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Abstract Background Despite the highly expected clinical application of nanoparticles (NPs), the translation of NPs from lab to the clinic has been relatively slow. Co-culture 3D spheroids account for the 3D arrangement of tumor cells and stromal components, e.g., cancer-associated fibroblasts (CAFs) and extracellular matrix, recapitulating microenvironment of head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated how the stroma-rich tumor microenvironment affects the uptake, penetration, and photodynamic efficiency of three lipid-based nanoformulations of approved in EU photosensitizer temoporfin (mTHPC): Foslip® (mTHPC in conventional liposomes), drug-in-cyclodextrin-in-liposomes (mTHPC-DCL) and extracellular vesicles (mTHPC-EVs). Results Collagen expression in co-culture stroma-rich 3D HNSCC spheroids correlates with the amount of CAFs (MeWo cells) in individual spheroid. The assessment of mTHPC loading demonstrated that Foslip®, mTHPC-DCL and mTHPC-EVs encapsulated 0.05 × 10− 15 g, 0.07 × 10− 15 g, and 1.3 × 10− 15 g of mTHPC per nanovesicle, respectively. The mid-penetration depth of mTHPC NPs in spheroids was 47.8 µm (Foslip®), 87.8 µm (mTHPC-DCL), and 49.7 µm (mTHPC-EVs), irrespective of the percentage of stromal components. The cellular uptake of Foslip® and mTHPC-DCL was significantly higher in stroma-rich co-culture spheroids and was increasing upon the addition of serum in the culture medium. Importantly, we observed no significant difference between PDT effect in monoculture and co-culture spheroids treated with lipid-based NPs. Overall, in all types of spheroids mTHPC-EVs demonstrated outstanding total cellular uptake and PDT efficiency comparable to other NPs. Conclusions The stromal microenvironment strongly affects the uptake of NPs, while the penetration and PDT efficacy are less sensitive to the presence of stromal components. mTHPC-EVs outperform other lipid nanovesicles due to the extremely high loading capacity. The results of the present study enlarge our understanding of how stroma components affect the delivery of NPs into the tumors.

Background: Despite the highly expected clinical application of nanoparticles (NPs), the translation of NPs from lab to the clinic has been relatively slow. Co-culture 3D spheroids account for the 3D arrangement of tumor cells and stromal components, e.g., cancer-associated fibroblasts (CAFs) and extracellular matrix, recapitulating microenvironment of head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated how the stroma-rich tumor microenvironment affects the uptake, penetration, and photodynamic efficiency of three lipid-based nanoformulations of approved in EU photosensitizer temoporfin (mTHPC): Foslip® (mTHPC in conventional liposomes), drug-in-cyclodextrin-in-liposomes (mTHPC-DCL) and extracellular vesicles (mTHPC-EVs). Results: Collagen expression in co-culture stroma-rich 3D HNSCC spheroids correlates with the amount of CAFs (MeWo cells) in individual spheroid. The assessment of mTHPC loading demonstrated that Foslip®, mTHPC-DCL and mTHPC-EVs encapsulated 0.05 × 10− 15 g, 0.07 × 10− 15 g, and 1.3 × 10− 15 g of mTHPC per nanovesicle, respectively. The mid-penetration depth of mTHPC NPs in spheroids was 47.8 µm (Foslip®), 87.8 µm (mTHPC-DCL), and 49.7 µm (mTHPC-EVs), irrespective of the percentage of stromal components. The cellular uptake of Foslip® and mTHPC-DCL was significantly higher in stroma-rich co-culture spheroids and was increasing upon the addition of serum in the culture medium. Importantly, we observed no significant difference between PDT effect in monoculture and co-culture spheroids treated with lipid-based NPs. Overall, in all types of spheroids mTHPC-EVs demonstrated outstanding total cellular uptake and PDT efficiency comparable to other NPs. Conclusions: The stromal microenvironment strongly affects the uptake of NPs, while the penetration and PDT efficacy are less sensitive to the presence of stromal components. mTHPC-EVs outperform other lipid nanovesicles due to the extremely high loading capacity. The results of the present study enlarge our understanding of how stroma components affect the delivery of NPs into the tumors. [ABSTRACT FROM AUTHOR]

Eucalyptol (Euc) is a natural monoterpene with insecticide effects. Being highly volatile and sensitive to ambient conditions, its encapsulation would enlarge its application. Euc‐loaded conventional liposomes (CL), cyclodextrin/drug inclusion complex, and drug‐in‐cyclodextrin‐in‐liposomes (DCL) are prepared to protect Euc from degradation, reduce its evaporation, and provide its controlled release. The liposomal suspension is freeze‐dried using hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) as cryoprotectant. The liposomes are characterized before and after freeze‐drying. The effect of Euc on the fluidity of liposomal membrane is also examined. A release study of Euc from delivery systems, in powder and reconstituted forms, is performed by multiple head extraction at 60 °C after 6 months of storage at 4 °C. CL and DCL suspensions are homogeneous, show nanometric vesicles size, spherical shape, and negative surface charge before and after freeze‐drying. Moreover, HP‐β‐CD does not affect the fluidity of liposomes. CL formulations present a weak encapsulation for Euc. The loading capacity of eucalyptol in DCL is 38 times higher than that in CL formulation. In addition, freeze‐dried DCL and HP‐β‐CD/Euc inclusion complex show a higher retention of eucalyptol than CL delivery system. Both carrier systems HP‐β‐CD/Euc and Euc‐loaded DCL decrease Euc evaporation and improve its retention. Practical Applications: Eucalyptol is a natural insecticide. It is highly volatile and poorly soluble in water. To enlarge its application, its encapsulation in three delivery systems (conventional liposomes, cyclodextrin/drug inclusion complex, combined system composed of cyclodextrin inclusion complex and liposome) is studied. In this paper it is proved that cyclodextrin/eucalyptol inclusion complex and eucalyptol‐in‐cyclodextrin‐in‐liposome are effective delivery systems for encalyptol encapsulation, retention, and release. [ABSTRACT FROM AUTHOR]

The essential oil component α-pinene has multiple biological activities. However, its application is limited owing to its volatility, low aqueous solubility, and chemical instability. For the aim of improving its physicochemical properties, α-pinene was encapsulated in conventional liposomes (CLs) and drug-in-cyclodextrin-in-liposomes (DCLs). Hydroxypropyl-β-cyclodextrin/α-pinene (HP-β-CD/α-pinene) inclusion complexes were prepared in aqueous solution, and the optimal solubilization of α-pinene occurred at HP-β-CD:α-pinene molar ratio of 7.5:1. The ethanol-injection method was applied to produce different formulations using saturated (Phospholipon 90H) or unsaturated (Lipoid S100) phospholipids in combination with cholesterol. The size, the phospholipid and cholesterol incorporation rates, the encapsulation efficiency (EE), and the loading rate (LR) of α-pinene were determined, and the storage stability of liposomes was assessed. The results showed that α-pinene was efficiently entrapped in CLs and DCLs with high EE values. Moreover, Lipoid S100 CLs displayed the highest LR (22.9 ± 2.2%) of α-pinene compared to the other formulations. Both carrier systems HP-β-CD/α-pinene inclusion complex and Lipoid S100 CLs presented a gradual release of α-pinene. Furthermore, the DPPH radical scavenging activity of α-pinene was maintained upon encapsulation in Lipoid S100 CLs. Finally, it was found that all formulations were stable after three months of storage at 4 °C.

[Display omitted] • β-cyclodextrin/vitamin D 3 inclusion complex was loaded in nanoliposomes (NLPs). • The NLPs were coated with gelatin by electrostatic interactions. • The coating of the nanoliposomes enhanced their thermal stability. • The NLPs showed a controlled release profile in gastrointestinal condition. • The core–shell structure of NLPs was approved by morphology study. The aim of this study was to synthesize of β-cyclodextrin/Vitamin D 3 (βCD/VitD 3) inclusion complex and encapsulation of this complex with gelatin-coated nanoliposomes (NLPs). Fourier transform infrared spectroscopy confirmed the formation of βCD/VitD 3 inclusion complex. In the next step, different gelatin concentrations (1, 2, and 4 mg/mL) were used to surface coat the blank NLPs. The concentration of 2 mg/mL of gelatin was chosen as the optimal concentration for coating the complex-loaded NLPs by considering particle size, morphology, and zeta potential. The particle size and zeta potential of the coated complex-loaded NLPs were 117 ± 2.55 nm and 19.8 ± 1.25 mV, respectively. The images taken by transmission electron microscopy confirmed the formation of a biopolymer layer of gelatin around the NLPs' vesicles. The complex encapsulation efficiency inside the NLPs was 81.09%. The βCD/VitD 3 complex loaded NLPs and its coated form exhibited a controlled release profile in simulated gastrointestinal condition. [ABSTRACT FROM AUTHOR]

The low solubility, poor bioavailability, and low chemical stability of quercetin (Quer) are the main drawbacks that limit its use as a food nutraceutical. In this study, the encapsulation in cyclodextrins (CDs), conventional liposomes (CLs), and drug-in-cyclodextrin-in-liposomes (DCLs) was conducted in order to improve the physicochemical properties of Quer. Phase solubility studies revealed an enhancement of Quer solubility upon complexation with various CDs. CLs composed of three different types of phospholipids (unsaturated egg Lipoid E80, unsaturated soybean Lipoid S100, and saturated soybean Phospholipon 90H) as well as DCLs were prepared by ethanol injection method and characterized. Liposomes constituted of Lipoid E80 showed small diameter, narrow size distribution, and higher encapsulation efficiency of Quer compared to the two other CLs. The photostability of Quer-loaded liposomes was also evaluated. Results show that Lipoid E80-liposomes allow a better protection of Quer against UV irradiation than those prepared using other lipids. This effect could be explained by their different membrane rigidity as determined by Atomic Force Microscopy (AFM). Moreover, the photostability of Quer was additionally improved when encapsulated in DCLs (SBE-β-CD/Quer inclusion complex in Lipoid E80 liposomes), in comparison to CLs. The same trend was obtained regarding the Quer stability in simulated gastrointestinal fluids. Finally, all liposome formulations were physically stable after 1 year of storage at 4 °C. [ABSTRACT FROM AUTHOR]

Nerolidol, a naturally occurring sesquiterpene with antimicrobial activities, is a promising candidate as a natural alternative for synthetic preservatives in food. However, its application is limited by low aqueous solubility and stability. In this study, conventional liposomes and drug-in-cyclodextrin-in-liposomes (DCLs) were evaluated for the first time as encapsulating materials for nerolidol. The size, encapsulation efficiency (EE%), loading rate (LR%), photo- and storage stabilities of both systems were characterized. Moreover, the in vitro release of nerolidol from liposomes and DCLs was investigated over time. Nerolidol was efficiently entrapped in both carriers with high EE% and LR% values. In addition, DCLs prolonged the release of nerolidol over one week and enhanced the photostability more effectively than conventional liposomes. Finally, all formulations were stable after 12 months of storage at 4 °C (>60% incorporated nerolidol). Therefore, DCLs are promising carriers for new applications of sesquiterpenes in the pharmaceutical and food industries. [ABSTRACT FROM AUTHOR]

Cyclodextrins (CDs) are cyclic oligosaccharides, consisting of glucopyranose units, which are able to form host–guest inclusion complexes with lipophilic molecules. The ability of CD to increase drug solubility may be used to increase drug entrapment in the aqueous compartment of liposomes and liposomes can protect CD/drug inclusion complexes until drug release. Liposomes are phospholipid vesicles composed of lipid bilayers enclosing one or more aqueous compartments. They have been widely used as safe and effective carriers for both hydrophilic and lipophilic drugs. However, lipophilic drugs incorporated in the membrane bilayers can be rapidly released, which limits the effectiveness of this drug delivery system. The coupling of both delivery systems by encapsulating CD/drug inclusion complex into liposomes is proposed to circumvent the drawbacks of each separate system. Here, we review the literature regarding the encapsulation of CD/drug inclusion complex into conventional, deformable and double loaded liposomes. The review highlights the characteristics of these systems and presents the advantages and disadvantages of each one. [ABSTRACT FROM AUTHOR]

The essential oil component α-pinene has multiple biological activities. However, its application is limited owing to its volatility, low aqueous solubility, and chemical instability. For the aim of improving its physicochemical properties, α-pinene was encapsulated in conventional liposomes (CLs) and drug-in-cyclodextrin-in-liposomes (DCLs). Hydroxypropyl-β-cyclodextrin/α-pinene (HP-β-CD/α-pinene) inclusion complexes were prepared in aqueous solution, and the optimal solubilization of α-pinene occurred at HP-β-CD:α-pinene molar ratio of 7.5:1. The ethanol-injection method was applied to produce different formulations using saturated (Phospholipon 90H) or unsaturated (Lipoid S100) phospholipids in combination with cholesterol. The size, the phospholipid and cholesterol incorporation rates, the encapsulation efficiency (EE), and the loading rate (LR) of α-pinene were determined, and the storage stability of liposomes was assessed. The results showed that α-pinene was efficiently entrapped in CLs and DCLs with high EE values. Moreover, Lipoid S100 CLs displayed the highest LR (22.9 ± 2.2%) of α-pinene compared to the other formulations. Both carrier systems HP-β-CD/α-pinene inclusion complex and Lipoid S100 CLs presented a gradual release of α-pinene. Furthermore, the DPPH radical scavenging activity of α-pinene was maintained upon encapsulation in Lipoid S100 CLs. Finally, it was found that all formulations were stable after three months of storage at 4 °C. [ABSTRACT FROM AUTHOR]

The aim of the present study was the loading of β-cyclodextrin/vitamin E (βCD/VitE) inclusion complex in liposomes (LPs) and coating of this nanocarrier with sodium caseinate (SC). The formation of βCD/VitE inclusion complex was approved by Fourier transforms infrared (FT-IR) spectroscopy. Three concentrations of SC (2, 4, and 6 mg/mL) were used for the coating of LPs. By considering particle size, zeta potential, and morphology, the 6 mg/mL concentration of SC was selected as the optimum concentration. The zeta potential and particle size of the coated complex-loaded LPs were +17.90 ± 0.80 mV and 173.9 ± 42.4 nm, respectively. The transmission electron microscopy of the coated complex-loaded LPs showed a spherical and core-shell structure. Additionally, the encapsulation efficiency of VitE in the LPs as the form of βCD/VitE inclusion complex was 83.8 ± 3.7%. The formation of hydrogen-bonding interactions among complex, LPs, and SC was confirmed by FT-IR spectroscopy. The coating of LPs with SC significantly improved their thermal stability. Moreover, the coated LPs exhibited a better-sustained release profile than the uncoated LPs in the simulated gastrointestinal condition. In conclusion, the developed nanocarrier has promising advantages and potential applications in the nutraceutical and medical fields. [Display omitted] • The βCD/VitE inclusion complex was loaded in nanoliposomes (NLPs). • The βCD/VitE loaded NLPs were successfully coated with sodium caseinate (SC). • The coated NLPs showed improved thermal stability and nano particle size. • The optimized coated liposome sample showed spherical and core-shell structure. • Coating of liposomes with SC provided controlled release under in vitro condition. [ABSTRACT FROM AUTHOR]