CD44 and CD221 directed magnetic cubosomes for the targeted delivery of helenalin to rhabdomyosarcoma cells

Confining chemotherapy to tumour sites by means of active targeting nanoparticles(NPs)may increase the treatment effectuality while reducing potential side effects.Cubosomes are one of the next-generation drug delivery nanocarriers by virtue of their biocompatibility and bioadhesion,sizeable payload encapsulation and high thermostability.Herein,an active tumour targeting system towards rhabdomyosarcoma(RMS)cells was evaluated.Cubosomes were loaded with helenalin(a secondary metabolite from Arnica plants),which we have previously shown to induce apoptosis in RMS cells.The functionalization of the cubosomes was accomplished to enable binding to membrane receptors and translocation under a magnetic field.RMS cells overexpress CD44 and CD221 on their membrane surface and,therefore,hyaluronic acid(HA,a ligand for CD44)and antibodies(Abs)against CD221 were coupled to cubosomes via electrostatic attraction and the thiol-Michael reaction,respectively.Magnetization of the cubic phase NPs was achieved by embedding superparamagnetic iron oxide NPs(SPIONPs)into the cubic matrix.Single-function and multi-function cubosomes had Im3m cubic phase structures with well-organized lattice patterns.Conjugation with 2%HA or anti-CD221 half Abs and/or 1%SPIONPs showed significantly higher uptake into RMS cells compared to unfunctionalized cubosomes.CD44 and CD221 directed magnetic(triple-function)cubosomes were capable of internalizing into RMS cells in an energy-independent mechanism.Helenalin-laden triple functionalized cubosomes showed limited impact on the viability of control fibroblast cells,while they induced a high degree cytotoxicity against RMS cells.Profound tumour cell death was observed in both two-dimensional(2D)culture and three-dimensional(3D)tumour spheroids.

In vitro and in vivo evaluation of cubosomes containing 5-fluorouracil for liver targeting

The objective of this study was to prepare cubosomal nanoparticles containing a hydrophilic anticancer drug 5-fluorouracil(5-FU) for liver targeting. Cubosomal dispersions were prepared by disrupting a cubic gel phase of monoolein and water in the presence of Poloxamer 407 as a stabilizer.Cubosomes loaded with 5-FU were characterized in vitro and in vivo. In vitro, 5-FU-loaded cubosomes entrapped 31.21% drug and revealed nanometer-sized particles with a narrow particle size distribution. In vitro 5-FU release from cubosomes exhibited a phase of rapid release of about half of the entrapped drug during the first hour, followed by a relatively slower drug release as compared to 5-FU solution. In vivo biodistribution experiments indicated that the cubosomal formulation significantly(Po 0.05) increased5-FU liver concentration, a value approximately 5-fold greater than that observed with a 5-FU solution.However, serum serological results and histopathological findings revealed greater hepatocellular damage in rats treated with cubosomal formulation. These results demonstrate the successful development of cubosomal nanoparticles containing 5-FU for liver targeting. However, further studies are required to evaluate hepatotoxicity and in vivo antitumor activity of lower doses of 5-FU cubosomal formulation in treatment of liver cancer.

Recent advances in drug delivery applications of cubosomes,hexosomes,and solid lipid nanoparticles

The use of lipid nanocarriers for drug delivery applications is an active research area,and a great interest has particularly been shown in the past two decades.Among different lipid nanocarriers,ISAsomes(Internally self-assembled somes or particles),including cubosomes and hexosomes,and solid lipid nanoparticles(SLNs)have unique structural features,making them attractive as nanocarriers for drug delivery.In this contribution,we focus exclusively on recent advances in formation and characterization of ISAsomes,mainly cubosomes and hexosomes,and their use as versatile nanocarriers for different drug delivery applications.Additionally,the advantages of SLNs and their application in oral and pulmonary drug delivery are discussed with focus on the biological fates of these lipid nanocarriers in vivo.Despite the demonstrated advantages in in vitro and in vivo evaluations including preclinical studies,further investigations on improved understanding of the interactions of these nanoparticles with biological fuids and tissues of the target sites is necessary for effcient designing of drug nanocarriers and exploring potential clinical applications.

Cubosome nanoparticles for enhanced delivery of mitochondria anticancer drug elesclomol and therapeutic monitoring via sub-cellular NAD(P) H multi-photon fluorescence lifetime imaging

Elesclomol (ELC) is an anticancer drug inducing mitochondria cytotoxicity through reactive oxygen species.Here,for the first time,we encapsulate the poorly water soluble ELC in monoolein-based cubosomes stabilized with Pluronic F127.Cellular uptake and nanocarrier accumulation close to the mitochondria with sub-micrometer distance is identified via three-dimensional (3D) confocal microscopy and edge-to-edge compartment analysis.To monitor the therapeutic effect of the ELC nanocarrier,we apply for the first time,label-free time-lapse multi-photon fluorescence lifetime imaging microscopy (MP-FLIM) to track NAD(P)H cofactors with sub-cellular resolution on live cells exposed to an anticancer nanocarrier.Improved in vitro cytotoxicity is verified when loading the pre-complexed ELC with copper (ELC-Cu).Importantly,for equivalent copper concentration,cubosomes loaded with ELC-Cu show higher cytotoxicity compared to the free drug.The novel nanocarrier shows promising features for systemic ELC-Cu administration,and furthermore we establish the MP-FLIM technique for the assessment of anticancer drug delivery systems.

Tailoring active compounds across biological membranes by cubosomal technology: an updated review

It is challenging for many drugs to be transported across various biological membranes. Furthermore, development of many drugs gets thwarted owing to their hydrophilic nature. The bioavailability of such drugs, which is the function of their ability to cross the membrane, tends to be low and exhibit high intra and inter subject variability. At present, formulation scientists are pursuing many projects for transdermal, nasal, target delivery of many active compounds, and it is prudent to explore alternative possibilities. Cubosomes offer transportation and tailoring of active compounds intended for both systemic and dermal delivery. Cubosomes are dispersed, self-assembled nanoparticles of bicontinuous cubic liquid crystalline phase formed from lipid and surfactant systems. Monoolein, poloxamer 407 and polyvinyl alcohol are the mostly used ingredients in the formulation of cubosomes. The adjustment in lipid composition can control the internal and structural changes of cubosomes. Based on the nodal surfaces, three structures of cubosomes proposed are Pn3m, Ia3d and Im3m. Top-down and bottom-up techniques are widely considered in the formulation process of extreme viscous bulk phase and aggregate from a precursor respectively. This article gives a bird's eye view about the engineering, characterization and evaluation of cubosomes, covering researches and applications of cubosomes done till date.

Efficient Access to Inverse Bicontinuous Mesophases via Polymerization-Induced Cooperative Assembly

Polymerization-induced cooperative assembly(PICA)is reported to efficiently access inverse bicontinuous mesophases within particles consisting of amphiphilic block copolymers(BCPs)and solvophobic copolymers.Reversible addition-fragmentation chain transfer(RAFT)dispersion alternating copolymerization of styrene and pentafluorostyrene is conducted in 2%v/v toluene/ethanol by simultaneously using poly(N,N-dimethylacrylamide)(PDMA29)as a macromolecular chain transfer agent(macro-CTA)and small molecule CTA.