Molybdenum-Iodine Cluster Loaded Polymeric Nanoparticles Allowing a Coupled Therapeutic Action with Low Side Toxicity for Treatment of Ovarian Cancer

The ability of cancer cells to develop resistance to anti-cancer drugs, known as multidrug resistance, remains a major cause of tumor recurrence and cancer metastasis. This work explores the double mechanism of toxicity of (D, L-lactide-co-glycolide) acid (PLGA) nanoparticles encapsulating a molybdenum cluster compound, namely Cs₂[{Mo₆I₈}(OOCC₂F₅)₆] (CMIF). Hemocompatibility and biocompatibility assays show the safe potential of CMIF loaded nanoparticles (CNPs) as delivery systems intended for tumor targeting for PDT of ovarian cancer with a slight hemolytic activity and a lack of toxicity up to 50 µM CMIF concentration. Cellular uptake shows a preferential uptake of CNPs in lysosomes, which is not interfering with CMIF activity. The double mechanism of CNPs consists in a production of ROS and a DNA damage activity, from 5 µM and 0.5 µM respectively (CMIF concentration). The cellular death mechanism comprises 80% of necrosis and 20% of direct apoptosis by direct DNA damages. This work confirms CMIF loaded PLGA nanoparticles as an efficient and relevant delivery system for PDT     

Development and characterization of 5-FU bearing ferritin appended solid lipid nanoparticles for tumour targeting

Ferritin coupled solid lipid nanoparticles were investigated for tumour targeting. Solid lipid nanoparticles were prepared using HSPC, cholesterol, DSPE and triolien. The SLNs without ferritin which has similar lipid composition were used for comparison. SLNs preparations were characterized for shape, size and percentage entrapment. The average size of SLNs was found to be in the range 110–152 nm and maximum drug entrapment was found to be 34.6–39.1%. In vitro drug release from the formulations is obeying fickian release kinetics. Cellular uptake and IC₅₀ values of the formulation were determined in vitro in MDA-MB-468 breast cancer cells. In vitro cell binding of Fr-SLN exhibits 7.7-folds higher binding to MDA-MB-468 breast cancer cells in comparison to plain SLNs. Ex-vivo cytotoxicity assay on targeted nanoparticles gave IC₅₀ of 1.28 µM and non-targeted nanoparticles gave IC₅₀ of 3.56 µM. In therapeutic experiments, 5-FU, SLNs and Fr-SLNs were administered at the dose of 10 mg 5-FU/kg body weight to MDA-MB-468 tumour bearing Balb/c mice. Administration of Fr-SLNs formulation results in effective reduction in tumour growth as compared with free 5-FU and plain SLNs. The result demonstrates that this delivery system possessed an enhanced anti-tumour activity. The results warrant further evaluation of this delivery system.     

Formulation,characterization and evaluation of cyclodextrin-complexed bendamustine-encapsulated PLGA nanospheres for sustained delivery in cancer treatment

PLGA nanospheres are considered to be promising drug carrier in the treatment of cancer. Inclusion complex of bendamustine (BM) with epichlorohydrin beta cyclodextrin polymer was prepared by freeze-drying method. Phase solubility study revealed formation of A_L type complex with stability constant (Ks?=?645?M^?1). This inclusion complex was encapsulated into PLGA nanospheres using solid-in-oil-in-water (S/O/W) technique. The particle size and zeta potential of PLGA nanospheres loaded with cyclodextrin-complexed BM were about 151.4?±?2.53?nm and???31.9?±?(?3.08)?mV. In-vitro release study represented biphasic release pattern with 20% burst effect and sustained slow release. DSC studies indicated that inclusion complex incorporated in PLGA nanospheres was not in a crystalline state but existed in an amorphous or molecular state. The cytotoxicity experiment was studied in Z-138 cells and IC₅₀ value was found to be 4.3?±?0.11?µM. Cell viability studies revealed that the PLGA nanospheres loaded with complex exerts a more pronounced effect on the cancer cells as compared to the free drug. In conclusion, PLGA nanospheres loaded with inclusion complex of BM led to sustained drug delivery. The nanospheres were stable after 3 months of storage conditions with slight change in their particle size, zeta potential and entrapment efficiency.     

Selective Targeting of the Novel CK-10 Nanoparticles to the MDA-MB-231 Breast Cancer Cells

The main objective of this project was to formulate novel decorated amphiphilic PLGA nanoparticles aiming for the selective delivery of the novel peptide (CK-10) to the cancerous/tumor tissue. Novel modified microfluidic techniques were used to formulate the nanoparticles. This technique was modified by using of Nano Assemblr associated with salting out of the organic solvent using K₂HPO₄. This modification is associated with higher peptide loading efficiencies, smaller size and higher uniformity. Size, zeta potential & qualitative determination of the adsorbed targeting ligands were measured by dynamic light scattering and laser anemometry techniques using the zeta sizer. Quantitative estimation of the adsorbed targeting ligands was done by colorimetry and spectrophotometric techniques. Qualitative and quantitative uptakes of the various PLGA nanoparticles were examined by the fluorescence microscope and the flow cytometer while the cytotoxic effect of the nanoparticles was measured by the colorimetric MTT assay. PLGA/poloxamer.FA, PLGA/poloxamer.HA, and PLGA/poloxamer.Tf have breast cancer MDA. MB321 cellular uptakes 83.8, 75.43 & 69.37 % which are higher than those of the PLGA/B cyclodextrin.FA, PLGA/B cyclodextrin.HA and PLGA/B cyclodextrin.Tf 80.87, 74.47 & 64.67 %. Therefore, PLGA/poloxamer.FA and PLGA/poloxamer.HA show higher cytotoxicity than PLGA/ poloxamer.Tf with lower breast cancer MDA-MB-231 cell viabilities 30.74, 39.15 & 49.23 %, respectively. The design of novel decorated amphiphilic CK-10 loaded PLGA nanoparticles designed by the novel modified microfluidic technique succeeds in forming innovative anticancer formulations candidates for therapeutic use in aggressive breast cancers.     

In vitro cytotoxicity and in vivo efficacy of 5-fluorouracil-loaded enteric-coated PEG-cross-linked chitosan microspheres in colorectal cancer therapy in rats

Purpose: Microspheres of chitosan (CS) cross-linked with polyethylene glycol (PEG) were prepared by emulsion-cross-linking followed by the solvent evaporation technique. The formulations were characterized and subjected to in vitro and in vivo tests to assess cell growth, changes in cell morphology, and activities by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on human HT-29 colon cancer cell-lines.

Methods: In vivo activity was evaluated for dimethyl hydrazine-induced colorectal cancer in albino male Wistar rats. Biochemical and histological parameters were evaluated to understand their effectiveness for colon cancer therapy.

Results: The 5-FU immediate release (IR) formulations suspended in SCMC produced an immediate cytotoxic effect, whereas microspheres inhibited proliferation of tumor cells to induce apoptosis over an extended time. Minimum inhibitory concentration (IC₅₀) values for both standard plain 5-FU and 5-FU-loaded microspheres were respectively 5.00?±?0.004?µg/mL and 165?±?1.9?µg/mL which showed the improved safety profile of the microsphere formulation. Tissue distribution showed high concentration of 5-FU in colon that was higher than IC₅₀ value required to stop the growth or death of colon cancer cells from the colonic dysplasia in Duke’s stage A. Significant reduction in tumor volume and multiplicity was observed with increased levels of liver enzymes in animals when treated with standard 5-FU formulation compared with 5-FU loaded microspheres. Elevated levels of serum albumin, creatinine, leukocytopenia, and thrombocytopenia were observed in animals for the standard 5-FU formulation.

Conclusion: The PEG cross-linked CS microspheres of this study slowly released 5-FU up to 24?h to colonic region and enhanced the antitumor activity.     

Preparation and in vitro evaluation of actively targetable nanoparticles for SN-38 delivery against HT-29 cell lines

SN-38 (7-ethyl-10-hydroxycamptothecin) is the active metabolite of irinotecan, which is 100-to 1000-fold more cytotoxic than irinotecan. Nevertheless, extreme hydrophobicity of SN-38 has prevented its clinical use. One way of improving the solubility and stability of SN-38 is to formulate the drug into nanoparticles. Folic acid has been widely used as a targeting moiety for various anticancer drugs. For folate-receptor–targeted anticancer therapy, SN-38 nanoparticles were produced using poly-lactide-co-glycolide–polyethylene glycol–folate (PLGA-PEG-FOL) conjugate by emulsification/solvent evaporation method. The FOL-conjugated di-block copolymer was synthesized by coupling the PLGA-PEG-NH₂ di-block copolymer with an activated folic acid. The conjugates were used for the formation of SN-38 nanoparticles with an average size of 200 nm in diameter. The SN-38 targeted nanoparticles showed a greater cytotoxicity against HT-29 cancer cells than SN-38 nontargeted nanoparticles. These results suggested that folate-targeted nanoparticles could be a potentially useful delivery system for SN-38 as an anticancer agent.From the Clinical EditorSN-38 is the active metabolite of the chemotherapy agent irinotecan, which is 100-1000 fold more cytotoxic than irinotecan, but its extreme hydrophobicity has prevented its clinical use. In this paper, the authors present a nanotechnology-based approach targeting the folate-receptor with SN-38 loaded nanoparticles, demonstrating stronger cytotoxicity against HT-29 cancer cells than with control nanoparticles.     

Intracellular drug delivery in Leishmania-infected macrophages: Evaluation of saponin-loaded PLGA nanoparticles

Drug delivery systems present an opportunity to potentiate the therapeutic effect of antileishmanial drugs. Colloidal carriers are rapidly cleared by the phagocytic cells of the reticuloendothelial system (RES), rendering them ideal vehicles for passive targeting of antileishmanials. This paper describes the development of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) for the antileishmanial saponin β-aescin. NPs were prepared using the combined emulsification solvent evaporation/salting-out technique. Confocal microscopy was used to visualise the internalisation and intracellular trafficking of fluorescein- and nile red-labelled PLGA NPs in J774A.1 macrophages infected with GFP-transfected Leishmania donovani. The in vitro activity of aescin and aescin-loaded NPs on L. infantum was determined in the axenic model as well as in the ex vivo model. The developed PLGA NPs were monodispersed with Z_ave<300?nm, exhibited negative zeta potentials and had relatively high drug loadings ranging from 5.80 to 8.68% w/w PLGA. The fluorescent NPs were internalised by the macrophages and trafficked towards the lysosomes after 2?h in vitro incubation. Co-localisation of the NPs and the parasite was not shown. A two-fold increase in activity was observed in the ex vivo macrophage model by encapsulating β-aescin in PLGA NPs (IC₅₀, 0.48–0.76 µg/mL vs. 1.55?±?0.32 µg/mL for the free drug).     

Design of a Multifunctional PLGA Nanoparticulate Drug Delivery System: Evaluation of its Physicochemical Properties and Anticancer Activity to Malignant Cancer Cells

Purpose  Several individual approaches were combined to fabricate a novel nanoparticulate drug delivery system to achieve targeting and anticancer effects in various malignant cancer cells. Methods  Doxorubicin was conjugated to Poly(lactic-co-glycolic acid) (PLGA), which was formulated into nanoparticle via solvent-diffusion method. The surface of the nanoparticles was subsequently linked with Poly(ethylene glycol) (PEG) and Arg-Gly-Asp (RGD) peptide to realize both passive and active targeting functions. The multifunctional nanoparticles were then tested against several malignant cancer cell lines. Results  The conjugation increased loading efficiency of doxorubicin to PLGA nanoparticles (the encapsulation efficiency was over 85%) and alleviated the drug burst release effect substantially. The drug was released from the polymeric matrix in a sustained release manner over a period of 12 days. The resultant nanoparticles were spherically uniform and well-dispersed. The nanoparticle targeting ability was proven through strong affinity to various integrin-expressing cancer cells, and much less affinity to the low integrin expression cancer cells. The nanoparticles also showed high efficacy in inducing apoptosis in specific malignant cancer cell. Conclusion  The developed multifunctional nanoparticles hold potential to treat malignant integrin-expressing cancers.     

Taribavirin and 5-Fluorouracil-Loaded Pegylated-Lipid Nanoparticle Synthesis,p38 Docking,and Antiproliferative Effects on MCF-7 Breast Cancer

Purpose

Breast cancer is the second most common cause of mortality in women in the United States. Targeted delivery of antitumor breast cancer drugs as a drug-delivery strategy may allow direct delivery into the tumor. Currently, chemotherapy is one of the principle strategies for cancer treatment, but it can have toxic side effects. Nanotechnology attempts to resolve these challenges by loading drugs in nanoparticles, such as solid lipid nanoparticles (SLN). In response to the breast cancer drug 5-fluorouracil (5-FU), p38MAPK signaling has been investigated since the 1990s. Ribavirin, a nucleotide derivative, inhibits p38MAPK in infected hepatocytes. A ribavirin prodrug, taribavirin (TBV), was recently synthesized to concentrate in the liver and have minimal concentration in red blood cells.

Methods

In this study, TBV and 5-FU-pegylated SLNs were prepared and characterized. The in vitro cytotoxicity was evaluated against MCF-7 breast cancer cells. Using molecular docking experiments, 5-FU and TBV were docked on p38MAPK protein.

Results

The TBV nanoformulation had the highest cytotoxic effects, achieving IC₅₀?=?0.690 μM after 24 h, compared with free TBV, which also achieved a good cytotoxic effect (IC₅₀?=?0.756 μM). However, there was a detectable cytotoxic effect and an undetectable IC₅₀ of 5-FU nanoparticles and free 5-FU on MCF-7 cells.

Conclusions

The effect of TBV nanoparticles on MCF-7 cells may be due to its inhibitory effect against p38MAPK protein, where it fits inside the active pocket site of the p38 protein molecular surface, with a minimum binding affinity of ?5.5 kcal/mol (rmsd of 1.07), and it formed strong hydrogen bonds with amino acids ASP’168, ILE’166, HIS’148, and ILE’147. Further studies are warranted to investigate the mechanistic details of the proposed approach.

     

Long circulating PEGylated PLGA nanoparticles of cytarabine for targeting leukemia

The present investigation was aimed at developing PEGylated PLGA nanoparticles of cytarabine. PLGA Nanoparticles were prepared by modified nanoprecipitation method, optimized for mean particle size (152?±?6?nm) and entrapment efficiency (41.1?±?0.8%) by a 3² factorial design. The PEGylated PLGA nanoparticles of cytarabine had a zeta potential of ?7.5?±?1.3?mV and sustained the release of cytarabine for 48?h by Fickian diffusion. The IC₅₀ values for L1210 cells were 6.5, 5.3, and 2.2?µM for cytarabine, cytarabine loaded PLGA nanoparticles and cytarabine loaded PLGA-mPEG nanoparticles respectively. Confocal microscopy and flow cytometry showed that the nanoparticles were internalized by the L1210 cells and not simply bound to their surface. Biodistribution studies showed that the PEGylated nanoparticles of cytarabine were present in significantly higher concentrations in blood circulation as well as in brain and bones and avoided RES uptake as compared to the free drug.     

Hyaluronidase Enzyme-responsive Targeted Nanoparticles for Effective Delivery of 5-Fluorouracil in Colon Cancer

Purpose

In this study, we have successfully prepared the hyaluronic acid (HA)-conjugated mesoporous silica nanoparticles loaded with 5-fluorouracil (5-FU) to increase the anticancer efficacy in colon cancers.

Methods

The particles were nanosized and perfectly spherical. In vitro release kinetics clearly showed the enzyme-sensitive release of 5-FU from HA-conjugated 5-FU loaded mesoporous silica nanoparticles (HA/FMSN).

Results

The presence of HA on the surface of nanoparticles targeted the CD44 receptors overexpressed in the colon cancer cells In vitro cell viability and apoptosis assay clearly showed the superior anticancer effect of HA/FMSN in HT29 colon cancer cells. HA/FMSN exhibited a remarkably higher 43% of cells in early apoptosis phase and 55% of cells in late apoptosis phase indicating the superior anticancer effect of HA/FMSN. HA/FMSN exhibited a significant reduction in the tumor burden compared to that of any group. HA/FMSN was 3-fold more effective than free drug and 2-fold more effective than -FU loaded mesoporous silica nanoparticles (FMSN).

Conclusions

Overall, results suggest that the novel delivery strategy could hold enormous potential in colon cancer targeting.

     

Surface modification of PLGA nanoparticles via human serum albumin conjugation for controlled delivery of docetaxel

Background

Poly lactic-co-glycolic acid (PLGA) based nanoparticles are considered to be a promising drug carrier in tumor targeting but suffer from the high level of opsonization by reticuloendothelial system due to their hydrophobic structure. As a result surface modification of these nanoparticles has been widely studied as an essential step in their development. Among various surface modifications, human serum albumin (HSA) possesses advantages including small size, hydrophilic surface and accumulation in leaky vasculature of tumors through passive targeting and a probable active transport into tumor tissues.

Methods

PLGA nanoparticles of docetaxel were prepared by emulsification evaporation method and were surface conjugated with human serum albumin. Fourier transform infrared spectrum was used to confirm the conjugation reaction where nuclear magnetic resonance was utilized for conjugation ratio determination. In addition, transmission electron microscopy showed two different contrast media in conjugated nanoparticles. Furthermore, cytotoxicity of free docetaxel, unconjugated and conjugated PLGA nanoparticles was studied in HepG2 cells.

Results

Size, zeta potential and drug loading of PLGA nanoparticles were about 199 nm, −11.07 mV, and 4%, respectively where size, zeta potential and drug loading of conjugated nanoparticles were found to be 204 nm, −5.6 mV and 3.6% respectively. Conjugated nanoparticles represented a three-phasic release pattern with a 20% burst effect for docetaxel on the first day. Cytotoxicity experiment showed that the IC50 of HSA conjugated PLGA nanoparticles (5.4 μg) was significantly lower than both free docetaxel (20.2 μg) and unconjugated PLGA nanoparticles (6.2 μg).

Conclusion

In conclusion surface modification of PLGA nanoparticles through HSA conjugation results in more cytotoxicity against tumor cell lines compared with free docetaxel and unconjugated PLGA nanoparticles. Albumin conjugated PLGA nanoparticles may represent a promising drug delivery system in cancer therapy.     

SS-31 peptide enables mitochondrial targeting drug delivery: a promising therapeutic alteration to prevent hair cell damage from aminoglycosides

Aminoglycoside-induced hearing loss stems from damage or loss of mechanosensory hair cells in the inner ear. Intrinsic mitochondrial cell death pathway plays a key role in that cellular dysfunction for which no proven effective therapies against oto-toxicities exist. Therefore, the aim of the present study was to develop a new mitochondrial targeting drug delivery system (DDS) that provided improved protection from gentamicin. Particularly, SS-31 peptide-conjugated geranylgeranylacetone (GGA) loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles were constructed successfully via emulsion-solvent evaporation method. The zebrafish lateral line sensory system was used as an in vivo evaluating platform to investigate the protective efficiency against gentamicin. SS-31 modification significantly reduced the activity of mechanoelectrical transduction (MET) channel and gentamicin uptake in zebrafish lateral line hair cells. As expected, SS-31 conjugated nanoparticles showed mitochondrial specific accumulation in hair cells when compared with unconjugated formulations. Furthermore, intracellular SS-31 modified PLGA NPs slightly enhanced mitochondrial membrane potential (MMP, ΔΨ_m) and then returned to a steady-state, indicating their effect on the respiratory chain complexes in mitochondria. GGA loaded SS-31 conjugated nanoparticles demonstrated the most favorable hair cells survivals against gentamicin when compared with unconjugated groups whereas blank formulations failed to exhibit potency, indicating that the efficiency was attributed to drug delivery of GGA. These results suggest that our constructed mitochondria-targeting PLGA based DDS have potential application in protecting hair cells from ototoxic agents.     

Calcium carbonate nanoparticles as cancer drug delivery system

Introduction: Calcium carbonate (CaCO₃) has broad biomedical utilizations owing to its availability, low cost, safety, biocompatibility, pH-sensitivity and slow biodegradability. Recently, there has been widespread interest in their application as drug delivery systems for different groups of drugs. Among them, CaCO₃ nanoparticles have exhibited promising potential as drug carriers targeting cancer tissues and cells. The pH-dependent properties, alongside the potential to be functionalized with targeting agents give them the unique property that can be used in targeted delivery systems for anticancer drugs. Also, due to the slow degradation of CaCO₃ matrices, these nanoparticles can be used as sustained release systems to retain drugs in cancer tissues for longer times after administration.

Areas covered: Development of drug delivery carriers using CaCO₃ nanoparticles has been reviewed. The current state of CaCO₃ nanoparticles as cancer drug delivery systems with focus on their special properties like pH-sensitivity and biodegradability has also been evaluated.

Expert opinion: According to our review, CaCO₃ nanoparticles, owing to their special characteristics, will have a potential role in safe and efficient cancer treatment in future.     

Preparation and passive target of 5-fluorouracil solid lipid nanoparticles

This work studied the intravenous injection formulation of solid lipid nanoparticles (SLNs) loaded with 5-fluorouracil (5-FU). The goal was to design longer drug residence in vivo and passive targeting nanoparticles which could improve therapeutic efficacy and reduce side-effects. Based on the optimized results of uniform design experiment, 5-FU-SLNs were prepared by multiple emulsion-ultrasonication (w/o/w). The SLNs were found to be relatively uniform in size (182.1?±?25.8?nm) with a negative zeta potential (?27.89?±?5.1 mV). The average drug entrapment efficiency and loading were 74% and 10%, respectively. Compared with the 5-FU solution (t_1/2β, 0.593h; MRT, 0.358h) after intravenous injection to rats, the pharmacokinetic parameters of 5-FU-SLNs exhibited a longer retention time. (t_1/2β, 4.0628h; MRT, 3.5321h). The area under curve of plasma concentration-time (AUC) of 5-FU-SLNs was 1.48 times greater than that of free drugs. The overall targeting efficiency (TE^C) of the 5-FU-SLNs was enhanced from 13.25–20.45% in the lung and from 11.48–23.16% in kidney while the spleen distribution of 5-FU was significantly reduced as compared with that of the 5-FU solution. These results indicated that 5-FU-SLNs were promising passive targeting therapeutic agents for curing primary lung carcinoma.     

Functionalized gold nanoparticles improve afatinib delivery into cancer cells

Objectives: A drug delivery system based on colloidal pegylated gold nanoparticles (PEGAuNPs) conjugated with the tyrosine kinase inhibitor afatinib was designed and tested for enhancing the drug activity against pancreatic and NSCLC cells.

Methods: PEGAuNPs were synthesized and characterized physicochemically. Confocal imaging was performed to evaluate the nanoparticle (NP) internalization in cancer cells. For cell-cycle distribution analysis, conjugated NPs and afatinib alone were incubated with cells and alterations on the cell-cycle profile subsequently analyzed by total DNA staining. Cancer cell survival and growth inhibition following incubation with afatinib and PEGAuNPs–afatinib (concentrations between 0.007 and 0.500 µM afatinib) were evaluated.

Results: A higher cellular uptake of PEGAuNPs was observed by cancer cells. Our data suggest an efficient conjugation of PEGAuNPs with the drug, enhancing the afatinib activity in comparison with afatinib alone. In fact, IC₅₀ and GI₅₀ results obtained show that the PEGAuNPs–afatinib conjugate is ca. 5 and 20 times more potent than afatinib alone in S2-013 and A549 cell lines, respectively.

Conclusions: Conjugating PEGAuNPs with afatinib is a promising antitumor delivery system for cancer therapy as it improves drug efficacy, allowing a reduction in drug dose used and minimizing possible toxicity-related side effects.     

PEGylated FePt@Fe2O3 core-shell magnetic nanoparticles: Potential theranostic applications and in vivo toxicity studies

Herein, we develop FePt@Fe₂O₃ core-shell magnetic nanoparticles as a T₂ magnetic resonance (MR) imaging contrast agent as well as a drug carrier for potential cancer theranostic applications. The FePt@Fe₂O₃ core-shell nanoparticles are synthesized and then functionalized with polyethylene glycol (PEG). Folic acid (FA) is conjugated on the surface of FePt@Fe₂O₃-PEG nanoparticles for effective targeting of folate receptor (FR)-positive tumor cells. A chemotherapy drug, doxorubicin (DOX), is then loaded onto those nanoparticles via hydrophobic physical adsorption, for targeted intracellular drug delivery and selective cancer cell killing. We then use those FePt@Fe₂O₃-PEG nanoparticles for in vivo MR imaging, observing obvious tumor MR contrasts, which resulted from both passive tumor accumulation and active tumor targeting of nanoparticles. Moreover, both in vitro and in vivo studies uncover no obvious toxicity for FePt@Fe₂O₃-PEG nanoparticles. Therefore, our PEGylated FePt@Fe₂O₃ core-shell nanoparticles could serve as a promising multifunctional theranostic nano-platform in imaging guided cancer therapy.From the Clinical EditorIn this study of PEGylated FePt@Fe₂O₃ core-shell magnetic nanoparticles, both therapeutic and diagnostic applications are demonstrated. Folic acid surface-conjugation resulted in uptake by folate receptor positive cancer cells, the iron oxide particles enabled MRI imaging using T2* weighted sequences, and the absorbed doxorubicin provided treatment effects in this model. Similar multi-modality approaches will hopefully find their way to clinical applications in the near future.     

Folate-mediated poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) nanoparticles for targeting drug delivery

A novel targeting drug delivery system (TDDS) has been developed. Such a TDDS was prepared by W₁/O/W₂ solvent extraction/evaporation method, adopting poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) [P(HB-HO)] as the drug carrier, folic acid (FA) as the targeting ligand, and doxorubicin (DOX) as the model anticancer drug. The average size, drug loading capacity and encapsulation efficiency of the prepared DOX-loaded, folate-mediated P(HB-HO) nanoparticles (DOX/FA–PEG–P(HB-HO) NPs) were found to be around 240 nm, 29.6% and 83.5%. The in vitro release profile displayed that nearly 50% DOX was released in the first 5 days. The intracellular uptake tests of the nanoparticles (NPs) in vitro showed that the DOX/FA–PEG–P(HB-HO) NPs were more efficiently taken up by HeLa cells compared to non-folate-mediated P(HB-HO) NPs. In addition, DOX/FA–PEG–P(HB-HO) NPs (IC₅₀ = 0.87 μM) showed greater cytotoxicity to HeLa cells than other treated groups. In vivo anti-tumor activity of the DOX/FA–PEG–P(HB-HO) NPs showed a much better therapeutic efficacy in inhibiting tumor growth, and the final mean tumor volume was 178.91 ± 17.43 mm³, significantly smaller than normal saline control group (542.58 ± 45.19 mm³). All these results have illustrated that our techniques for the preparing of DOX/FA–PEG–P(HB-HO) NPs developed in present work are feasible and these NPs are effective in selective delivery of anticancer drug to the folate receptor-overexpressed cancer cells. The new TDDS may be a competent candidate in application in targeting treatment of cancers.     

Preparation and characterization of a biodegradable drug targeting system for anticancer drug delivery: Microsphere-antibody conjugate

Targeted delivery of anticancer drugs is one of the most actively pursued goals in anticancer chemotherapy. A major disadvantage of anticancer drugs is their lack of selectivity for tumour tissue, which causes severe side effects and results in low cure rates. Any strategy by which a cytotoxic drug is targeted to the tumour, thus increasing the therapeutic index of the drug, is a way of improving cancer chemotherapy and minimizing systematic toxicity. This study covers the preparation of the gelatin microsphere (GM)-anti-bovine serum albumin (anti-BSA) conjugate for the development of a drug targeting approach for anticancer drug delivery. Microspheres of 5% (w/v) gelatin content were prepared by crosslinking with glutaraldehyde (GTA) at 0.05 and 0.50% (v/v) concentration. Microspheres were in the size range of 71–141 μm. The suitability of these microspheres as drug carriers for anticancer drug delivery was investigated in vitro by studying the release profiles of loaded methotrexate (MTX) and 5-fluorouracil (5-FU) and the cytotoxicities on cancer cell lines. The in vitro MTX release profiles (～22–46% released in 24 h depending on the amount of GTA used) were much slower compared to 5-FU (～42–91% released in 24 h). Both drugs demonstrated an initial fast release, which was followed by gradual, sustained drug release. The MTT cytotoxicity test results of GMs loaded with 5-FU and MTX showed ～54–70% and ～52–67% cytotoxicities in 4 days. In general, incorporation of MTX and 5-FU in microspheres enhanced the cytotoxic effect in a more prolonged manner compared to the free drugs. Gelatin micospheres were chemically conjugated to anti-BSA and the antigen–antibody activities were studied by immunofluorescence. Results indicated ～80% binding with conjugated anti-BSA and BSA-FITC. Based on their low cytotoxicity and the high antigen binding efficiencies, anti-BSA conjugated gelatin microspheres could be suitable targeted drug carrier systems for selective and long-term delivery of anticancer drugs to a specific body compartment (i.e. bladder cancer).     

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 (P<0.05) increased 5-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.Key words: 5-Fluorouracil, Hydrophilic drug, Cubosomes, Liver targeting, Hepatotoxicity