Recent advanced lipid-based nanomedicines for overcoming cancer resistance.

The increasing prevalence of cancer drug resistance not only critically limits the efficiency of traditional therapies but also causes relapses or recurrences of cancer. Consequently, there remains an urgent need to address the intricate landscape of drug resistance beyond traditional cancer therapies. Recently, nanotechnology has played an important role in the field of various drug delivery systems for the treatment of cancer, especially therapy-resistant cancer. Among advanced nanomedicine technologies, lipid-based nanomaterials have emerged as effective drug carriers for cancer treatment, significantly improving therapeutic effects. Due to their biocompatibility, simplicity of preparation, and potential for functionalization, lipid-based nanomaterials are considered powerful competitors for resistant cancer. In this review, an overview of lipid-based nanomaterials for addressing cancer resistance is discussed. We summarize the recent progress in overcoming drug resistance in cancer by these lipid-based nanomaterials, and highlight their potential in future applications to reverse cancer resistance.

Polymethoxyflavones from Kaempferia parviflora ameliorate skin aging in primary human dermal fibroblasts and ex vivo human skin.

Skin aging is accompanied by an increase in the number of senescent cells, resulting in various pathological outcomes. These include inflammation, impaired barrier function, and susceptibility to skin disorders such as cancer. Kaempferia parviflora (Thai black ginger), a medicinal plant native to Thailand, has been shown to counteract inflammation, cancer, and senescence. This study demonstrates that polymethoxyflavones (5,7-dimethoxyflavone, 5,7,4'-trimethoxyflavone, and 3,5,7,3',4'-pentamethoxyflavone) purified from K. parviflora rhizomes suppressed cellular senescence, reactive oxygen species, and the senescence-associated secretory phenotype in primary human dermal fibroblasts. In addition, they increased tropocollagen synthesis and alleviated free radical-induced cellular and mitochondrial damage. Moreover, the compounds mitigated chronological aging in a human ex vivo skin model by attenuating senescence and restoring expression of essential components of the extracellular matrix, including collagen type I, fibrillin-1, and hyaluronic acid. Finally, we report that polymethoxyflavones enhanced epidermal thickness and epidermal-dermal stability, while blocking age-related inflammation in skin explants. Our findings support the use of polymethoxyflavones from K. parviflora as natural anti-aging agents, highlighting their potential as active ingredients in cosmeceutical and nutraceutical products.

Clove Oil-Nanostructured Lipid Carriers: A Platform of Herbal Anesthetics in Whiteleg Shrimp (Penaeus vannamei).

Whiteleg shrimp (Penaeus vannamei) have been vulnerable to the stress induced by different aquaculture operations such as capture, handling, and transportation. In this study, we developed a novel clove oil-nanostructured lipid carrier (CO-NLC) to enhance the water-soluble capability and improve its anesthetic potential in whiteleg shrimp. The physicochemical characteristics, stability, and drug release capacity were assessed in vitro. The anesthetic effect and biodistribution were fully investigated in the shrimp body as well as the acute multiple-dose toxicity study. The average particle size, polydispersity index, and zeta potential value of the CO-NLCs were 175 nm, 0.12, and -48.37 mV, respectively, with a spherical shape that was stable for up to 3 months of storage. The average encapsulation efficiency of the CO-NLCs was 88.55%. In addition, the CO-NLCs were able to release 20% of eugenol after 2 h, which was lower than the standard (STD)-CO. The CO-NLC at 50 ppm observed the lowest anesthesia (2.2 min), the fastest recovery time (3.3 min), and the most rapid clearance (30 min) in shrimp body biodistribution. The results suggest that the CO-NLC could be a potent alternative nanodelivery platform for increasing the anesthetic activity of clove oil in whiteleg shrimp (P. vannamei).

In silico and in vitro design of cordycepin encapsulation in liposomes for colon cancer treatment.

Cordycepin or 3'-deoxyadenosine is an interesting anti-cancer drug candidate that is found in abundance in the fungus Cordyceps militaris. It inhibits cellular growth of many cancers including lung carcinoma, melanoma, bladder cancer, and colon cancer by inducing apoptosis, anti-proliferation, anti-metastasis and by arresting the cell cycle. Cordycepin has, however, poor stability and low solubility in water, resulting in loss of its bioactivity. Liposomes can be used to overcome these obstacles. Our aim is to improve cordycepin's anti-colon cancer activity by liposome encapsulation. Cordycepin-encapsulated liposomes were designed and fabricated based on a combination of theoretical and experimental studies. Molecular dynamics (MD) simulations and free energy calculations suggest that phosphatidylcholine (PC) lipid environment is favorable for cordycepin adsorption. Cordycepin passively permeates into PC lipid bilayers without membrane damage and strongly binds to the lipids' polar groups by flipping its deoxyribose sugar toward the bilayer center. Our fabricated liposomes containing 10 : 1 molar ratio of egg yolk PC : cholesterol showed encapsulation efficiency (%EE) of 99% using microfluidic hydrodynamic focusing (MHF) methods. In our in vitro study using the HT-29 colon cancer cell line, cordycepin was able to inhibit growth by induction of apoptosis. Cell viability was significantly decreased below 50% at 125 µg mL-1 dosage after 48 h treatment with non-encapsulated and encapsulated cordycepin. Importantly, encapsulation provided (1) a 2-fold improvement in the inhibition of cancer cell growth at 125 µg mL-1 dosage and (2) 4-fold increase in release time. These in silico and in vitro studies indicate that cordycepin-encapsulated liposomes could be a potent drug candidate for colon cancer therapy.

Improvement of the multi-performance biocharacteristics of cordycepin using BiloNiosome-core/chitosan-shell hybrid nanocarriers.

Cordycepin, a derivative of the nucleotide adenosine, has displayed several pharmacological activities including enhanced apoptosis and cancer cells inhibition. However, oral administration of cordycepin has limited practical use due to its poor bioavailability in the intestine. Herein, we developed and demonstrated a hybrid nanocarrier system in the form of biloniosome-core/chitosan-shell hybrid nanocarriers (HNCs) in order to improve the bio-characteristics of cordycepin. In this study, HNCs were prepared by using a solvent (ethanol) injection method involving cordycepin as the biloniosome core and mucoadhesive chitosan biopolymer as a coating shell. Our results showed that the cordycepin-loaded HNCs were positively charged with enhanced mucoadhesive characteristics and highly stable in gastric fluid. The increased permeability of cordycepin-loaded HNCs compared with standard cordycepin was confirmed by in vitro intestinal permeation study across the human intestinal barrier. In addition, we demonstrated that the cordycepin-loaded HNCs are able to release their components in an active form resulting in enhanced anti-cancer activity in two-dimensional (2D) cell cultures as well as in three-dimensional (3D) multi-cellular spheroids of colon cancer cells. Further, quantitative real time PCR analysis of apoptotic gene expression revealed that cordycepin HNCs can induce apoptosis in cancer cells by negatively regulating the expression of B-cell lymphoma-extra large (BCL-XL). I Overall our results showed that the hybrid nanocarrier systems represent a promising strategy for improving the bio-characteristics of cordycepin which can be considered as a potential anti-cancer agent for colorectal cancer chemotherapy.

Active targeting liposome-PLGA composite for cisplatin delivery against cervical cancer.

Cisplatin (Cis) is a widely used chemotherapeutic drug for cancer treatment. However, toxicities and drug resistance limit the use of cisplatin. This study was aimed to improve cisplatin delivery using a targeting strategy to reduce the toxicity. In the present study, combinations of poly lactic-co-glycolic acids (PLGA) and liposomes were used as carriers for cisplatin delivery. In addition, to target the nanoparticle towards tumor cells, the liposome was conjugated with Avastin®, an anti-VEGF antibody. Cisplatin was loaded into PLGA using the double emulsion solvent evaporation method and further encapsulated in an Avastin® conjugated liposome (define herein as L-PLGA-Cis-Avastin®). Their physicochemical properties, including particle size, ζ-potential, encapsulation efficiency and drug release profiles were characterized. In addition, a study of the efficiency of tumor targeted drug delivery was conducted with cervical tumor bearing mice via intravenous injection. The therapeutic effect was examined in a 3D spheroid of SiHa cell line and SiHa cells bearing mice. The L-PLGA-Cis-Avastin® prompted a significant effect on cell viability and triggered cytotoxicity of SiHa cells. A cell internalization study confirmed that the L-PLGA-Cis-Avastin® had greater binding specificity to SiHa cells than those of L-PLGA-Cis or free drug, resulting in enhanced cellular uptake. Tumor targeting specificity was finally confirmed in xenograft tumors. Taken together, this nanoparticle could serve as a promising specific targeted drug for cervical cancer treatment.

Crinamine Induces Apoptosis and Inhibits Proliferation, Migration, and Angiogenesis in Cervical Cancer SiHa Cells.

Crinumasiaticum is a perennial herb widely distributed in many warmer regions, including Thailand, and is well-known for its medicinal and ornamental values. Crinum alkaloids contain numerous compounds, such as crinamine. Even though its mechanism of action is still unknown, crinamine was previously shown to possess anticancer activity. In this study, we demonstrate that crinamine was more cytotoxic to cervical cancer cells than normal cells. It also inhibited anchorage-independent tumor spheroid growth more effectively than existing chemotherapeutic drugs carboplatin and 5-fluorouracil or the CDK9 inhibitor FIT-039. Additionally, unlike cisplatin, crinamine induced apoptosis without promoting DNA double-strand breaks. It suppressed cervical cancer cell migration by inhibiting the expression of positive regulators of epithelial-mesenchymal transition SNAI1 and VIM. Importantly, crinamine also exerted anti-angiogenic activities by inhibiting secretion of VEGF-A protein in cervical cancer cells and blood vessel development in zebrafish embryos. Gene expression analysis revealed that its mechanism of action might be attributed, in part, to downregulation of cancer-related genes, such as AKT1, BCL2L1, CCND1, CDK4, PLK1, and RHOA. Our findings provide a first insight into crinamine's anticancer activity, highlighting its potential use as an alternative bioactive compound for cervical cancer chemoprevention and therapy.

Gonadotropin-releasing hormone-modified chitosan as a safe and efficient gene delivery vector for spermatogonia cells.

The use of male gonadal tissue as a site for the local delivery of DNA is an interesting concept. Previously, we reported synthesis, physiochemical and biological properties of gonadotropin-releasing hormone (GnRH)-conjugated chitosan as a carrier for DNA delivery to GnRH receptor-overexpressing cells. In this study, the application of modified chitosan as a potential vector for gene delivery to testicular cells was carried out. Transfection efficiency was investigated in mouse-derived spermatogonia cells (GC-1 cells) using green fluorescent protein as a reporter gene. GnRH-conjugated chitosan exhibited higher transfection activity and specificity compared to the unmodified chitosan. Furthermore, the GnRH-modified chitosan showed less cytotoxicity. In conclusion, we have developed and successfully tested the GnRH-modified chitosan for delivery of a transgene of interest to spermatogonia cells in vitro. Such vector could be useful in particular for testis-mediated gene transfer.

Chitosan-based DNA delivery vector targeted to gonadotropin-releasing hormone (GnRH) receptor.

The main purpose of this study was to investigate the application of modified chitosan as a potential vector for gene delivery to gonadotropin-releasing hormone receptor (GnRHR)-expressing cells. Such design of gene carrier could be useful in particular for gene therapy for cancers related to the reproductive system, gene disorders of sexual development, and contraception and fertility control. In this study, a decapeptide GnRH was successfully conjugated to chitosan (CS) as confirmed by proton nuclear magnetic resonance spectroscopy (1H NMR) and Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). The synthesized GnRH-conjugated chitosan (GnRH-CS) was able to condense DNA to form positively charged nanoparticles and specifically deliver plasmid DNA to targeted cells in both two-dimensional (2D) and three-dimensional (3D) cell cultures systems. Importantly, GnRH-CS exhibited higher transfection activity compared to unmodified CS. In conclusion, GnRH-conjugated chitosan can be a promising carrier for targeted DNA delivery to GnRHR-expressing cells.

Margination propensity of vascular-targeted spheres from blood flow in a microfluidic model of human microvessels.

Many variants of vascular-targeted carriers (VTCs) have been investigated for therapeutic intervention in several human diseases. However, in order to optimize the functionality of VTC in vivo, carriers' physical properties, such as size and shape, are important considerations for a VTC design that evades the reticuloendothelial system (RES) and successfully interacts with the targeted vessel wall. Nonetheless, little evidence has been presented on the role of size in VTC's interactions with the vascular wall, particularly in the microcirculation. Thus, in this work, we explore how particle size, along with hemodynamics (blood shear rate and vessel size) and hemorheology (blood hematocrit) affect the capacity for spheres to marginate (localize and adhere) to inflamed endothelium in a microfluidic model of human microvessels. Microspheres, particularly the 2 µm spheres, were found to show disproportionately higher margination than nanospheres in all hemodynamic conditions evaluated due to the poor ability of the latter to localize to the wall region from midstream. This work represents the first evidence that nanospheres may not exhibit "near wall excess" in microvessels, e.g., arterioles and venules, and therefore may not be suitable for imaging and drug delivery applications in cancer and other diseases affecting microvessels.

Targeting therapeutics to the vascular wall in atherosclerosis--carrier size matters.

OBJECTIVE: Vascular-targeted imaging and drug delivery systems are promising for the treatment of atherosclerosis due to the vast involvement of endothelium in the initiation and growth of plaque. Herein, we investigated the role of particle size in dictating the ability of vascular-targeted spherical particles to interact with the vascular wall (VW) from pulsatile and recirculating human blood flow relevant in atherosclerosis. METHODS: In vitro parallel plate flow chambers (PPFC) with straight or vertical step channel were used to examine the localization and binding efficiency of inflammation-targeted polymeric spheres sized from 0.2 to 5 µm to inflamed endothelium from disturbed reconstituted and whole blood flow. Apolipoprotein deficient mice were used to study particle localization and binding to plaque in vivo. RESULTS: The efficiency of particle binding in disturbed reconstituted blood flow increases as spherical diameter increases from 500 nm to 5 µm. No significant difference was observed between adhesion of 200 nm and 500 nm spheres. Binding efficiency for all particle size was enhanced in disturbed whole blood flow except adhesion of 5 µm in pulsatile whole blood. The adhesion trend in the in vivo model confirmed the binding pattern observed in in vitro assays. CONCLUSIONS: The presented data shows that the binding efficiency of vascular-targeted drug carriers in blood flow is a function of particle size, wall shear rate, flow type, blood composition and ligand characteristics. Overall, the presented results suggest that micron-sized spherical particles (2 µm), not nanospheres, are optimal for vascular-targeted drug delivery applications in medium to large vessel relevant in atherosclerosis.