Correction: Neratinib-loaded solid lipid nanoparticles in dissolvable microneedles for enhanced transdermal breast cancer therapy.

Neratinib, an FDA-approved drug for breast cancer, faces challenges such as poor solubility, limited permeability, and adverse side effects. To address these issues, we developed dissolving microneedles incorporating Neratinib-loaded solid lipid nanoparticles (SLNs) to enhance transdermal delivery and minimize systemic toxicity. SLNs were formulated via hot homogenization using glyceryl monostearate as the lipid matrix and were evaluated for particle size, drug entrapment efficiency, drug loading, and stability. The optimized formulation (F7) exhibited a particle size of 209.4nm and 87.57% entrapment efficiency. SLNs were integrated into microneedles using a micro-molding technique. Characterization included IR spectroscopy, scanning electron microscopy, mechanical strength, and insertion ability. Ex vivo studies on porcine skin demonstrated 80.71 ± 1.43% cumulative drug release over 24h, confirming effective skin penetration. In vitro cytotoxicity on MCF-7 breast cancer cells showed greater efficacy of the SLN formulation over free Neratinib, with lower IC50 values (55.965 vs. 66.568µg/mL), indicating enhanced cellular uptake and sustained release. The findings support dissolvable microneedles loaded with Neratinib-SLNs as a promising transdermal approach for targeted breast cancer therapy, offering improved bioavailability, reduced side effects, and better patient compliance.

Estrogen replacement therapy (ERT) is very effective in relieving many menopausal symptoms such as hot flushes, night sweats, urogenital atrophy and psychological disturbances. Moreover, it is effective in the prevention of postmenopausal osteoporosis and has a favourable effect on some risk factors for cardiovascular disease in the long term, via several mechanisms including mediating effects on the lipid profile. Most of these beneficial effects are maintained with transdermal estradiol therapy, involving the use of a cutaneous delivery system attached to the skin which delivers a controlled rate of estradiol over a period of up to 4 days. However, the clear demonstration of a favourable effect on some risk factors for cardiovascular disease remains to be established. Transdermal administration of estradiol appears to be at least as effective as oral conjugated estrogen therapy on most of the end-points which have been evaluated, but allows a lower dose to be used, avoiding some of the metabolic adverse effects experienced with oral treatment. Endocrinological adverse effects, such as breast tenderness, breakthrough bleeding and fluid retention, are similar in both treatments, and can be minimised by dose adjustments in most cases. The most common adverse effects related to transdermal therapy are local skin reactions at the site of application. These are usually mild and transient in nature, and can be overcome by changing the site of application. Serious risks of transdermal therapy appear to be the same as those for other forms of ERT, namely an increased risk of endometrial hyperplasia and cancer with estrogen therapy alone. However, combination therapy involving the sequential administration of a progestogen has been shown to substantially reduce the risk of endometrial proliferation. The potential increased risk of breast cancer has been controversial and appears to be minimal with ERT. The role of progestogens on breast cancer risk remains controversial, but the data to date do not indicate any significant change in risk when progestogens are added to ERT.

Dissolving microneedles (DMNs) hold great popularity because of their precise drug delivery and administration portability. DMNs with different lengths could reach different depths of punctures that consequently resulted in different diffusive effects. Therefore, to clarify the effect of the length of the needles on in vivo fate of DMNs is of great significance. In this study, solid lipid nanoparticles (SLNs) were chosen as the model NC loaded in DMNs. To unambiguously determine the biological fate of the DMNs, P4 probe with aggregation caused quenching property was encapsulated in SLNs to enable the visualization of the process of the disintegration of SLNs. P4-encapsulated SLNs were loaded into DMNs with the lengths of 1200 μm, 800 μm, and 400 μm (named as DMN-1200, DMN-800, and DMN-400). By tracking the fluorescence signal distribution after skin piercing, the influence of the lengths of the needles on DMNs to the in vivo fate of the intact SLNs was explored. In the spatial dimension, intact NC loaded DMNs showed a length-dependent diffusion depth. In the temporal dimension, the diffusion rates of DMN-1200, DMN-800, and DMN-400 were similar within 24 h after insertion. It was inferred that DMNs with shorter needles would be ideal for the diseases on the superficial layer of the skin, while the ones with longer needles could be utilized in the treatment of diseases in deeper dermal and subcutaneous layers. The results of the study can act as a valuable guidance for future design and development of NC-loaded DMNs.

Recently, colloidal dispersions made of mixtures from solid and liquid lipids have been described to overcome the poor drug loading capacity of solid lipid nanoparticles (SLN). It has been proposed that these nanostructured lipid carriers (NLC) are composed of oily droplets, which are embedded in a solid lipid matrix. High loading capacities and controlled release characteristics have been claimed. It is the objective of the present paper to investigate these new NLC particles in more detail to obtain insights into their structure. Colloidal lipid dispersions were produced by high-pressure homogenization. Particle sizes were estimated by laser diffraction and photon correlation spectroscopy. The hydrophobic fluorescent marker nile red (NR) was used as model drug, and by fluorometric spectroscopy, the molecular environment (polarity) was elucidated because of solvatochromism of NR. The packaging of the lipid nanoparticles was investigated by Raman spectroscopy and by densimetry. The light propagation in lipid nanodispersions was examined by refractometry to obtain further insights into the nanostructural compositions of the carriers. Fluorometric spectroscopy clearly demonstrates that NLC nanoparticles offer two nanocompartments of different polarity to accommodate NR. Nevertheless, in both compartments, NR experiences less protection from the outer water phase than in a nanoemulsion. In conventional SLN, lipid crystallization leads to the expulsion of the lipophilic NR from the solid lipid. Measurements performed by densimetry and Raman spectroscopy confirm the idea of intact glyceryl behenate lattices in spite of oil loading. The lipid crystals are not disturbed in their structure as it could be suggested in case of oil incorporation. Refractometric data reveal the idea of light protection because of incorporation of sensitive drug molecules in NLC. Neither SLN nor NLC lipid nanoparticles did show any advantage with respect to incorporation rate compared to conventional nanoemulsions. The experimental data let us conclude that NLC lipid nanoparticles are not spherical solid lipid particles with embedded liquid droplets, but they are rather solid platelets with oil present between the solid platelet and the surfactant layer.

Development of solid dispersion lipid nanoparticles for improving skin delivery

High aggressiveness and recurrence of melanoma tumors require multiple systemic drug administrations, causing discomfort and severe side effects to the patients. Topical treatment strategies that provide repetitively controllable and precise drug administrations will greatly improve treatment effects.Methods: In this study, a spatiotemporally controlled pulsatile release system, which combined dissolving microneedles (DMNs) and thermal-sensitive solid lipid nanoparticles (SLNs), was constructed to realize multiple doses of dual-modal chemo-photothermal therapy in a single administration. Paclitaxel (PTX) and photothermal agent IR-780 were encapsulated into SLNs and were concentrated in the tips of DMNs (PTX/IR-780 SLNs @DMNs). Equipped with several needles, the DMN patch could be directly inserted into the tumor site and provide a stable “Zone accumulation” to constrain the PTX/IR-780 SLNs at the tumor site with uniform distribution.Results: In vitro experiments showed that after irradiation with near-infrared light, the PTX/IR-780 SLNs gradually underwent phase transition, thereby accelerating the release of PTX. When irradiation was switched off, the PTX/IR-780 SLNs cooled to re-solidify with limited drug release. Compared with intravenous and intratumoral injections, very few SLNs from PTX/IR-780 SLNs @DMNs were distributed into other organs, resulting in enhanced bioavailability at the tumor site and good safety. In vivo analysis revealed that PTX/IR-780 SLNs @DMNs exhibited significant anti-tumor efficacy. In particular, the primary tumor was completely eradicated with a curable rate of 100% in 30 days and the highest survival rate of 66.67% after 100 days of treatment.Conclusion: Herein, we developed a DMN system with a unique spatiotemporally controlled pulsatile release feature that provides a user-friendly and low-toxicity treatment route for patients who need long-term and repeat treatments.

In the study of triple-negative breast cancer (TNBC) therapeutic approaches, researchers have recently focused on exploiting P-glycoprotein (P-gp) and hypoxia-inducible factor (HIF) inhibitors to enhance the effectiveness of chemotherapeutic agents, which are often limited by poor specificity and high toxicity. Additionally, herbal medicines have shown promising results as non-toxic P-gp and HIF inhibitors. However, the co-administration of chemotherapeutic agents with natural P-gp inhibitors, such as curcumin (CUR) or HIF-inhibitors like 6-aminoflavon (AF), remains challenging due to pharmacokinetic constraints. In the present work, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are employed as drug delivery systems. CUR, AF, and a lipophilic doxorubicin (DOXO) ester (C12-DOXO) were individually loaded into both systems and subsequently used in combination. SLNs, both naked and hyaluronic acid (HA)-decorated, and NLCs were prepared and characterized. Given that NLCs have not yielded fully satisfactory results regarding drug entrapment and recovery, we have, for the time being, focused further characterization studies and cell line experiments exclusively on SLNs. SLNs were therefore tested on DOXO-sensitive and DOXO-resistant TNBC cell lines (MDA-MB-231 and MDA-MB-231/DX cells, respectively). HA-decorated SLNs showed effective C12-DOXO accumulation in P-gp-expressing cells, significantly reducing cell viability, including in DOXO-resistant cells. The combination of HA-decorated SLNs containing C12-DOXO (SLN-C12-DOXO-HA) with HA-decorated SLNs containing CUR (SLN-CUR-HA) or AF (SLN-AF-HA) demonstrated a significant reduction in cell viability across all concentrations, exceeding the cytotoxicity noted in the application of SLN-C12-DOXO-HA alone, especially at higher concentrations in both DOXO sensitive and resistant cell lines.

Recently, colloidal dispersions made of mixtures from solid and liquid lipids have been described to combine controlled-release characteristics with higher drug-loading capacities than solid lipid nanoparticles (SLNs). It has been proposed that these nanostructured lipid carriers (NLCs) are composed of oily droplets that are embedded in a solid lipid matrix. The present work investigates the structure and performance of NLCs. Colloidal lipid dispersions were produced by high-pressure homogenization and characterized by laser diffraction, photon correlation spectroscopy, wide-angle x-ray scattering, and differential scanning calorimetry. Proton nuclear magnetic resonance spectroscopy and electron spin resonance experiments were performed to investigate the mobility of the components and the molecular environment of model drugs. Furthermore, a nitroxide reduction assay with ascorbic acid was conducted to explore the accessibility of the lipid model drug from the outer aqueous phase. Proton nuclear magnetic resonance spectra clearly demonstrate that NLC nanoparticles differ from nanoemulsions and from SLNs by forming a liquid compartment that is in strong interaction to the solid lipid. The electron spin resonance model drug was found to be accommodated either on the particle surface with close water contact (SLN) or additionally in the oil (NLC). The oil compartment must be localized on the particle surface, because it can be easily reached by ascorbic acid. Neither SLN nor NLC lipid nanoparticles showed any advantage with respect to incorporation rate or retarded accessibility to the drug compared with conventional nanoemulsions. The experimental data let us conclude that NLCs are not spherical solid lipid particles with embedded liquid droplets, but they are rather solid platelets with oil present between the solid platelet and the surfactant layer.

Lipid nanoparticles (LNPs), composed of ionized lipids, helper lipids, and cholesterol, provide general therapeutic effects by facilitating intracellular transport and avoiding endosomal compartments. LNP-based drug delivery has great potential for the development of novel gene therapies and effective vaccines. Solid lipid nanoparticles (SLNs) are derived from physiologically acceptable lipid components and remain robust at body temperature, thereby providing high structural stability and biocompatibility. By enhancing drug delivery through blood vessels, SLNs have been used to improve the efficacy of cancer treatments. Breast cancer, the most common malignancy in women, has a declining mortality rate but remains incurable. Recently, as an anticancer drug delivery system, SLNs have been widely used in breast cancer, improving the therapeutic efficacy of drugs. In this review, we discuss the latest advances of SLNs for breast cancer treatment and their potential in clinical use.

In this study, the effect of particle size of genistein-loaded solid lipid particulate systems on drug dissolution behavior and oral bioavailability was investigated. Genistein-loaded solid lipid microparticles and nanoparticles were prepared with glyceryl palmitostearate. Except for the particle size, other properties of genistein-loaded solid lipid microparticles and nanoparticles such as particle composition and drug loading efficiency and amount were similarly controlled to mainly evaluate the effect of different particle sizes of the solid lipid particulate systems on drug dissolution behavior and oral bioavailability. The results showed that genistein-loaded solid lipid microparticles and nanoparticles exhibited a considerably increased drug dissolution rate compared to that of genistein bulk powder and suspension. The microparticles gradually released genistein as a function of time while the nanoparticles exhibited a biphasic drug release pattern, showing an initial burst drug release, followed by a sustained release. The oral bioavailability of genistein loaded in solid lipid microparticles and nanoparticles in rats was also significantly enhanced compared to that in bulk powders and the suspension. However, the bioavailability from the microparticles increased more than that from the nanoparticles mainly because the rapid drug dissolution rate and rapid absorption of genistein because of the large surface area of the genistein-solid lipid nanoparticles cleared the drug to a greater extent than the genistein-solid lipid microparticles did. Therefore, the findings of this study suggest that controlling the particle size of solid-lipid particulate systems at a micro-scale would be a promising strategy to increase the oral bioavailability of genistein.

Lipid nanoparticles (LNs) are colloidal particles having a biocompatible lipid matrix and nanoparticle (NP) sizes between 100 nm and 400 nm. They are called "nanosafe" carriers and show outstanding tolerability. Solid lipid nanoparticles use lipid as the skeleton material which has a high melting point. SLNs have the characteristics of high physical stability, relatively less drug leakage and good slow release, low toxicity and easy to mass production. The structure of the solid particle matrix allows solid lipid nanoparticles (SLNs) to be distinguished from nanostructured lipid carriers (NLCs). NLC is prepared by mixing liquid lipids and solid lipids. NLC improves the solubility of the active substance, improves the release ability of the substance, and also prolongs the storage life of the active substance in the carrier. Plenty of characteristics for skin application of pharmaceuticals and cosmetics are displayed by SLNs and NLC, such as drug targeting, regulated release of active ingredients, occlusion properties, and related enhancements to penetration and skin hydration. This review focuses on the characteristic of SLNs and NLCS, analyzing their advantages and disadvantages and lipid nanoparticles application in cosmetics are described in detail.

ABSTRACTIntroduction: Solid matrix mediated lipid nanoparticle formulations (LNFs) retain some of the best features of ideal drug carriers necessary for improving the oral absorption and bioavailability (BA) of both hydrophilic and hydrophobic drugs. LNFs with solid matrices may be typically categorized into three major types of formulations, viz., solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs) and lipid–drug conjugate nanoparticles (LDC-NPs). Solid matrix based LNFs are, potentially, the most appropriate delivery systems for poorly water soluble drugs in need of improved drug solubility, permeability, absorption, or increased oral BA. In addition, LNFs as matrices are able to encapsulate both hydrophobic and hydrophilic drugs in a single matrix based on their excellent ability to form cores and shells. Interestingly, LNFs also act as delivery devices to impart chemical stability to various orally administered drugs.Areas covered: Aim of the review is to forecast the presentation of pharmacokinetic characteristics of solid lipid matrix based nanocarriers which are typically biocompatible, biodegradable and non-toxic carrier systems for efficient oral delivery of various drugs. Efficient delivery is broadly mediated by the fact that lipophilic drugs are readily soluble in lipidic substrates that are capable of permeating across the gut epithelium following oral administration, subsequently delivering the moiety of interest more efficiently across the gut mucosal membrane. This enhances the overall BA of many drugs facing oral delivery challenges by improving their pharmacokinetic profile. This article specifically focuses on the biopharmaceutical and pharmacokinetic aspects of such solid lipid matrix based nanoformulations and possible mechanisms for better drug absorption and improved BA following oral administration. It also briefly reviews methods to access the efficacy of LNFs for improving oral BA of drugs, regulatory aspects and some interesting lipid-derived commercial formulations, with a concluding remark.Expert opinion: LNFs enhance the overall BA of many drugs facing oral delivery challenges by improving their pharmacokinetic profile.

This study focuses on the development and evaluation of solid lipid nanoparticles (SLNs) as an efficient carrier for the co-delivery of paclitaxel (PTX) and kaempferol (KMF) in breast cancer treatment. PTX, a BCS (Biopharmaceutics Classification System)-IV class drug, was combined with KMF, a flavonoid extracted and isolated from bee pollen, to enhance therapeutic efficacy. The optimal synergistic ratio of PTX and KMF was incorporated into SLNs using a hot homogenization technique, resulting in PTX-KMF-SLNs with a stable core-shell structure, narrow size distribution (166.1 ± 3.2 nm), and high encapsulation efficiency (86.15 ± 4.52%). In vitro studies demonstrated that PTX-KMF-SLNs exhibited five times greater cytotoxicity against breast cancer cells compared to the free drug combination while minimizing systemic toxicity. Preclinical evaluation further confirmed a significant reduction in tumor volume, highlighting the enhanced therapeutic potential of the nanoformulation. The antioxidant properties of KMF contributed to improved drug stability and targeted delivery, making PTX-KMF-SLNs a promising nanocarrier system for breast cancer therapy. The nanoformulation SLNs effectively reduced tumor volume in preclinical models, showing strong therapeutic potential. Future prospects include clinical translation, personalized therapy, application to other cancers, and development of targeted or stimuli-responsive delivery systems. This formulation represents a promising strategy for safe and effective breast cancer therapy.

In the present study gamma-oryzanol, an antioxidant, was incorporated into three different types of solid lipid: wax, triglycerides, a mixture of glycerides as solid lipid nanoparticles (SLN) and liquid lipid (Miglyol 812) as nanoemulsion (NE). Instability was found only from NE due to its significant increase in particle size and decreased entrapment efficiency (%EE) at a storage temperature of 45°C. Solid lipid type in SLN plays an important role only on %EE, but not chemical stability. A decrease in crystallinity of SLN was observed with the incorporation of gamma-oryzanol and low recrystallization index were found with two glycerides-based SLN. The in vitro release studies demonstrated that a biphasic release pattern fitted well with the Higuchi model of SLN formulations. In comparison, nearly constant release was observed in NE comprised of similar composition. Wax-based SLN demonstrated the lowest cytotoxicity. NE, wax-based SLN and a mixture of glycerides-based SLN were considered to enhance the antioxidant activity of gamma-oryzanol.

Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) were prepared as delivery system for water-insoluble anticancer agent, paclitaxel (PTX). The dispersion of SLNs was consisted of 5 % w/w tristearin, 3.75 % w/w egg phosphatidylcholine (egg PC) and 1 % w/w polysorbate 80 in water. NLCs were prepared using the same composition as SLNs except that 10 % of the solid lipid was replaced by triolein. PTX was incorporated into SLNs and NLCs to attain 0.025 % w/w in the dispersion. The particle size of the prepared SLNs and NLCs were 167.9 ± 21.3 and 121.9 ± 28.3 nm, respectively, and slightly increased to 239.1 ± 32.6 and 183.6 ± 36.2 nm by PTX incorporation. PTX incorporation also increased polydispersity index suggesting broader size distribution compared to that for empty particles. SLNs and NLCs showed sustained release of PTX in cell culture media containing 10 % fetal bovine serum at 37 °C compared to the commercial micellar formulation consisted of Cremophor EL and ethanol. PTX in SLNs and NLCs showed comparable cytotoxicity to the commercial formulation and free PTX against human breast cancer cell line, MCF-7. On the contrary, PTX in SLNs and NLCs showed higher anticancer activity against multidrug resistant (MDR) cancer cell line, MCF-7/ADR, compared to the free PTX delivered in DMSO, which indicates that both SLNs and NLCs would be effective carriers to avoid efflux pump expressed in MDR cancer cells. In conclusion, the SLNs and NLCs prepared in the present study showed similar characteristics each other and both can be used as effective delivery system for PTX.