Nanovehicles For Drug Delivery Research Articles

Nanosuspension as a Novel Nanovehicle for Drug Delivery: A Recent Update on Patents and Therapeutic Applications

Abstract: Solubility is a critical factor for the therapeutic action of drugs and does not depend on the administration of routes. Various conventional methods are used to enhance the solubility of the drug, which show limited applicability. Nanotechnology is used to improve the solubility and bioavailability of drugs that belong to BCS classes II and IV. Nanosuspension is the dispersion of pure drug nanoparticles in aqueous with a minimum amount of surfactant, stabilizing the formula-tion. Various techniques, such as the bottom-up approach, dissocubes, nanopure, nanoedge, nano-jet process, supercritical fluid, dry co-grinding, milling media, and nanoprecipitation, have been used to formulate nanosuspension. Nanosuspension can be administered orally, inhalation, trans-dermal, ocular, injectable, topical, and pulmonary. To resolve the problem of solubility and stabil-ity, nanosuspension has received much attention because of its technical simplicity, cost-effectiveness, and ease of significant scale-up. Nanosuspension can control particle size surface charge properties and release the drug at specific sites at an optimal rate. Recently, more than 100 patents have been published on nanosuspension. This review article covers the different prepara-tion methods, formulation composition, marketed products, characterization, and recent patents on nanosuspension. The various benefits and evaluation of the parameters of nanosuspension are discussed briefly. This patent-based review will enhance the knowledge of control drug delivery and related patents on nanosuspension.

RSM-CCD optimized hollow mesoporous silica nanospheres encapsulating sorafenib induce mitochondrial membrane potential mediated apoptotic cell death in non-small cell lung cancer

Hollow mesoporous silica nanoparticles (HMSNs) are considered appealing nanovehicles for drug delivery due to their exceptional drug loading and release potential. This study plans to synthesize HMSNs using a novel, quick, and economical procedure in co-relation with traditional mesoporous silica nanoparticles (MSNs) and optimize their synthesis by using the RSM-CCD approach. The influence of independent variables, i.e., CTAB (X1), TEOS (X2), and pH (X3), was evaluated by a 3-factorial design and ANOVA. RSM-CCD depicted the best synthesis formulation. CTAB: 0.3 g, TEOS: 3 ml, pH: 11.5. Optimized MSNs and HMSNs were characterized by DLS, XRD, SEM, FTIR, TEM, BET, XPS, and FE-SEM. Subsequently, hemocompatibility analysis revealed excellent compatibility of the nanosamples toward human RBCs. The drug loading efficiency of SF-MSNs and SF-HMSNs was 13.71 ± 0.33 % and 51.31 ± 0.94 %, respectively. A drug dissolution study revealed that sorafenib (SF) was released sustainably, with a cumulative release percentage of 67 % (HMSNs) and 77 % (MSNs) at 72 h, proving the superiority of SF-HMSNs over sustained release. In-vitro cell culture studies explored the anti-tumorigenic prospects of free and encapsulated SF. Cell cytotoxicity was assessed by MTT assay against A549 cells, indicating enhanced toxicity for optimized SF-HMSNs. The IC50 value substantially decreased from 10.5 to 5.8 μg/ml (a 1.8-fold decrease) after encapsulation. Additionally, In-vitro assays reflected MMP-mediated apoptotic cell death in A549 cells due to increased drug sensitivity and ROS generation. Collectively, these findings suggest that HMSNs are an ideal drug delivery vehicle due to the sustainable release of SF for NSCLC treatment.

An updatein the applications of exosomes in cancer theranostics: from research to clinical trials.

Exosomes are nanosized extracellular vesicles secreted by nearly all viable cells following the fusing of multivesicular bodies and the plasma membrane and discharged into the encircling bodily fluids. Exosomes can transport cell-specific components from the source cell to the target cell. Given the enormous potential of exosomes as non-invasive diagnostic biomarkers and therapeutic nanovehicles. Lately, accumulated evidence has demonstrated that exosomes serve an important role in prognosis, diagnosis, and even treatment strategies. While several reviews have collective information on the biomedical application of exosomes, a comprehensive review incorporating updated and improved methodologies for beneficial applications of such vesicles in cancer theranostics is indispensable. In the current review, we first provided a comprehensive review of the introduction of exosomes, featuring their discovery, separation, characterization, function, biogenesis, secretion. The implications of exosomes as promising nanovehicles for drug and gene delivery, application of exosome inhibitors in the management of cancers, completed and ongoing clinical trials on the biological relevance of exosomes are then discussed in detail. As the field of exosome research grows, a better understanding of the subcellular parts and mechanisms involved in exosome secretion and targeting of specific cells will help figure out what their exact physiological functions are in the body.

Nanoparticle toxicity may cause testicular dysfunction

Nanoparticle toxicity may cause testicular dysfunction

A conjugated aptamer and oligonucleotides-stabilized gold nanoclusters nanoplatform for targeted fluorescent imaging and efficient drug delivery

A facile approach is designed for the configuration of aptamer-gold nanoclusters nanohybrid for dual-modal of targeted fluorescent imaging and efficient drug delivery. Morphological and structural investigations indicate that Apt-C30 @AuNCs with intrinsic fluorescence consists in oligonucleotides dopped with AuNCs with an average diameter of 2–3 nm. Based on cell viability assays, Apt-C30 @AuNCs exhibit good biocompatibility. Considering that chemotherapeutic drugs such as DOX can intercalate into the base pairs of DNA, Apt-C30 @AuNCs is performed to delivery DOX. Results clearly demonstrate that Apt-C30 @AuNCs/DOX can be effectively inhibit the growth of cancer cells growth. Moreover, functionalized with aptamer, Apt-C30 @AuNCs owns the ability to bind specifically to MUC1 protein overexpressed on HeLa cells, and the viability of HeLa cells is quite low after treated with Apt-C30 @AuNCs/DOX. In vitro, fluorescent imaging results demonstrate that Apt-C30 @AuNCs present a significantly increase in the internalization and bioimaging ability, attributing to the biofunctionalization of C30 @AuNCs with aptamer. Apt-C30 @AuNCs could be successfully exploited as nanovehicles for efficient drug delivery and fluorescent agents for cellular staining, which can be used in potential application of image-guided cancer diagnosis and therapy fields.

A Novel Method for Carbon Nanotube Functionalization Using Immobilized Candida antarctica Lipase.

Carbon nanotubes (CNTs) have been proposed as nanovehicles for drug or antigen delivery since they can be functionalized with different biomolecules. For this purpose, different types of molecules have been chemically bonded to CNTs; however, this method has low efficiency and generates solvent waste. Candida antarctica lipase is an enzyme that, in an organic solvent, can bind a carboxylic to a hydroxyl group by esterase activity. The objective of this work was to functionalize purified CNTs with insulin as a protein model using an immobilized lipase of Candida antarctica to develop a sustainable functionalization method with high protein attachment. The functionalized CNTs were characterized by scanning electron microscope (SEM), Raman spectroscopy, Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS–PAGE). The enzymatic functionalization of insulin on the surface of the CNTs was found to have an efficiency of 21%, which is higher in conversion and greener than previously reported by the diimide-activated amidation method. These results suggest that enzymatic esterification is a convenient and efficient method for CNT functionalization with proteins. Moreover, this functionalization method can be used to enhance the cellular-specific release of proteins by lysosomal esterases.

Poly(N-vinylpyrrolidone)-block-Poly(dimethylsiloxane)-block-Poly(N-vinylpyrrolidone) Triblock Copolymer Polymersomes for Delivery of PARP1 siRNA to Breast Cancers.

Nearly 20% of HER2-positive breast cancers develop resistance to HER2-targeted therapies requiring the use of advanced therapies. Silencing RNA therapy may be a powerful modality for treating resistant HER2 cancers due to its high specificity and low toxicity. However, the systemic administration of siRNAs requires a safe and efficient delivery platform because of siRNA's low stability in physiological fluids, inefficient cellular uptake, immunoreactivity, and rapid clearance. We have developed theranostic polymeric vesicles to overcome these hurdles for encapsulation and delivery of small functional molecules and PARP1 siRNA for in vivo delivery to breast cancer tumors. The 100 nm polymer vesicles were assembled from biodegradable and non-ionic poly(N-vinylpyrrolidone)14-block-poly(dimethylsiloxane)47-block-poly(N-vinylpyrrolidone)14 triblock copolymer PVPON14-PDMS47-PVPON14 using nanoprecipitation and thin-film hydration. We demonstrated that the vesicles assembled from the copolymer covalently tagged with the Cy5.5 fluorescent dye for in vivo imaging could also encapsulate the model drug with high loading efficiency (40%). The dye-loaded vesicles were accumulated in tumors after 18 h circulation in 4TR breast tumor-bearing mice via passive targeting. We found that PARP1 siRNA encapsulated into the vesicles was released intact (13%) into solution by the therapeutic ultrasound treatment as quantified by gel electrophoresis. The PARP1 siRNA-loaded polymersomes inhibited the proliferation of MDA-MB-361TR cells by 34% after 6 days of treatment by suppressing the NF-kB signaling pathway, unlike their scrambled siRNA-loaded counterparts. Finally, the treatment by PARP1 siRNA-loaded vesicles prolonged the survival of the mice bearing 4T1 breast cancer xenografts, with the 4-fold survival increase, unlike the untreated mice after 3 weeks following the treatment. These biodegradable, non-ionic PVPON14-PDMS47-PVPON14 polymeric nanovesicles capable of the efficient encapsulation and delivery of PARP1 siRNA to successfully knock down PARP1 in vivo can provide an advanced platform for the development of precision-targeted therapeutic carriers, which could help develop highly effective drug delivery nanovehicles for breast cancer gene therapy.

Effect and Mechanism of the Lenvatinib@H-MnO2-FA Drug Delivery System in Targeting Intrahepatic Cholangiocarcinoma.

To investigate the effects of the Lenvatinib@H-MnO2-FA administration system on the proliferation and apoptosis of Intrahepatic cholangiocarcinoma (ICC) and the underlying molecular mechanism. In this research, hollow MnO2 (H-MnO2) was synthesized via the modified Stöber method, and H-MnO2 was modified with polyethylene glycol-bis (Amine) (NH2-PEG-NH2) and folic acid (FA) to obtain H-MnO2-PEG-FA (H-MnO2-FA). Lenvatinib was coated in the hollow cavity of H-MnO2-PEG-FA to further form a nanometre drug-carrying system (Lenvatinib@H-MnO2-PEG-FA). Lenvatinib@H-MnO2-FA was characterized through transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Fourier transform infrared spectroscopy (FT-IR) was used to verify that Lenvatinib was loaded on nanoparticles. Functionally, confocal laser scanning microscopy (CLSM), 2-(4-Amidinophenyl)-6-indolecarbamidine dihydrochloride (DAPI) staining, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were performed to determine the effect of Lenvatinib@H-MnO2-FA on the proliferation and apoptosis of ICC cells (9810 cells). Finally, the protein levels of Raf-1MEK1/2-ERK1/2 signalling pathway components were detected through Western blotting analysis. We successfully synthesised a Lenvatinib@H-MnO2-PEG-FA administration system. The resulting nanomaterials had excellent biological stability and improved targeting effects. Functionally, Lenvatinib@ H-MnO2-FA inhibited the proliferation of 9810 cells. The Bcl-2 protein level was significantly downregulated, and the caspase-3 protein level was significantly upregulated, indicating that Lenvatinib@H-MnO2- PEG- FA promoted the apoptosis of 9810 cells. Mechanistically, Lenvatinib@H-MnO2-FA increased the phosphorylation levels of Raf, MEK1/2, and ERK1/2. H-MnO2-FA can more effectively deliver Lenvatinib to inhibit proliferation and promote apoptosis in ICC, which could be the promising drug delivery nano-vehicles for delivery drugs.

Cluster of D-maltose clicked to β-cyclodextrin: preparation and its application as a biocompatible drug delivery nanovehicle

ABSTRACT In the current study, it was tried to design and synthesize a new derivative of β-cyclodextrin (β-CD) as a result of reaction with D-maltose (β-CD-M) to compare and investigate its capability as an anticancer drug nanocarrier. The success in the β-CD-M synthesis was validated via common characterization techniques: nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FT-IR), and scanning electron microscopy (SEM). The SEM results indicate that the obtained β-CD-M molecule has a crystalline structure with a size of less than 100 nm. In the following, methotrexate (MTX) and doxorubicin (DOX) as the model of anticancer drugs were separately loaded in β-CD-M and their release profile was obtained. The outcome of the cytotoxic assay against MCF 10A cells indicated that β-CD-M is biocompatible and could be used as a drug carrier. Overall, from the obtained results, the synthesized biocompatible β-CD-M with more drug loading capacity and a controlled release profile in comparison to unmodified β-CD could be proposed as a potential nanocarrier for anticancer drug delivery.

An Overview of Gadolinium-Based Oxide and Oxysulfide Particles: Synthesis, Properties, and Biomedical Applications

In the last decade, the publications presenting novel physical and chemical aspects of gadolinium-based oxide (Gd2O3) and oxysulfide (Gd2O2S) particles in the micro- or nano-scale have increased, mainly stimulated by the exciting applications of these materials in the biomedical field. Their optical properties, related to down and upconversion phenomena and the ability to functionalize their surface, make them attractive for developing new probes for selective targeting and emergent bioimaging techniques, either for biomolecule labeling or theranostics. Moreover, recent reports have shown interesting optical behavior of these systems influenced by the synthesis methods, dopant amount and type, particle shape and size, and surface functionality. Hence, this review presents a compilation of the latest works focused on evaluating the optical properties of Gd2O3 and Gd2O2S particles as a function of their physicochemical and morphological properties; and also on their novel applications as MRI contrast agents and drug delivery nanovehicles, discussed along with their administration routes, biodistribution, cytotoxicity, and clearance mechanisms. Perspectives for this field are also identified and discussed.

Evaluating the mucoprotective effects of glycyrrhizic acid-loaded polymeric nanoparticles in a murine model of 5-fluorouracil-induced intestinal mucositis via suppression of inflammatory mediators and oxidative stress.

5-Fluorouracil (5-FU), a chemotherapeutic drug, has severe deteriorating effects on the intestine, leading to mucositis. Glycyrrhizic acid is a compound derived from a common herbal plant Glycyrrhiza glabra, with mucoprotective, antioxidant and anti-inflammatory actions, however, associated with poor pharmacokinetics. Owing to the remarkable therapeutic action of glycyrrhizic acid-loaded polymeric nanocarriers in inflammatory bowel disease, we explored their activity against 5-FU-induced intestinal mucositis in mice. Polymeric nanocarriers have proven to be efficient drug delivery vehicles for the long-term treatment of inflammatory diseases, but have not yet been explored for 5-FU-induced mucositis. Therefore, this study aimed to produce glycyrrhizic acid-loaded polylactic-co-glycolic acid (GA-PLGA) nanoparticles to evaluate their protective and therapeutic effects in a 5-FU-induced mucositis model. GA-PLGA nanoparticles were prepared using a modified double emulsion method, physicochemically characterized, and tested for in vitro drug release. Thereafter, mucositis was induced by 5-FU (50mg/kg; IP) administration to the mice for the first 3 days (day 0, 1, 2), and mice were treated orally with GA-PLGA nanoparticles for 7 days (day 0-6). GA-PLGA nanoparticles significantly reduced mucositis severity measured by body weight, diarrhea score, distress, and anorexia. Further, 5-FU induced intestinal histopathological damage, altered villi-crypt length, reduced goblet cell count, elevated pro-inflammatory mediators, and suppressed antioxidant enzymes, all of which were reversed by GA-PLGA nanoparticles. Morphological, behavioral, histological, and biochemical results suggested that GA-PLGA nanoparticles were efficient, biocompatible, targeted, and sustained release drug delivery nano-vehicle for enhanced mucoprotective, anti-inflammatory, and antioxidant effects in 5-FU-induced intestinal mucositis.

Efficient Anti-Glioma Therapy Through the Brain-Targeted RVG15-Modified Liposomes Loading Paclitaxel-Cholesterol Complex.

BackgroundGlioma is the most common primary malignant brain tumor with a dreadful overall survival and high mortality. One of the most difficult challenges in clinical treatment is that most drugs hardly pass through the blood–brain barrier (BBB) and achieve efficient accumulation at tumor sites. Thus, to circumvent this hurdle, developing an effectively traversing BBB drug delivery nanovehicle is of significant clinical importance. Rabies virus glycoprotein (RVG) is a derivative peptide that can specifically bind to nicotinic acetylcholine receptor (nAChR) widely overexpressed on BBB and glioma cells for the invasion of rabies virus into the brain. Inspired by this, RVG has been demonstrated to potentiate drugs across the BBB, promote the permeability, and further enhance drug tumor-specific selectivity and penetration.MethodsHere, we used the RVG15, rescreened from the well-known RVG29, to develop a brain-targeted liposome (RVG15-Lipo) for enhanced BBB permeability and tumor-specific delivery of paclitaxel (PTX). The paclitaxel-cholesterol complex (PTX-CHO) was prepared and then actively loaded into liposomes to acquire high entrapment efficiency (EE) and fine stability. Meanwhile, physicochemical properties, in vitro and in vivo delivery efficiency and therapeutic effect were investigated thoroughly.ResultsThe particle size and zeta potential of PTX-CHO-RVG15-Lipo were 128.15 ± 1.63 nm and −15.55 ± 0.78 mV, respectively. Compared with free PTX, PTX-CHO-RVG15-Lipo exhibited excellent targeting efficiency and safety in HBMEC and C6 cells, and better transport efficiency across the BBB in vitro model. Furthermore, PTX-CHO-RVG15-Lipo could noticeably improve the accumulation of PTX in the brain, and then promote the chemotherapeutic drugs penetration in C6luc orthotopic glioma based on in vivo imaging assays. The in vivo antitumor results indicated that PTX-CHO-RVG15-Lipo significantly inhibited glioma growth and metabasis, therefore improved survival rate of tumor-bearing mice with little adverse effect.ConclusionOur study demonstrated that the RVG15 was a promising brain-targeted specific ligands owing to the superior BBB penetration and tumor targeting ability. Based on the outstanding therapeutic effect both in vitro and in vivo, PTX-CHO-RVG15-Lipo was proved to be a potential delivery system for PTX to treat glioma in clinic.

Metal–polymer-coordinated complexes as potential nanovehicles for drug delivery

Metal–polymer-coordinated complexes as potential nanovehicles for drug delivery

The role of extracellular vesicles in the physiological and pathological regulation of the blood-brain barrier.

Extracellular vesicles (EVs) are a subclass of biological nanoparticles secreted by most cell types. Once secreted, EVs can travel long distances to deliver their content to target cells thereby playing a key role in cell‐to‐cell communication and supporting both physiological and pathological processes. In recent years, the functional versatility of EVs has come to be more widely appreciated. Their heterogeneous structure encloses solubilized bioactive cargoes including proteins and nucleic acids. EVs mirror the secreting cell in composition therefore representing a novel source of diagnostic and prognostic biomarkers. Moreover, due to their unique structure, EVs constitute a promising class of biocompatible nanovehicles for drug delivery as well. Importantly, and of burgeoning interest, is the fact that EVs have the intrinsic ability to breach biological barriers including the complex blood–brain barrier (BBB), whose restrictive nature represents a significant therapeutic challenge. EVs have been shown to contribute to the progression of a variety of brain diseases including metastatic brain cancer, neurodegenerative diseases, and acute pathologies including infections and ischemia. In this review, the role of EVs in the maintenance and regulation of the BBB under normal physiological and pathologic conditions are discussed. Applications of EVs as therapeutic and diagnostic tools in the treatment of diseases that affect the central nervous system are presented as are limitations hindering their broad translation and potential solutions to resolve them.

Self-assembling ferritin-dendrimer nanoparticles for targeted delivery of nucleic acids to myeloid leukemia cells

BackgroundIn recent years, the use of ferritins as nano-vehicles for drug delivery is taking center stage. Compared to other similar nanocarriers, Archaeoglobus fulgidus ferritin is particularly interesting due to its unique ability to assemble-disassemble under very mild conditions. Recently this ferritin was engineered to get a chimeric protein targeted to human CD71 receptor, typically overexpressed in cancer cells.ResultsArchaeoglobus fulgidus chimeric ferritin was used to generate a self-assembling hybrid nanoparticle hosting an aminic dendrimer together with a small nucleic acid. The positively charged dendrimer can indeed establish electrostatic interactions with the chimeric ferritin internal surface, allowing the formation of a protein-dendrimer binary system. The 4 large triangular openings on the ferritin shell represent a gate for negatively charged small RNAs, which access the internal cavity attracted by the dense positive charge of the dendrimer. This ternary protein-dendrimer-RNA system is efficiently uptaken by acute myeloid leukemia cells, typically difficult to transfect. As a proof of concept, we used a microRNA whose cellular delivery and induced phenotypic effects can be easily detected. In this article we have demonstrated that this hybrid nanoparticle successfully delivers a pre-miRNA to leukemia cells. Once delivered, the nucleic acid is released into the cytosol and processed to mature miRNA, thus eliciting phenotypic effects and morphological changes similar to the initial stages of granulocyte differentiation.ConclusionThe results here presented pave the way for the design of a new family of protein-based transfecting agents that can specifically target a wide range of diseased cells.Graphic abstract

A Review on Natural Sources Derived Protein Nanoparticles as Anticancer Agents.

Cancer notably carcinoma represents a prominent health challenge worldwide. A variety of chemotherapeutic agents are being used to deal with a variety of carcinomas. However, these delivering agents not only enter the targeted site but also affect normal tissues yielding poor therapeutic outcomes. Chemotherapeutic-associated problems are being attributed to drug non-specificity resulting from poor drug delivery systems. These problems are now being solved using nanomedicine, which entails using nanoparticles as drug delivery systems or nanocarriers. This nanoparticle-based drug delivery system enhances clinical outcomes by enabling targeted delivery, improving drug internalization, enhanced permeability, easy biodistribution, prolonged circulation and enhanced permeability rate, thereby improving the therapeutic effectiveness of several anticancer agents. Natural Protein-based Nanoparticles (PNPs) such as ferritin, lipoprotein, and lectins from natural sources have gained extensive importance at a scientific community level as nanovehicle for effective drug delivery and photo acoustic labeling replacing several synthetic nanocarriers that have shown limited therapeutic outcomes. The bioavailability of PNP, the chance of genetic engineering techniques to modify their biological properties made them one of the important raw material sources for drug delivery research. This current review highlighted different chemotherapeutic agents used in the treatment of some carcinomas. It also focused on the wide variety of natural protein sources derived nanoparticles (NPs) as anticancer delivery of agents for cancer therapy.

Adsorption of melphalan anticancer drug on C24, B12N12, B12C6N6, B6C12N12 and B6C6N12 nanocages: A comparative DFT study

Anticancer drug delivery is becoming a central scientific defy since it allows locating drug release near the tumor cell and circumventing secondary side effects. Based on density functional theory (DFT) calculations, adsorption of most abundant melphalan anticancer drug specie at physiological pH on a series of small 24 atoms nanoclusters (C24, B12N12 and carbon doped boron nitride molecules: B12C6N6, B6C12N6 and B6C6N12), was carried out both in vacuum and solvent (water) environment conditions at B3LYP-D3(BJ)/6-31G(d,p) level of theory. The most stable chemisorption state for melphalan was through oxygen atom onto all nanocluster under study, in comparison with chlorine and nitrogen atoms and comparing both environments, the computed results indicate that the adsorption of melphalan in the solvent environment is in general more stable. According to our results, boron nitride and some of its mixed nanoclusters may serve as potential drug delivery nanovehicles for melphalan drug. The results from this work are expected to motivate further inquiries concerning these systems, using both theoretical and experimental approaches, in order to validate their versatility as nanovehicles.

Drug Delivery: Hydrophobic DrugEncapsulation into Amphiphilic Block CopolymerMicelles.

Drug encapsulation into amphiphilic block copolymer micelles aims to increase drug solubility and minimize drug degradation upon administration, avoid undesirable side effects and ameliorate drug bioavailability. Drug encapsulation methodologies including thin-film hydration method and organic cosolvent method are described in this chapter. Often, it is desirable to determine the most efficient solubilization protocol leading to functional drug delivery nanovehicles in each case. The encapsulation of curcumin into PEO-b-PPO-b-PEO (Pluronic F-127) polymeric micelles through thin-film hydration method presents the most promising results. Indomethacin can be loaded successfully into the hydrophobic cores of PEO-b-PCL amphiphilic block copolymer micelles following both encapsulation protocols.

Cinnamyl modified polymer micelles as efficient carriers of caffeic acid phenethyl ester

A synthetic strategy towards modular polymer platform capable of further tunable degree of modification is presented. Initially, a well-defined amphiphilic block copolymer with alkyne side groups distributed along the biodegradable hydrophobic block was successfully prepared applying controlled ring-opening copolymerization of D,L-lactide and an acetylene-functional cyclic carbonate initiated by polyoxyethylene macroinitiator. In the second synthetic step a desired number of cinnamyl pendant groups was introduced into the hydrophobic block via “click” reaction. The functional block copolymers self-associated in aqueous media into stable micelles with narrow size distribution and average diameters of around 50 nm. The micelles' functional hydrophobic cores were loaded with caffeic acid phenethyl ester (CAPE) as bioactive compound with great potential for therapeutic application. It was demonstrated that the initial drug-release profiles, hence the stability of the loaded nanocarriers during circulation, can be modulated via the number of cinnamyl groups into the micelles core. Initial in-vitro evaluations were preformed on empty and drug-loaded functional polymer micelles indicating their potential for application in nanomedicine as safe and biocompatible drug-delivery nanovehicles with enhanced stability. • Amphiphilic block copolymers with cinnamyl pendant groups are synthesized. • Functional micelles with enhanced stability are formed. • Caffeic acid phenethyl ester is encapsulated into the functional micelles core. • The drug-release profile is modulated by the number of functional side-groups. • The micelles are safe, biocompatible and suitable for drug delivery application.

Norepinephrine transporter-derived homing peptides enable rapid endocytosis of drug delivery nanovehicles into neuroblastoma cells

BackgroundCurrently, the diagnosis and treatment of neuroblastomas—the most frequent solid tumors in children—exploit the norepinephrine transporter (hNET) via radiolabeled norepinephrine analogs. We aim to develop a nanomedicine-based strategy towards precision therapy by targeting hNET cell-surface protein with hNET-derived homing peptides.ResultsThe peptides (seq. GASNGINAYL and SLWERLAYGI) were shown to bind high-resolution homology models of hNET in silico. In particular, one unique binding site has marked the sequence and structural similarities of both peptides, while most of the contribution to the interaction was attributed to the electrostatic energy of Asn and Arg (< − 228 kJ/mol). The peptides were comprehensively characterized by computational and spectroscopic methods showing ~ 21% β-sheets/aggregation for GASNGINAYL and ~ 27% α-helix for SLWERLAYGI. After decorating 12-nm ferritin-based nanovehicles with cysteinated peptides, both peptides exhibited high potential for use in actively targeted neuroblastoma nanotherapy with exceptional in vitro biocompatibility and stability, showing minor yet distinct influences of the peptides on the global expression profiles. Upon binding to hNET with fast binding kinetics, GASNGINAYLC peptides enabled rapid endocytosis of ferritins into neuroblastoma cells, leading to apoptosis due to increased selective cytotoxicity of transported payload ellipticine. Peptide-coated nanovehicles significantly showed higher levels of early apoptosis after 6 h than non-coated nanovehicles (11% and 7.3%, respectively). Furthermore, targeting with the GASNGINAYLC peptide led to significantly higher degree of late apoptosis compared to the SLWERLAYGIC peptide (9.3% and 4.4%, respectively). These findings were supported by increased formation of reactive oxygen species, down-regulation of survivin and Bcl-2 and up-regulated p53.ConclusionThis novel homing nanovehicle employing GASNGINAYLC peptide was shown to induce rapid endocytosis of ellipticine-loaded ferritins into neuroblastoma cells in selective fashion and with successful payload. Future homing peptide development via lead optimization and functional analysis can pave the way towards efficient peptide-based active delivery of nanomedicines to neuroblastoma cells.