Brain targeted delivery of anticancer drugs: prospective approach using solid lipid nanoparticles

A brain tumour is amongst most devastating and challenging condition to overcome with suitable treatment as the drug has to cross the blood–brain barrier (BBB) with several physiological barriers like opsonisation by the reticuloendothelial system. Presently various techniques such as surgical, chemotherapeutic agents, and radiotherapy techniques have performed to extend the lifespan of patients diagnosed with glioblastoma, which did not maximise the overall survival of patients with a tumour. Nanotechnology is relied upon to diminish the requirement for intrusive methods for conveyance of therapeutics to the central nervous system. Colloidal nanocarriers sizing range 1–1000 nm have been utilised to cross BBB delivers the drug at cell levels with enhanced bioavailability and reduced toxicity. However, solid lipid nanoparticles (SLNs) are considered a highly flexible carrier for more successful remedially in brain tumour. The treatment of a brain tumour via SLNs is gaining greater potency due to its inimitable size and lipidic nature. This review focuses and represents the current strategies of SLNs in the brain tumour treatment with appropriate techniques adopted are highlighted. Based on this review, the authors concluded that SLNs embrace exclusive promising lipidic nanocarrier that could be utilised to target a brain tumour effectively.Inspec keywords: brain, cancer, nanoparticles, blood, molecular biophysics, tumours, nanomedicine, neurophysiology, radiation therapy, colloids, biomedical materials, drug delivery systems, nanofabrication, drugs, cellular biophysicsOther keywords: chemotherapeutic agents, radiotherapy techniques, central nervous system, colloidal nanocarriers sizing range 1–1000 nm, BBB, drug, solid lipid nanoparticles, brain tumour therapeutical uses, lipidic nature, brain tumour treatment, brain targeted delivery, anticancer drugs, prospective approach, blood–brain barrier, physiological barriers, reticuloendothelial system, surgical agents, lipidic nanocarrier, size 1.0 nm to 1000.0 nm     

SiRNA drug delivery by biodegradable polymeric nanoparticles

RNA interference (RNAi) is an emerging technology in which the introduction of double-stranded RNA (dsRNA) into a diverse range of organisms and cell types causes degradation of the complementary mRNA. It offers a broad spectrum of applications in both biological and medical research. Small interference RNA (siRNA) was recently explored for its therapeutical potential. However, the drug delivery of siRNA oligos is very novel and is in great need of future research. To this end, a biodegradable poly(D,L-lactide-co-glycolide) (PLGA) nanoparticle drug carrier system was prepared to load siRNA oligos with desired physicochemical properties. The nanoparticles were characterized by scanning electron microscopy and laser diffraction particle sizer. The delivery of siRNA into the targeted 293T cells was observed using fluorescent-labeled double-stranded Cy3-oligos. The model siRNA oligos, si-GFP-RNA, were also successfully loaded into PLGA nanoparticles and delivered in 293T cells. The gene silencing effect and the inhibition of GFP expression were investigated using fluorescent microscopy. Both positive and negative controls were used to compare with the new siRNA nanoparticle delivery system. It was found that nanoparticles offered both effective delivery of siRNA and prominent GFP gene silencing effect. Compared to conventional carrier systems, the new biodegradable polymeric nanoparticle system may also offer improved formulation stability, which is practically beneficial and may be used in the future clinical studies of siRNA therapeutics.     

Cytocompatible chitosan-graft-mPEG-based 5-fluorouracil-loaded polymeric nanoparticles for tumor-targeted drug delivery

Biodegradable materials like chitosan (CH) and methoxy polyethylene glycol (mPEG) are widely being used as drug delivery carriers for various therapeutic applications. In this study, copolymer (CH-g-mPEG) of CH and carboxylic acid terminated mPEG was synthesized by carbodiimide-mediated acid amine reaction. The resultant hydrophilic copolymer was characterized by Fourier transform infrared spectroscopy and ¹H NMR studies, revealing its relevant functional bands and proton peaks, respectively. Blank polymeric nanoparticles (B-PNPs) and 5-fluorouracil loaded polymeric nanoparticles (5-FU-PNPs) were formulated by ionic gelation method. Furthermore, folic acid functionalized FA-PNPs and FA-5-FU-PNPs were prepared for folate receptor-targeted drug delivery. FA-5-FU-PNPs were characterized by particle size, zeta potential, and in vitro drug release studies, resulting in 197.7?nm,?+29.9?mv, and sustained drug release of 88% in 24?h, respectively. Cytotoxicity studies were performed for FA-PNPs and FA-5-FU-PNPs in MCF-7 cell line, which exhibited a cell viability of 80 and 41%, respectively. In vitro internalization studies were carried out for 5-FU-PNPs and FA-5-FU-PNPs which demonstrated increased cellular uptake of FA-5-FU-PNPs by receptor-mediated transport. Significant (p?相似文献   

Folate targeted PEGylated titanium dioxide nanoparticles as a nanocarrier for targeted paclitaxel drug delivery

A novel titanium dioxide nanocarrier was synthesized for targeted delivery of the anticancer drug, paclitaxel, by grafting folic acid (FA) onto the PEGylated titanium dioxide nanoparticles. Titanium dioxide is used in biomedical field for its stability and no toxicity characteristics. Titanium dioxide is one of the most promising nanoparticles (NPs) capable of a wide variety of applications in medicine and life science. Polyethylene glycol (PEG), when attached to the surface of the nanoparticles, increases the biocompatibility of the nanoparticles. PEGylated nanocarriers evade the reticuloendothelial system (RES). Folic acid (FA) is used as the ligand to target folate receptors, which are found abundant in cancer cells. FA–PEG–TiO₂ nanoparticles when used as drug carriers have the ability to target cancer cells and also capable of evading the reticuloendothelial system. Titanium dioxide nanoparticles were synthesized by wet chemical method. It was annealed at 450° for 3 h. XRD analysis confirms the formation of anatase titanium dioxide. Analyses by transmission electron microscopy (TEM) and dynamic light scattering (DLS) revealed that the nanoparticles had an average size of 12 nm and uniform size distribution. The PEGylation and folic acid grafting was confirmed by UV spectroscopy, Fourier transform infrared (FTIR) spectroscopy, and thermogravimetric analysis (TGA). The study on the loading of anticancer drug paclitaxel revealed that the titanium dioxide nanocarrier possessed a considerably higher adsorption capability. In addition, the in vitro release profile of paclitaxel from FA–PEG–TiO₂ nanoparticles was characterized by an initial fast release followed by a sustained release phase.     

An adenoviral platform for selective self-assembly and targeted delivery of nanoparticles

Metallic nanoparticles (NPs) can be used for the diagnosis, imaging, and therapy of tumors and cardiovascular disease. However, targeted delivery of NPs to specific cells remains a major limitation for clinical realization of these potential treatment options. Herein, a novel strategy for the specific coupling of NPs to a targeted adenoviral (Ad) platform to deliver NPs to specific cells is defined. Genetic manipulation of the gene-therapy vector is combined with a specific chemical coupling strategy. In particular, a high-affinity interaction between a sequence of six-histidine amino acid residues genetically incorporated into Ad capsid proteins and nickel(II) nitrilotriacetic acid on the surface of gold NPs is employed. The selective self-assembly of gold NPs and Ad vectors into multifunctional platforms does not negatively affect the targeting of Ad to specific cells. This opens the possibility of using Ad vectors for targeted NP delivery, thereby providing a new type of combinatorial approach for the treatment of diseases that involves both nanotechnology and gene therapy.     

Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery

Nanoparticles are used for delivering therapeutics into cells. However, size, shape, surface chemistry and the presentation of targeting ligands on the surface of nanoparticles can affect circulation half-life and biodistribution, cell-specific internalization, excretion, toxicity and efficacy. A variety of materials have been explored for delivering small interfering RNAs (siRNAs)--a therapeutic agent that suppresses the expression of targeted genes. However, conventional delivery nanoparticles such as liposomes and polymeric systems are heterogeneous in size, composition and surface chemistry, and this can lead to suboptimal performance, a lack of tissue specificity and potential toxicity. Here, we show that self-assembled DNA tetrahedral nanoparticles with a well-defined size can deliver siRNAs into cells and silence target genes in tumours. Monodisperse nanoparticles are prepared through the self-assembly of complementary DNA strands. Because the DNA strands are easily programmable, the size of the nanoparticles and the spatial orientation and density of cancer-targeting ligands (such as peptides and folate) on the nanoparticle surface can be controlled precisely. We show that at least three folate molecules per nanoparticle are required for optimal delivery of the siRNAs into cells and, gene silencing occurs only when the ligands are in the appropriate spatial orientation. In vivo, these nanoparticles showed a longer blood circulation time (t(1/2) ≈ 24.2 min) than the parent siRNA (t(1/2) ≈ 6 min).     

Doxorubicin loaded PVA coated iron oxide nanoparticles for targeted drug delivery

Magnetic drug targeting is a drug delivery system that can be used in locoregional cancer treatment. Coated magnetic particles, called carriers, are very useful for delivering chemotherapeutic drugs. Magnetic carriers were synthesized by coprecipitation of iron oxide followed by coating with polyvinyl alcohol (PVA). Characterization was carried out using X-ray diffraction, TEM, TGA, FTIR and VSM techniques. The magnetic core of the carriers was magnetite (Fe₃O₄), with average size of 10 nm. The room temperature VSM measurements showed that magnetic particles were superparamagnetic. The amount of PVA bound to the iron oxide nanoparticles were estimated by thermogravimetric analysis (TGA) and the attachment of PVA to the iron oxide nanoparticles was confirmed by FTIR analysis. Doxorubicin (DOX) drug loading and release profiles of PVA coated iron oxide nanoparticles showed that up to 45% of adsorbed drug was released in 80 h, the drug release followed the Fickian diffusion-controlled process. The binding of DOX to the PVA was confirmed by FTIR analysis. The present findings show that DOX loaded PVA coated iron oxide nanoparticles are promising for magnetically targeted drug delivery.     

Nanoparticle systems for the targeted release of active principles of proteic nature

The preparation and characterization of nanoparticles based on biodegradable/bioerodible polymers is reported. They have been designed for the controlled-targeted release of proteic drugs such as -interferon and for the release of active principles in tissue engineering. The amenability of some of the prepared polymeric matrices to be used in the fabrication of micro and nano patterned scaffolds is also described.     

Intracellular delivery of cysteine protease inhibitor cystatin by polymeric nanoparticles

Two polymers chitosan and poly(lactide-co-glycolide) copolymer (PLGA) were investigated to develop nanoparticles (NPs) for delivery of protein drug substance into tumour cells. Cystatin was selected as a model protein drug due to its high potential to inhibit cysteine proteases, known to trigger the invasive process. Ionotropic gelation of chitosan with tripolyposphate and precipitation of PLGA polymer from a double emulsion system by a solvent diffusion process were used to produce 250-300 nm in diameter NPs. The cellular uptake of NPs was tested on a transformed human breast epithelial cell line, MCF-10A neoT, characterized by an increased expression of cysteine proteases and highly invasive cell phenotype. The influence of NPs on cell viability was evaluated by MTT test showing IC50 400 microg/ml for PLGA and 5 mg/ml for chitosan NPs. As determined by fluorescence microscopy chitosan NPs did not enter the cells during 1-hour incubation whereas the same amount of PLGA NPs were in the cells already after 5 min of incubation. Cystatin delivered into MCF-10A neoT cells by PLGA NPs effectively inhibited intracellular proteolytic activity of cathepsin B, as detected by specific fluorogenic substrate Z-Arg2 cresyl violet. On the contrary, free cystatin in solution did not internalise into the cells and inhibit cathepsin B. To conclude, PLGA NPs with cystatin but not chitosan NPs were targeted through endocytosis to the lysosomal compartments that are rich of proteases enzymes. Our results suggest new strategy to inactivate intracellular tumour-associated proteases, and consequently the invasion behaviour of tumour cells, which could contribute to cancer therapy.     

Electroporation of polymeric nanoparticles: an alternative technique for transdermal delivery of insulin

Purpose: The aim was to study transdermal electroporation of insulin-loaded nanocarriers as a methodology for delivering macromolecules. Methods: The efficacy of electroporation of insulin as solution and nanoparticles was compared in vitro and in vivo. Histology and confocal laser scanning microscopy were used to assess the effects of electroporation on skin structure, whereas the latter also demonstrated the depth of permeation of the nanoparticles. In vivo studies were performed on streptozotocin-diabetic male Wistar rats and compared with subcutaneous administration. Results: A linear increase in insulin flux was noted on increasing the applied voltage (R² = 0.9514), the number of pulses (R² = 0.8515), and the pulse length (R² = 0.9937). Electroporation of nanoparticles resulted in fourfold enhancement in insulin deposition in rat skin in contrast to solution. In vivo studies showed maximum reduction of 77 ± 5% (87.2 ± 6.4 mIU/mL, t = 2 hours) and 85 ± 8% (37.8 ± 10.2 mIU/mL, t = 4 hours) in blood glucose levels for solution and nanoparticles, respectively, with therapeutic levels maintained for 24 and 36 hours. Conclusion: Overall, electroporation of polymeric nanosystems proved to be an ideal alternative to injectable administration.     

Layered double hydroxide monolayers for controlled loading and targeted delivery of anticancer drugs

Two-dimensional (2D) nanomaterials have gained tremendous attention in the field of biomedicine because of their high specific surface areas and fascinating physicochemical properties. Herein, 2D monolayered double hydroxide (MLDH) nanosheets were employed to localize doxorubicin (DOX), an anticancer drug, with a loading capacity of as high as 3.6 mg·mg^–1 (w/w). Structural characterizations and theoretical calculations indicate that the DOX molecule is uniformly arranged and oriented at the surface of the MLDHs with a binding energy of 15.90 eV, showing significant electrostatic interaction. With the assistance of the targeting agent folic acid (FA), DOX-FA/MLDHs demonstrate targeted cellular uptake and superior anticancer behavior based on in vitro tests performed with cancer cells. In addition, this composite material exhibits a selective release toward cancer cells and good biocompatibility with normal cells, which would guarantee its practical applications in cancer therapy.

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Design of polymeric nanoparticles and its applications as drug delivery systems for acne treatment

Objective: The aim of this study was to evaluate a formulation made of poly(lactide-co-glycolide) (PLGA) nanoparticles containing azelaic acid for potential acne treatment.

Methods: Azelaic acid-loaded PLGA nanoparticles were prepared by spontaneous emulsification processes using poloxamer 188 as stabilizer. Several manufacturing parameters such as stirring rate, concentration of stabilizer and different recovery methods were investigated. Nanoparticles were evaluated in terms of size, zeta potential, encapsulation efficiency, release kinetics and permeation kinetics in vitro. Furthermore, in vitro toxicological studies were performed in Saccharomyces cerevisiae model.

Results: The results showed that by adjusting some formulation conditions it was possible to obtain nanoparticles with high loading and a controlled drug release. Freeze-dried recovery altered the nanoparticles structure by enhancing porous structures and mannitol was required to control the mean particle size. The centrifugation recovery was found to be the best approach to nanoparticles recovery. Similar toxicity profiles were observed for both drug-free and azelaic acid-loaded nanoparticles, with concentration-dependent decreases in cell viability.

Conclusion: These results indicate a potential formulation for controlled release delivery of azelaic acid to the follicular unit.     

Cyclodextrin conjugated magnetic colloidal nanoparticles as a nanocarrier for targeted anticancer drug delivery

A novel magnetic nanocarrier (CD-GAMNPs) was fabricated for targeted anticancer drug delivery by grafting cyclodextrin (CD) onto gum arabic modified magnetic nanoparticles (GAMNPs) using hexamethylene diisocyanate (HMDI) as a linker. Analyses by transmission electron microscopy (TEM) and dynamic light scattering (DLS) revealed that the product had a mean diameter of 17.1?nm and a mean hydrodynamic diameter of 44.1?nm. The CD grafting was confirmed by Fourier transform infrared (FTIR) spectroscopy, and thermogravimetric analysis (TGA) indicated that the amount of CD grafted on the GAMNPs was 16.8?mg?g(-1). The study on the loading of anticancer drug all-trans-retinoic acid (retinoic acid) revealed that the newly fabricated magnetic nanocarrier possessed a considerably higher adsorption capability as compared to GAMNPs due to the special hydrophobic cavity structure of CD, which could act as a host-guest complex with retinoic acid. Furthermore, it was found that the complexation of CD-GAMNPs with retinoic acid was exothermic and the presence of a surfactant (sodium dodecyl sulfate) led to the decrease in the inclusion of retinoic acid because the linear structure of sodium dodecyl sulfate made it easier to enter the cavity of CD as compared to less linear retinoic acid. In addition, the in vitro release profile of retinoic acid from CD-GAMNPs was characterized by an initial fast release followed by a delayed release phase.     

Synthesis of biomolecule-modified mesoporous silica nanoparticles for targeted hydrophobic drug delivery to cancer cells

Synthetic methodologies integrating hydrophobic drug delivery and biomolecular targeting with mesoporous silica nanoparticles are described. Transferrin and cyclic-RGD peptides are covalently attached to the nanoparticles utilizing different techniques and provide selectivity between primary and metastatic cancer cells. The increase in cellular uptake of the targeted particles is examined using fluorescence microscopy and flow cytometry. Transferrin-modified silica nanoparticles display enhancement in particle uptake by Panc-1 cancer cells over that of normal HFF cells. The endocytotic pathway for these particles is further investigated through plasmid transfection of the transferrin receptor into the normal HFF cell line, which results in an increase in particle endocytosis as compared to unmodified HFF cells. By designing and attaching a synthetic cyclic-RGD, selectivity between primary cancer cells (BT-549) and metastatic cancer cells (MDA-MB 435) is achieved with enhanced particle uptake by the metastatic cancer cell line. Incorporation of the hydrophobic drug Camptothecin into these two types of biomolecular-targeted nanoparticles causes an increase in mortality of the targeted cancer cells compared to that caused by both the free drug and nontargeted particles. These results demonstrate successful biomolecular-targeted hydrophobic drug delivery carriers that selectively target specific cancer cells and result in enhanced drug delivery and cell mortality.     

Glucose-conjugated chitosan nanoparticles for targeted drug delivery and their specific interaction with tumor cells

A novel targeted drug delivery system, glucose-conjugated chitosan nanoparticles （GCNPs）, was developed for specific recognition and interaction with glucose transporters （Gluts） over-expressed by tumor cells. GC was synthesized by using succinic acid as a linker between glucosamine and chitosan （CS）, and successful synthesis was confirmed by NMR and elemental analysis. GCNPs were prepared by ionic crosslinking method, and characterized in terms of morphology, size, and zeta potential. The optimally prepared nanoparticles showed spherical shapes with an average particle size of （187.9 ± 3.8） nm and a zeta potential of （-15.43 ± 0.31） mV. The GCNPs showed negligible cytotoxicity to mouse embryo fibroblast and 4T1 cells. Doxorubicin （DOX） could be efficiently entrapped into GCNPs, with a loading capacity and encapsulation efficiency of 20.11% and 64.81%, respectively. DOX-Ioaded nanoparticles exhibited sustained-release behavior in phosphate buffered saline （pH 7.4）. In vitro cellular uptake studies showed that the GCNPs had better endocytosis ability than CSNPs, and the antitumor activity of DOX/GCNPs was 4-5 times effectiveness in 4T1 cell killing than that of DOX/CSNPs. All the results demonstrate that nanoparticles decorated with glucose have specific interactions with cancer cells via the recognition between glucose and Gluts. Therefore, Gluts-targeted GCNPs may be promising delivery agents in cancer therapies.     

RGD peptide targeted lipid-coated nanoparticles for combinatorial delivery of sorafenib and quercetin against hepatocellular carcinoma

Context: Combination therapies provide a potential solution to address the tumor heterogeneity and drug resistance issues by taking advantage of distinct mechanisms of action of the multiple therapeutics.

Objective: To design arginine-glycineaspartic acid (RGD) modified lipid-coated nanoparticles (NPs) for the co-delivery of the hydrophobic drugs against hepatocellular carcinoma (HCC).

Materials and methods: RGD modified lipid-coated PLGA NPs were developed for the targeted delivery of both sorafenib (SRF) and quercetin (QT) (RGD-SRF-QT NPs). Chemical–physical characteristics and release profiles were evaluated. In vitro cell viability assays were carried out on HCC cells. In vivo antitumor efficacies were evaluated in HCC animal model.

Results and discussion: The combination of SRF and QT formulations was more effective than the single drug formulations in both NPs and solution groups. RGD-SRF-QT NPs achieved the most significant tumor growth inhibition effect in vitro and in vivo.

Conclusion: The resulting NPs could provide a promising platform for co-delivery of multiple anticancer drugs for achievement of combinational therapy and could offer potential for enhancing the therapeutic efficacy on HCC.     

Silanized polymeric nanoparticles for DNA isolation

The aim of this study is to prepare silanized polymeric nanoparticles for DNA isolation. Polymeric p(HEMA)-IMEO-PBA nanoparticles around 85.7 nm diameter, was obtained by surfactant free emulsion polymerization for DNA isolation. Synthesized nanoparticles for characterization studies were realized scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and Zeta-size. Surface area, average particle size and size distribution were also performed. The surface area of synthesized silanized polymeric nanoparticles was 2460 m²/g. Synthesized polymeric nanoparticles were silanized with 3-(2-imidazoline-1-yl)propyl (triethoxysilane) (IMEO). After that, phenylboronic acid (PBA) which is DNA specific ligand were covalently binded to silanized polymeric nanoparticles. The amount of DNA adsorbed onto the p(HEMA)-IMEO-PBA nanoparticles first increased and then reached a saturation value at around 14.0 mg/mL of DNA concentration. The maximum adsorption was 672.41 mg/g silanized polymeric nanoparticles in the optimum adsorption medium. The maximum DNA adsorption was achieved at 4 °C. The overall recovery of DNA was calculated as 95%. In repetitive adsorption–desorption circles, it is observed not being important decrease in DNA adsorption capacities. The results were shown that silanized polymeric nanoparticles can be a good alternative for DNA isolation.     

Composite polymeric magnetic nanoparticles for co-delivery of hydrophobic and hydrophilic anticancer drugs and MRI imaging for cancer therapy

Exercising complementary roles of polymer-coated magnetic nanoparticles for precise drug delivery and image contrast agents has attracted significant attention in biomedical applications. The objective of this study was to prepare and characterize magnetic nanoparticles embedded in polylactide-co-glycolide matrixes (PLGA-MNPs) as a dual drug delivery and imaging system capable of encapsulating both hydrophilic and hydrophobic drugs. PLGA-MNPs were capable of encapsulating both hydrophobic and hydrophilic drugs in a 2:1 ratio. Biocompatibility, cellular uptake, cytotoxicity, membrane potential, and apoptosis were carried out in two different cancer cell lines (MCF-7 and PANC-1). The molecular basis of induction of apoptosis was validated by Western blotting analysis. For targeted delivery of drugs, targeting ligand such as Herceptin was used, and such a conjugated system demonstrated enhanced cellular uptake and an augmented synergistic effect in an in vitro system when compared with native drugs. Magnetic resonance imaging was carried out both in vitro and in vivo to assess the efficacy of PLGA-MNPs as contrast agents. PLGA-MNPs showed a better contrast effect than commercial contrast agents due to higher T(2) relaxivity with a blood circulation half-life ～ 47 min in the rat model. Thus, our results demonstrated the dual usable purpose of formulated PLGA-MNPs toward either, in therapeutics by delivering different hydrophobic or hydrophilic drugs individually or in combination and imaging for cancer therapeutics in the near future.     

Mucoadhesive polymeric hydrogels for nasal delivery of acyclovir

The study evaluated different mucoadhesive polymeric hydrogels for nasal delivery of acyclovir. Gels containing poly-N-vinyl-2-pyrrolidone (PVP) were prepared with crosslinking achieved by irradiation with a radiation dose of 15 kGy being as efficient as 20 kGy. Gels containing chitosan and carbopol were also evaluated. The mucoadhesive properties of gels were measured by a modification of a classical tensile experiment, employing a tensile tester and using freshly excised sheep nasal mucosa. Considering the mucoadhesive force, chitosan gel and gel prepared with 3% PVP in presence of polyethylene glycol (PEG) 600 were the most efficient. The in vitro drug release depended on the gel composition. Higher release rates were obtained from PVP gels compared to chitosan or carbopol gels. The release rate of drug from PVP gels was increased further in presence of PEG or glycerol. Histopathological investigations proved that the PVP was a safe hydrogel to be used for mucosal delivery. The PEG in gel formulations caused less damages to the nasal mucosal compared to formulation containing glycerol.