Compritol-Based Alprazolam Solid Lipid Nanoparticles for Sustained Release of Alprazolam: Preparation by Hot Melt Encapsulation.

The current study was designed to investigate the feasibility of incorporating the water-insoluble lipophilic drug Alprazolam (Alp) into solid lipid nanoparticles (SLNs) to offer the combined benefits of the quick onset of action along with the sustained release of the drug. Therefore, compritol-based alprazolam-loaded SLNs (Alp-SLNs) would provide early relief from anxiety and sleep disturbances and long-lasting control of symptoms in patients with depression, thereby enhancing patient compliance. The optimized Alp-SLNs analyzed by DLS and SEM showed consistent particle size of 92.9 nm with PI values and standard deviation of the measurements calculated at <0.3 and negative surface charge. These characteristic values demonstrate the desired level of homogeneity and good physical stability of Alp-SLNs. The SLNs had a good entrapment efficiency (89.4%) and high drug-loading capacity (77.9%). SEM analysis revealed the smooth spherical morphology of the SLNs. The physical condition of alprazolam and absence of interaction among formulation components in Alp-SLNs was confirmed by FTIR and DSC analyses. XRD analysis demonstrated the molecular dispersion of crystalline alprazolam in Alp-SLNs. The in vitro release study implied that the release of Alp from the optimized Alp-SLN formulation was sustained as compared to the Alp drug solution because Alp-SLNs exhibited sustained release of alprazolam over 24 h. Alp-SLNs are a promising candidate to achieve sustained release of the short-acting drug Alp, thereby reducing its dosing frequency and enhancing patient compliance.

Folate targeted lipid chitosan hybrid nanoparticles for enhanced anti-tumor efficacy.

Folic acid is often used for active targeting of tumor cells to enhance therapeutic outcomes. Here, folic acid was conjugated with chitosan and folate-conjugated chitosan-lipid hybrid nanoparticles were prepared by ionic gelation method using anionic lipid. These nanoparticles were in size range of 200 to 400 nm with spherical shape. In vitro drug release data suggested a sustained release of cisplatin. The therapeutic efficacy of the folate-conjugated hybrid nanoparticles was evaluated in SK-OV-3, A2780 and MCF-7 cancer cell lines. A significant increase in cytotoxicity was observed with folate targeted LPHNPs compared to non-targeted LPHNPs. Significantly enhanced cellular uptake and cell cycle arrest resulting from folate-targeted nanoparticles were confirmed using fluorescence microscopy and flow cytometry. The therapeutic efficacy and tumor penetration were further evaluated in 3D spheroid tumor models. These studies suggest that folate-conjugated lipid-chitosan nanoparticles could enhance therapeutic activity and may represent a promising platform for active targeting of tumor cells.

Mechanistic Approaches of Internalization, Subcellular Trafficking, and Cytotoxicity of Nanoparticles for Targeting the Small Intestine.

Targeting the small intestine employing nanotechnology has proved to be a more effective way for site-specific drug delivery. The drug targeting to the small intestine can be achieved via nanoparticles for its optimum bioavailability within the systemic circulation. The small intestine is a remarkable candidate for localized drug delivery. The intestine has its unique properties. It has a less harsh environment than the stomach, provides comparatively more retention time, and possesses a greater surface area than other parts of the gastrointestinal tract. This review focuses on elaborating the intestinal barriers and approaches to overcome these barriers for internalizing nanoparticles and adopting different cellular trafficking pathways. We have discussed various factors that contribute to nanocarriers' cellular uptake, including their surface chemistry, surface morphology, and functionalization of nanoparticles. Furthermore, the fate of nanoparticles after their uptake at cellular and subcellular levels is also briefly explained. Finally, we have delineated the strategies that are adopted to determine the cytotoxicity of nanoparticles.

Folate decorated lipid chitosan hybrid nanoparticles of 5-fluorouracil for enhanced anticancer efficacy against colon cancer.

The study aimed to develop folate decorated lipid chitosan hybrid nanoparticles for targeted delivery of 5-fluorouracil in colon cancer by utilizing the overexpressed folate receptors on the surface of HT-29 and HCT 116 cancer cell lines. The developed formulations were prepared by the ionic gelation method with slight modifications. The developed formulations exhibited spherical morphology, smaller particle size (158 to 225 nm), zeta potential (32.24 to 35.95 mV), PDI (0.19 to 0.35), and high encapsulation efficiency (85.3 % to 94.2 %) with optimal physicochemical characteristics. The in vitro release showed a biphasic release pattern with an initial burst release followed by a sustained release for 48 h. Moreover, the in vitro cell line study revealed that FA-CLPN-2 exhibited an enhanced cellular uptake and greater cytotoxic effect in HT-29 and HCT 116 cell lines compared to non-targeted CLPN-2 and free drug solution due to the folate receptor facilitated endocytosis process. The in vivo toxicity study revealed the safety and biocompatibility of the developed formulations in biological systems. The stability study demonstrates the stability of the developed formulations. Overall, these results suggest that the folate decorated lipid chitosan hybrid nanoparticles could be used as a potential delivery system for tumor-targeted therapy with reduced side effects.

Investigation of Eutectic Mixtures of Fatty Acids as a Novel Construct for Temperature-Responsive Drug Delivery.

Background: Most of the traditional nanocarriers of cancer therapeutic moieties present dose-related toxicities due to the uptake of chemotherapeutic agents in normal body cells. The severe life-threatening effects of systemic chemotherapy are well documented. Doxorubicin, DOX is the most effective antineoplastic agent but with the least specific action that is responsible for severe cardiotoxicity and myelosuppression that necessitates careful monitoring while administering. Stimuli-sensitive/intelligent drug delivery systems, specifically those utilizing temperature as an external stimulus to activate the release of encapsulated drugs, have become a subject of recent research. Thus, it would be ideal to have a nanocarrier comprising safe excipients and controllable drug release capacity to deliver the drug at a particular site to minimize unwanted and toxic effects of chemotherapeutics. We have developed a simple temperature-responsive nanocarrier based on eutectic mixture of fatty acids. This study aimed to develop, physicochemically characterize and investigate the biological safety of eutectic mixture of fatty acids as a novel construct for temperature-responsive drug release potential. Methods: We have developed phase change material, PCM, based on a series of eutectic mixtures of fatty acids due to their unique and attractive physicochemical characteristics such as safety, stability, cost-effectiveness, and ease of availability. The reversible solid-liquid phase transition of PCM is responsible to hold firm or actively release the encapsulated drug. The eutectic mixtures of fatty acids (stearic acid and myristic acid) along with liquid lipid (oleic acid) were prepared to exhibit a tunable thermoresponsive platform. Doxorubicin-loaded lipid nanocarriers were successfully developed with combined hot melt encapsulation (HME) and sonication method and characterized to achieve enhanced permeability and retention (EPR) effect-based solid tumor targeting in response to exogenous temperature stimulus. The cytotoxicity against melanoma cell lines and in vivo safety studies in albino rats was also carried out. Results: Doxorubicin-loaded lipid nanocarriers have a narrow size distribution (94.59-219.3 nm), and a PDI (0.160-0.479) as demonstrated by photon correlation microscopy and excellent colloidal stability (Z.P value: -22.7 to -32.0) was developed. Transmission electron microscopy revealed their spherical morphology and characteristics of a monodispersed system. A biphasic drug release pattern with a triggered drug release at 41°C and 43°C and a sustained drug release was observed at 37°C. The thermoresponsive cytotoxic potential was demonstrated in B16F10 cancer cell lines. Hemolysis assay and acute toxicity studies with drug-free and doxorubicin lipid nanocarrier formulations provided evidence for their non-toxic nature. Conclusion: We have successfully developed a temperature-responsive tunable platform with excellent biocompatibility and intelligent drug release potential. The formulation components being from natural sources present superior characteristics in terms of cost, compatibility with normal body cells, and adaptability to preparation methods. The reported preparation method is adapted to avoid complex chemical processes and the use of organic solvents. The lipid nanocarriers with tunable thermoresponsive characteristics are promising biocompatible drug delivery systems for improved localized delivery of chemotherapeutic agents.

Glyceryl Monostearate based Solid Lipid Nanoparticles for Controlled Delivery of Docetaxel.

BACKGROUND: Solid lipid nanoparticles (SLNs) is the drug delivery system that has the capability to improve drug release at the desired tumor site. The aim of the present study is to develop glyceryl monostearate (GMS) based SLNs for the controlled delivery of docetaxel. METHODS: Hot melt encapsulation (HME) method was employed avoiding the use of organic solvents and, therefore, regarded as green synthesis of SLNs. RESULTS: Optimized DTX-SLNs showed desirable size (100 nm) with low poly dispersity index and excellent entrapment efficiency. Surface charge confirmed the stability of formulation. transmission electron microscope (TEM) analysis showed spherical shaped particles and fourier transform infrared microscopy (FTIR) revealed compatibility among formulation excipients. Differential scanning calorimeter (DSC) analysis revealed that the melting transition peak of optimized formulation was also greater than 40°C indicating that SLNs would be solid at body temperature. In-vitro release profile (68% in 24 hours) revealed the controlled release profile of DTX-SLNs, indicating lipophilic docetaxel drug was entrapped inside high melting point lipid core. Cytotoxicity study revealed that blank SLNs were found to be biocompatible while dose dependent cytotoxicity was shown by DTX-SLNs. CONCLUSION: These studies suggest that DTX-SLNs have the potential for controlled delivery of docetaxel and improved therapeutic outcome.