronger interactions that may improve drug delivery. We confirmed the drug’s effective interaction with amino acids without impairing proteins. Furthermore, calculated results predicted a minimal acidic environment of malignant growth, CM, NU and LOMU drugs could start to release from the Sb surface without significantly altering the structural properties. This study illustrates how Sb nanosheet holds promise as an effective carrier for drug delivery in biomedical applications.

Preparation and characterization of ovomucin self-assembly nanoparticles under glycerol compression for astaxanthin delivery: Sustained release and antioxidant activity.

Astaxanthin (AST) is a natural hydrophobic nutrient with various biological activities, but its low solubility limits its application. In this study, self-assembly nanoparticles were prepared by ovomucin (OVM) and Ca2+ with the enhancement of glycerol to deliver AST. Glycerol compressed the particle size of nanoparticles from 175.7±1.8 to 142.9±0.6nm, and the nanoparticles had a strong negative charge (-28.9±0.6mV). Ultraviolet-visible spectroscopy and X-ray diffraction (XRD) confirmed the successful encapsulation of AST in an amorphous form with a high encapsulation efficiency (82.9%±2.1%). Fourier transform infrared and circular dichroism analyses demonstrated that nanoparticles formation mainly involved electrostatic interactions and hydrophobic interactions. AST in nanoparticles presented excellent gastric juice resistance and sustained release ability, whereas free radical scavenging efficiency reached up to 75%. In addition, the nanoparticles had no apparent toxicity to cell viability. This study is expected to provide a new insight into the safe and efficient delivery of AST, while demonstrating the potential of OVM as a delivery carrier in the food and health industries.

Enhanced neural activity detection with microelectrode arrays modified by drug-loaded calcium alginate/chitosan hydrogel

Microelectrode arrays (MEAs) are pivotal brain-machine interface devices that facilitate in situ and real-time detection of neurophysiological signals and neurotransmitter data within the brain. These capabilities are essential for understanding neural system functions, treating brain disorders, and developing advanced brain-machine interfaces. To enhance the performance of MEAs, this study developed a crosslinked hydrogel coating of calcium alginate (CA) and chitosan (CS) loaded with the anti-inflammatory drug dexamethasone sodium phosphate (DSP). By modifying the MEAs with this hydrogel and various conductive nanomaterials, including platinum nanoparticles (PtNPs) and poly (3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT: PSS), the electrical properties and biocompatibility of the electrodes were optimized. The hydrogel coating matches the mechanical properties of brain tissue more effectively and, by actively releasing anti-inflammatory drugs, significantly reduces post-implantation tissue inflammation, extends the electrodes' lifespan, and enhances the quality of neural activity detection. Additionally, this modification ensures high sensitivity and specificity in the detection of dopamine (DA), displaying high-quality dual-mode neural activity during in vivo testing and revealing significant functional differences between neuron types under various physiological states (anesthetized and awake). Overall, this study showcases the significant application value of bioactive hydrogels as excellent nanobiointerfaces and drug delivery carriers for long-term neural monitoring. This approach has the potential to enhance the functionality and acceptance of brain-machine interface devices in medical practice and has profound implications for future neuroscience research and the development of strategies for treating neurological diseases.

Chitosan/pre-gelatinized waxy corn starch composite edible orally disintegrating film for taurine delivery

In this study, chitosan/per-gelatinized waxy corn starch composite edible orally disintegrating films (ODFs) incorporated with taurine were prepared and the morphology, release behavior and storage stability of the ODFs were investigated. The XRD, ATR-FTIR and microscopic investigation results revealed that taurine could be uniformly dispersed in the film matrix. The optimal level of taurine addition was 1.0% (w/w). The incorporation of taurine improved the apparent morphology, mechanical properties and water holding capacity while slightly increased the film thickness, disintegration time and contact angle of the composite films. In addition, taurine exhibited a rapid release behavior in the films. The fitted results of the Ritger-Peppas model indicated that the release mechanism of taurine in the composite films was mainly Fickian diffusion with minor skeleton erosion. As a delivery carrier, the composite film had a positive effect on the preservation of taurine, increasing the retention of taurine by 8.34% ± 1.48% during storage. The study confirmed the feasibility for the development of taurine ODF carriers and provided a basis for the development of functional packaging materials.

Design and Development of Gastro-retentive Gel Forming System Comprising Curcumin Loaded Nanostructured Lipid Carrier for Stomach Specific Delivery

Design and Development of Gastro-retentive Gel Forming System Comprising Curcumin Loaded Nanostructured Lipid Carrier for Stomach Specific Delivery

Overcoming Biopotency Barriers: Advanced Oral Delivery Strategies for Enhancing the Efficacy of Bioactive Food Ingredients.

Bioactive food ingredients contribute to the promotion and maintenance of human health and wellbeing. However, these functional ingredients often exhibit low biopotency after food processing or gastrointestinal transit. Well-designed oral delivery systems can increase the ability of bioactive food ingredients to resist harsh environments inside and outside the human body, as well as allow for controlled or triggered release of bioactives to specific sites in the gastrointestinal tract or other tissues and organs. This review presents the characteristics of common bioactive food ingredients and then highlights the barriers to their biopotency. It also discusses various oral delivery strategies and carrier types that can be used to overcome these biopotency barriers, with a focus on recent advances in the field. Additionally, the advantages and disadvantages of different delivery strategies are highlighted. Finally, the current challenges facing the development of food-grade oral delivery systems are addressed, and areas where future research can lead to new advances and industrial applications of these systems are proposed.

Characterizing diffusion-controlled release of small-molecules using quantitative MRI in view of applications to orthopedic infection.

Calcium sulfate is an established carrier for localized drug delivery, but a means to non-invasively measure drug release, which would improve our understanding of localized delivery, remains an unmet need. We aim to quantitatively estimate the diffusion-controlled release of small molecules loaded into a calcium sulfate carrier through a gadobutrol-based contrast agent, which acts as a surrogate small molecule. A central cylindrical core made of calcium sulfate, either alone or within a metal scaffold, is loaded with contrast agents that release into agar. Multi-echo scans are acquired at multiple time points over 4weeks and processed into R2* and quantitative susceptibility mapping (QSM) maps. Mean R2* values are fit to a known drug delivery model, which are then compared with the decrease in core QSM. Fitting R2* measurements of calcium sulfate core while constraining constants to a drug release model results in an R2-value of 0.991, yielding a diffusion constant of 4.59 × 10-11m2s-1. Incorporating the carrier within a metal scaffold results in a slower release. QSM shows the resulting loss of susceptibility in the non-metal core but is unreliable around metal. R2* characterizes the released gadobutrol, and QSM detects the resulting decrease in core susceptibility. The addition of a porous metal scaffold slows the release of gadobutrol, as expected.

Docetaxel-tethered di-Carboxylic Acid Derivatised Fullerenes: A Promising Drug Delivery Approach for Breast Cancer.

Docetaxel (DTX) has become widely accepted as a first-line treatment for metastatic breast cancer; however, the frequent development of resistance provides challenges in treating the disease.C60 fullerene introduces a unique molecular form of carbon, exhibiting attractive chemical and physical properties. Our study aimed to develop dicarboxylic acid-derivatized C60 fullerenes as a novel DTX delivery carrier. This study investigated the potential of water-soluble fullerenes to deliver the anti-cancer drug DTX through a hydrophilic linker. The synthesis was carried out using the Prato reaction. The spectroscopic analysis confirmed the successful conjugation of DTX molecules over fullerenes. The particle size of nanoconjugate was reported to be 122.13 ± 1.63nm with a conjugation efficiency of 76.7 ± 0.14%. The designed conjugate offers pH-dependent release with significantly less plasma pH, ensuring maximum release at the target site. In-vitro cell viability studies demonstrated the enhanced cytotoxic nature of the developed nanoconjugate compared to DTX. These synthesized nanoscaffolds were highly compatible with erythrocytes, indicating the safer intravenous route administration. Pharmacokinetic studies confirmed the higher bioavailability (~ 6 times) and decreased drug clearance from the system vis-à-vis plain drug. The histological studies reveal that nanoconjugate-treated tumour cells exhibit similar morphology to normal cells. Therefore, it was concluded that this developed formulation would be a valuable option for clinical use.

Targeted delivery of letrozole-loaded Mg-doped cobalt ferrite nanoparticles for breast cancer treatment

Breast cancer is the most common cancer in women globally. Letrozole is an aromatase inhibitor used as an anticancer drug. Conventional Letrozole therapies for breast cancer often cause adverse effects when administered orally or parenterally. Efforts have been made to develop an advanced drug delivery system for breast cancer treatment, aiming to improve drug release accuracy and therapeutic efficacy while minimizing side effects. This study focuses on magnesium-doped cobalt ferrite nanoparticles (Mg-doped CFNPs) as potential drug delivery carrier for breast cancer treatment. Mg-doped CFNPs with the chemical formula Co1-xMgxFe2O4 (where x = 0.0, 0.05, 0.10, 0.15, 0.20 and 0.25) were synthesized with different concentrations of 5 %, 10 %, 15 %, 20 %, and 25 % by the sol gel method with a fine size of 30–70 nm and their characteristics such as surface morphology, structural properties, chemical composition, and charge were investigated using scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and zeta potential analysis respectively. After synthesis, the Mg-doped CFNPs were coated with Poly ethylene glycol (PEG) and encapsulated with Letrozole, which exhibited <10 % hemolytic activity across all concentrations, as well as minimal cytotoxic effects on non-cancerous cells (HEK-293) but exhibited significant toxicity towards breast cancer cell lines (MCF-7, MDA-MB-231).The best results were obtained at a concentration of 25 % in both the hemolytic assay and the MTT assay, which indicated that increasing the amount of magnesium in cobalt decreased the toxicity and increased the drug release efficiency of nanoparticles.

Lysosome Targeted Nanoparticle Aggregation Reverses Immunosuppressive Tumor Microenvironment for Cancer Immunotherapy.

Nanotechnology has proven its enormous application value in clinical practice. However, current research on nanomedicines mainly focuses on developing nanoparticles as delivery carriers to maximize the bioavailability of therapeutic agents, with little attention on exploring their potential to directly regulate physiological processes. In this study, inspired by the lysosomal swelling caused by excessive accumulation of undegraded substances, this work presents a lysosomal-targeting aggregated nanoparticle (LTANP) for cancer treatment. By rationally engineering surface composition, properties, and interparticle interactions, LTANP achieves efficient tumor accumulation and selective targeted aggregation in lysosomes of cancer cells, leading to unrelievable lysosomal swelling, and ultimately inducing lysosomal membrane permeabilization (LMP) of cancer cells. Further analysis shows that nanoparticle aggregation-mediated LMP can effectively trigger immunogenic cell death (ICD) by impairing autophagy-lysosome pathway, evoking robust antitumor immune responses and reversing tumor immunogenicity from "cold" to "hot" in a melanoma model. Additionally, LTANP can combine with clinically approved programmed death ligand-1 (PD-L1) antibodies to further unleash T cell-mediated antitumor immunity, significantly enhancing antitumor performance, inhibiting tumor recurrence and metastasis. This work demonstrates the potential of rationally engineered nanostructures in directly combating cancer and provides novel insights for the development of advanced nanoparticle-based cancer treatment.

Clathrin-Mediated Endocytosis of Multiple Nanoparticles Tends to Be Less Cooperative: A Computational Study.

The internalization of nanoparticles is of great significance for their biological applications. Clathrin-mediated endocytosis (CME) is one of the main endocytic pathways. However, there is still a lack of a fundamental understanding regarding the internalization of multiple nanoparticles via CME. Therefore, in this study, we conducted computational investigations to uncover detailed molecular mechanisms and kinetic pathways for differently shaped nanoparticles in the presence of clathrin. Particular focus is given to understanding the CME of multiple-nanoparticle systems. We found that unlike receptor-mediated endocytosis, multiple nanoparticles did not get cooperatively wrapped by the membrane but tended to undergo independent endocytosis in the presence of clathrin. To further investigate the endocytosis mechanism, we studied the effects of clathrins, nanoparticle shape, nanoparticle size, nanoparticle arrangement, and membrane surface tension. The self-assembly of clathrin prefers independent endocytosis for multiple nanoparticles. Besides, the cooperative behavior is weak with increasing nanoparticle-shape anisotropy. However, when the membrane tension is reduced, the endocytosis pathway for multiple nanoparticles is cooperative endocytosis. Moreover, we found that the self-assembly of clathrins reduces the critical size of nanoparticles to undergo cooperative wrapping by the cell membrane. Our results provide valuable insights into the molecular mechanisms of multiple nanoparticles through CME and offer useful guidance for the design of nanoparticles as drug/gene delivery carriers.

Combinatorial Synthesis of Alkyl Chain-Capped Poly(β-Amino Ester)s for Effective siRNA Delivery.

Poly (β-amino ester) (PBAE) is a class of biodegradable polymers containing ester bonds in their main chain, extensively investigated as cationic polymer carriers for siRNA. Most current PBAE carriers rely on termination with hydrophilic or charged amines. In this study, a polymer platform consisting of 168 PBAE polymers with hydrophobic alkyl chain terminals is constructed through sequential aza-Michael addition. A large number of effective carriers are identified through in vitro screening of the PBAE platform for siLuc delivery to HeLa-Luc cells. Specifically, PA8-C6 and PA8-C8 achieve remarkable gene knockdown efficacies of up to 80% with low cytotoxicity. Certain materials from the PA2 and PA5 series demonstrate potent siRNA delivery capabilities associated with elevated cytotoxicity. The pKa value of PBAE is predominantly determined by the hydrophilic amine side chains rather than the end-capping groups. A pKa range of ≈6.2-6.5 may contribute to the excellent delivery capability for PA8 series carriers. The co-formulation of PBAE carriers with helper lipids leads to the reduced size and surface charges of the polyplex NPs with siRNA, consequently decreasing the cytotoxicity and enhancing siRNA delivery efficacy. These findings hold significant implications for the development of novel degradable polymer carriers for siRNA delivery.

PH-driven fabrication of a caseinate-pectin polyelectrolyte complex as a promising carrier for lutein and zeaxanthin delivery: Microencapsulation, stability, and sustained release properties.

In this study, caseinate-pectin polyelectrolyte complexes and co-solutions were successfully fabricated at pH3.0 and 7.0, respectively, to encapsulate bioactive molecules. During the fabrication process, the effect of the sequence in which each component was added on lutein/zeaxanthin (Lut/Zx) complexation with sodium caseinate (NaCas) was investigated. The protective effect of the polyelectrolyte complex and co-solution for Lut/Zx in liquid formulations was compared with that of a binary system containing only caseinate and Lut/Zx. Compared with the binary system, the polyelectrolyte complex at pH3.0 further enhanced the chemical stability of Lut/Zx during storage, whereas the co-solution at pH7.0 did not exhibit this ability. Unexpectedly, NaCas-Lut/Zx-pectin (NC-L/Z-P) with a theoretically sandwich structure did not exhibit better protection than NaCas-pectin-Lut/Zx (NC-P-L/Z). Fluorescence quenching spectra revealed that the addition of NaCas to Lut/Zx and ultimately to pectin resulted in the formation of a sandwich structure, which was soon followed by structural rebalancing. Finally, freshly prepared NC-L/Z-P complexes were lyophilized to stabilize their sandwich structure, resulting in improved encapsulation and sustained-release properties compared with those of the dried NC-P-L/Z. These results suggest that protein-polysaccharide complexes, combined with timely dehydration, enhance the combination of Lut/Zx with caseinate, leading to heightened protective effects.

Study on preparation of “ping-pong” shaped chitosan oligosaccharide -based hollow mesoporous carbon as a carrier for efficient anthocyanin loading

Carriers for efficient loading and delivery of compounds are urgently needed. A multifunctional nanoplatform of ordered hollow mesoporous carbon (HMC) was developed to load anthocyanins (AN) efficiently. The morphology, specific surface area, binding mode, and biocompatibility of HMC were verified. HMCs were uniformly spherical with well-defined cavities and mesoporous shells, similar to a “ping-pong” ball shape, and this shape of HMC provided a more spatial location for the load of the AN. And the best loading result of AN was 33.39 % ± 3.00 %. Coarse-grained molecular dynamics (CGMD) simulations showed that HMC and AN may bind by electrostatic interaction and hydrogen bonding, the binding process indicated that HMC contributed to the loading of AN, and the cytotoxicity results showed no significant toxicity of the complex. The homogeneous morphology and good biocompatibility of HMC offer new probabilities for the high effectiveness of oral delivery of active substances.

Utilization of Polymers for the Development of Nanomaterials

AbstractThis study highlights the significance of polymers in the progress of nanoparticles across various areas. The molecules of polymers are highly regarded for their ability to adapt and self‐assemble, making them essential components in the creation of nanomaterials. The variety of polymers include natural polymers such as chitosan, synthetic polymers like polyethylene, and biodegradable polymers like poly(lactic‐co‐glycolic acid) (PLGA). These kinds of polymers possess distinct advantages such as high strength, environmental sustainability, and biocompatibility. Incorporation of nanoscale fillers into polymer matrices, which enhances the mechanical, thermal, and electrical properties of materials, is crucial for the development of nanocomposites. Illustration instances encompass carbon nanotube‐polymer composites and polymer clay hybrids, which find application in the construction, automotive, and aerospace sectors. Composites can employ many synthetic methods to generate nanostructures. Nanofibers have utility in tissue engineering, whereas polymer nanoparticles function as carriers for medical delivery. Also, polymers enhance nanomaterials by modifying their surfaces, a crucial factor for their application in membrane technology, catalysis, and sensing. A collaborative synergy between polymers and nanoparticles fosters a wide range of applications, showcasing the versatility and potential of polymers in altering the characteristics of nanomaterials. The resulting partnership continues to generate pioneering breakthroughs that address complex challenges and unveil unprecedented prospects in the domains of science, technology, and business.

Enhancing osteogenic differentiation of diabetic tendon stem/progenitor cells through hyperoxia: Unveiling ROS/HIF-1α signalling axis.

Diabetic calcific tendinopathy is the leading cause of chronic pain, mobility restriction, and tendon rupture in patients with diabetes. Tendon stem/progenitor cells (TSPCs) have been implicated in the development of diabetic calcified tendinopathy, but the molecular mechanisms remain unclear. This study found that diabetic tendons have a hyperoxic environment, characterized by increased oxygen delivery channels and carriers. In hyperoxic environment, TSPCs showed enhanced osteogenic differentiation and increased levels of reactive oxygen species (ROS). Additionally, hypoxia-inducible factor-1a (HIF-1a), a protein involved in regulating cellular responses to hyperoxia, was decreased in TSPCs by the ubiquitin-proteasome system. By intervening with antioxidant N-acetyl-L-cysteine (NAC) and overexpressing HIF-1a, we discovered that blocking the ROS/HIF-1a signalling axis significantly inhibited the osteogenic differentiation ability of TSPCs. Animal experiments further confirmed that hyperoxic environment could cause calcification in the Achilles tendon tissue of rats, while NAC intervention prevented calcification. These findings demonstrate that hyperoxia in diabetic tendons promotes osteogenic differentiation of TSPCs through the ROS/HIF-1a signalling axis. This study provides a new theoretical basis and research target for preventing and treating diabetic calcified tendinopathy.

Preparation, Swelling, and Drug Release Studies of Chitosan-based Hydrogels for Controlled Delivery of Buspirone Hydrochloride.

Buspirone is used for the management of depression and anxiety disorders. Due to its short half-life and low bioavailability, it requires multiple daily doses and is associated with some side effects. This study aimed to develop chitosan-based hydrogels as drug-controlled release carriers. The objective of this study is to prepare chitosan-based hydrogels as controlled release carriers in order to overcome the side effects of buspirone HCl and improve patients' compliance and their life quality. Polymer chitosan was polymerized with two monomers, acrylic acid and itaconic acid, to synthesize pH-sensitive hydrogel. The Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analysis were performed to confirm the structure formation and thermal stability. Water penetration capability and loading of the drug were performed by porosity and drug loading studies. The swelling and dissolution tests were performed to analyze the pH-sensitive nature of the developed hydrogels. FTIR, TGA, and DSC demonstrated that the chitosan-based hydrogels were successfully prepared. An increase in water penetration and drug loading into the hydrogel network was seen with the high incorporation of chitosan, acrylic acid, and itaconic acid. The swelling and dissolution studies revealed that prepared hydrogel offered the greatest swelling and drug release at a high pH of 7.4. The swelling and drug release from the hydrogel were affected by the concentrations of the incorporated contents. A controlled release of the drug was achieved by using chitosan-based hydrogel as a delivery carrier compared to commercial tablets of buspirone. The results showed that the developed chitosan-based hydrogel can be considered one of the most suitable drug carrier systems for the controlled delivery of buspirone.

Niosome as a drug delivery carrier for Sorafenib: Preparation, investigation of physicochemical properties, and in vitro effects on HepG2 cell line

Purpose: Sorafenib is known as one of the oral anti-cancer drugs used in liver cancer. However, its lipophilic nature can lead to side effects, variable pharmacokinetics, and poor absorption. The use of novel drug delivery systems, such as niosomes, may help address these issues and improve the effectiveness of sorafenib. Methods: Different niosomal formulations of sorafenib were prepared. The morphology, size analysis, and physical stability were investigated. The encapsulation efficiency percent of the selected formulations was measured using the dialysis method, and the release of sorafenib was checked for four hours using the Franz diffusion cell. The cytotoxicity and in vitro effect on the HepG2 cell line was investigated using the MTT assay and flow cytometry. Results: The mean volume diameter of Span 60/ Tween 60/ cholesterol (45/45/10 mole%) niosomal formulation was 6 µm with minimal size changes and good stability over six months of storage. The encapsulation efficiency percent of this formulation was 66.40±1.11, and 61.43±1.42 percent of the drug was released within four h. In vitro release followed Higuchi kinetics. Cytotoxicity tests showed an IC50 of 7.5 µg/mL for the niosomal formulation, compared to 15.96 µg/mL for the sorafenib solution. Conclusion: Niosomes containing Span 60/ Tween 60/ cholesterol (45/45/10 mole%) are promising for loading and sustained release of sorafenib. The use of niosome as a carrier can enhance the effectiveness of sorafenib on the HepG2 cell line. This niosomal formulation of sorafenib shows potential for future studies.

Development of Nanostructured Lipid Carriers for Donepezil Hydrochloride Effective Nose to Brain Delivery

ABSTRACT: This study focuses on the development and evaluation of nanostructured lipid carriers (NLCs) for the efficient intranasal delivery of donepezil hydrochloride. The NLCs were prepared using the microemulsion technique. Each excipient used in the formulation was thoroughly evaluated for stability, assessing factors such as color change, phase separation, precipitation, and texture. Characterization of the NLCs included the construction of a pure calibration curve, differential scanning calorimetry (DSC), infrared spectroscopy (IR), and the IR analysis of physical mixtures. The donepezil hydrochloride-loaded NLCs were then incorporated into a thermosensitive gel using Pluronic F127, which was also prepared using the microemulsion technique. The NLCs were further characterized by evaluating their zeta potential, entrapment efficiency, and particle size. The thermosensitive gel's properties were assessed by measuring the gelation temperature and viscosity. Drug release studies were conducted using a dialysis membrane to compare the release profiles of the pure drug, donepezil-HCl-loaded NLCs, and the NLC-loaded thermosensitive gel, focusing on their potential for controlled drug release.

Nanoemulsion-based transdermal delivery of third-generation steroidal and non-steroidal aromatase inhibitors in preclinical models.

Aromatase inhibitors are effective in treating hormone receptor-positive breast cancer, particularly in postmenopausal women. However, the challenges of inconsistent dissolution, variable absorption and side effects with oral administration persist. To address these issues, transdermal delivery has emerged as a viable alternative. In our study, we have developed nanoemulsion-based transdermal creams containing third-generation aromatase inhibitors Exemestane (EXE) or Letrozole (LE) and evaluated their toxicity, anti-tumour effects and androgenic potency using preclinical models including Bama minipigs, DMBA-induced breast cancer rats and orchidectomized male rats. The results of our study are significant, suggesting that both creams effectively penetrated the skin, demonstrating an impressive anti-breast cancer effect. Importantly, EXE cream had no organ toxicity at the tested dose, providing a reassuring safety profile for its use. In contrast, LE cream displayed reversible toxicity from drug molecule itself in animals at the given dose, dissipating after 3 weeks of withdrawal and recovery. This study establishes a solid foundation for the safe clinical use of third-generation aromatase inhibitors. It highlights transdermal creams as a promising drug delivery carrier for administering them.