Lipid Nanoparticles: An Effective Tool to Improve the Bioavailability of Nutraceuticals.

Nano-range bioactive colloidal carrier systems are envisaged to overcome the challenges associated with treatments of numerous diseases. Lipid nanoparticles (LNPs), one of the extensively investigated drug delivery systems, not only improve pharmacokinetic parameters, transportation, and chemical stability of encapsulated compounds but also provide efficient targeting and reduce the risk of toxicity. Over the last decades, nature-derived polyphenols, vitamins, antioxidants, dietary supplements, and herbs have received more attention due to their remarkable biological and pharmacological health and medical benefits. However, their poor aqueous solubility, compromised stability, insufficient absorption, and accelerated elimination impede research in the nutraceutical sector. Owing to the possibilities offered by various LNPs, their ability to accommodate both hydrophilic and hydrophobic molecules and the availability of various preparation methods suitable for sensitive molecules, loading natural fragile molecules into LNPs offers a promising solution. The primary objective of this work is to explore the synergy between nature and nanotechnology, encompassing a wide range of research aimed at encapsulating natural therapeutic molecules within LNPs.

Equilibrium, kinetics, thermodynamics and docking studies of Cu2+ ion adsorption over ion-exchange resin and kappa carrageenan blends in blood samples.

Cupric ions are hazardous to human beings and their removal from the body is very necessary. The blends of IRP69H (AMBERLITE IRP-69 [H+] RESIN), DC20H (DOWEX™ 20 [H+] Resin), DMSCH (DOWEX™ MARATHON™ MSC [H+] Resin) and Kappa Carrageenan (κ-) were utilized for the removal of ions of Cu2+ from the blood. They were subjected to docking studies which showed that there is no significant interaction with the blood albumin. IER dose of 0.5 mg/10mL of IRP69H/κ-, DMSCH/κ-, and DC20H/κ- was essential for the 2+ ion removal. At pH 5.4, optimal 2+ ions adsorption efficiency was attained. The adsorption capacities of 2+ were in the order of IRP69H/κ->DC20H/κ->DMSCH/κ-. While the data fitted well to Freundlich, Langmuir and Dubinin-Radushkevich. Pseudo-second order was followed for 2+ adsorption for DMSCH/κ- and DC20H/κ- while the pseudo-first order was demonstrated well for IRP69H/κ-.

An assessment of bioavailability of acrylate based pH-sensitive complexes of lovastatin.

Lovastatin (LSN), a potent anti-hyperlipidemic drug, possesses poor bioavailability due to its very low aqueous solubility. The objective of this study was to establish a relationship between increased drug solubility before reaching site of absorption or increasing drug solubility at target absorption site for accentuated bioavailability of LSN. Composites of LSN with oppositely natured pH-sensitive acrylate polymers, cationic Eudragit EPO (EPO) and anionic Eudragit L100 (L100), were fabricated with physical trituration and kneading methods. Formulations were characterized for solubility, FTIR, PXRD, DSC, SEM, dissolution and bioavailability studies in rats. Interestingly, we observed that physical mixtures of EPO outmatched its kneaded formulations, whereas the physical mixtures and kneaded dispersions of L100 were virtually similar in characteristics. EPO was superior in boosting LSN solubility in the respective medium than the L100. Moreover, EPO produced immediate release profile in gastric environment whereas L100 offered sustained release of LSN in intestinal milieu. Bioavailability studies in rats further supported the EPO formulation in terms of shorter Tmax, higher Cmax and heightened AUC.

Clove oil based co-surfactant free microemulsion of flurbiprofen: Improved solubility with ameliorated drug-induced gastritis.

Flurbiprofen, an NSAID, is a water insoluble drug that is also notorious for gastric irritation and inflammation. This study was aimed at using a natural gastrprotective oil as the internal phase to develop flurbiprofen micro emulsion (ME) to improve it solubility and ameliorate its gastric side effects. Upon screening of ME components for drug solubility, clove oil, tween 80 and transcutol were identified as the oil, surfactant and co surfactant, respectively, with higher flurbiprofen solubility. Pseudo-ternary phase diagrams revealed that the ME made with surfactant only and without co-surfactant displayed the similar ME region as made with the mixture of surfactant and co-surfactant. Furthermore, drug loaded oil was also used to draw pseudo-ternary phase diagram and a very little decrease in the ME region was observed. Therefore, co-surfactant free flurbiprofen loaded ME was developed to avoid side effects associated with the use of excessive surfactant quantities. ME were found to possess size in the range of 11-41 nm with PDI <0.5 and a slightly negative charge. Conductivity, pH and refractive indices of the selected MEs were well in the range. Drug release studies indicated maximum drug release from MEs within 5 min. Analysis of the gastric mucosa of rats after oral administration of drug solution and drug loaded ME confirmed that clove oil based ME provided significant protection against the NSAIDs induced gastric damage.

Enhanced oral bioavailability of 10-hydroxycamptothecin through the use of poly (n-butyl cyanoacrylate) nanospheres.

The article describes the preparation, physicochemical characterization, drug release, and in vivo behavior of 10-hydroxycamptothecin-loaded poly (n-butyl cyanoacrylate) (PBCA) nanospheres (HCPT-PBCA-NSs). HCPT-PBCA-NSs were successfully prepared via emulsion polymerization of n-butyl cyanoacrylate (BCA) monomer in acidic medium with the aid of two colloidal stabilizers (Poloxamer 188 and Dextran 70). The influence of pH, the time of polymerization, and the dosage of the drug on particle size and encapsulation efficiency (EE) were studied. HCPT-PBCA-NSs were of spherical shape and uniformly dispersed with a particle size of 135.7 nm, and zeta potential of -18.18 mV. EE, drug loading (DL), and yield of HCPT-PBCA-NSs were 51.52, 0.63, and 88.25%, respectively. FTIR, 1H NMR, and DSC showed complete polymerization of BCA monomer and HCPT existed in the form of molecular or amorphous in NSs. In vitro release of the drug from HCPT-PBCA-NSs exhibited sustained-release behavior with an initial burst release and about 60% of HCPT was released from the formulation within 24 h of dialysis. The pharmacokinetic study in healthy rats after oral administration showed that encapsulation of HCPT into PBCA-NSs increased the Cmax about 3.84 times and increased AUC0-t about 5.40 times compared with that of HCPT suspension. It was concluded that PBCA-NSs could be a promising drug carrier to load HCPT for oral drug delivery if efforts are made in the future to improve its poor DL capacity.

Amorphous solid dispersion with increased gastric solubility in tandem with oral disintegrating tablets: a successful approach to improve the bioavailability of atorvastatin.

CONTEXT: Serious efforts have been made to overcome the bioavailability problems of ever increasing number of poorly soluble drugs, including atorvastatin (ATO); however, enhancing its gastric solubility has not received much attention. OBJECTIVES: To improve the bioavailability of ATO by increasing its gastric solubility in a stable oral disintegration tablet (ODT) formulation. MATERIALS AND METHODS: Amorphous solid dispersion (ASD) of ATO with Eudragit® EPO was used as API in ODT formulation. Characterization using Differential scanning calorimetry, Powder X-ray diffraction, Fourier transform infrared drug-polymer interaction simulated by molecular modeling, solubility, dissolution and stability studies together with in vivo evaluation. RESULTS AND DISCUSSION: In ASD there was uniform distribution of drug in the polymer and it retained the amorphous nature without any chemical interactions except the possibility of hydrogen bond formation, with substantially higher gastric solubility. The dissolution profile of the ODT containing ASD was significantly improved >90% within 15 min compared with 25% of plain ATO formulation. In vivo results showed an overall enhancement in the apparent bioavailability (83% and 434% more than Lipitor® and plain amorphous ATO tablets, respectively). Combining the ASD with ODT presents a reliable solution to overcome the low solubility and bioavailability problems of ATO in a simple, robust and cost effective formulation.

Dual-targeted enzyme-sensitive hyaluronic acid nanogels loading paclitaxel for the therapy of breast cancer.

In this study, a CD44 and biotin receptors dual-targeted enzyme-sensitive hyaluronic acid nanogel loading paclitaxel (PTX/Bio-NG) for targeting breast cancer was constructed. Spherical nanogels with a mean particle size of 149.1 ± 1.6 nm, higher entrapment efficiency (90.17 ± 0.52 %) and drug loading (15.28 ± 0.10 %) were obtained. PTX/Bio-NG quickly released drugs under the catalysis of hyaluronidase and/or lipase. Cell studies revealed that the uptake of Bio-NG by 4T1 cells was mediated by CD44 receptor and Bio-specific receptor. Compared with PTX-loaded biotin-free NG (PTX/NG), PTX/Bio-NG had higher cytotoxicity against breast cancer cells (4T1 cells). The rats pharmacokinetic profile indicated higher AUC0-t but lower clearance rates of PTX/NG (6.24 times and 15.96 %, respectively) and PTX/Bio-NG (6.66 times and 14.89 %, respectively) than control group (Taxol). In vivo studies showed that PTX/Bio-NG possessed excellent therapeutic efficacy in 4T1 tumor-bearing Balb/c mice, which suggest that PTX/Bio-NG could be an excellent candidate for the treatment of breast cancer.

Engineering Exosome-Like Nanovesicles Derived from Asparagus cochinchinensis Can Inhibit the Proliferation of Hepatocellular Carcinoma Cells with Better Safety Profile.

BACKGROUND: Exosomes are a type of membrane vesicles secreted by living cells. Recent studies suggest exosome-like nanovesicles (ELNVs) from fruits and vegetables are involved in tissue renewal process and functional regulation against inflammatory diseases or cancers. However, there are few reports on ELNVs derived from medicinal plants. METHODS: ELNVs derived from Asparagus cochinchinensis (Lour.) Merr. (ACNVs) were isolated and characterized. Cytotoxicity, antiproliferative and apoptosis-inducing capacity of ACNVs against hepatoma carcinoma cell were assessed. The endocytosis mechanism of ACNVs was evaluated on Hep G2 cells in the presence of different endocytosis inhibitors. In vivo distribution of ACNVs was detected in healthy and tumor-bearing mice after scavenger receptors (SRs) blockade. PEG engineering of ACNVs was achieved through optimizing the pharmacokinetic profiles. In vivo antitumor activity and toxicity were evaluated in Hep G2 cell xenograft model. RESULTS: ACNVs were isolated and purified using a differential centrifugation method accompanied by sucrose gradient ultracentrifugation. The optimized ACNVs had an average size of about 119 nm and showed a typical cup-shaped nanostructure containing lipids, proteins, and RNAs. ACNVs were found to possess specific antitumor cell proliferation activity associated with an apoptosis-inducing pathway. ACNVs could be internalized into tumor cells mainly via phagocytosis, but they were quickly cleared once entering the blood. Blocking the SRs or PEGylation decoration prolonged the blood circulation time and increased the accumulation of ACNVs in tumor sites. In vivo antitumor results showed that PEGylated ACNVs could significantly inhibit tumor growth without side effects. CONCLUSION: This study provides a promising functional nano platform derived from edible Asparagus cochinchinensis that can be used in antitumor therapy with negligible side effects.

Lactoferrin/phenylboronic acid-functionalized hyaluronic acid nanogels loading doxorubicin hydrochloride for targeting glioma.

Herein, lactoferrin (Lf)/phenylboronic acid (PBA)-functionalized hyaluronic acid nanogels crosslinked with disulfide-bond crosslinker was developed as a reduction-sensitive dual-targeting glioma therapeutic platform for doxorubicin hydrochloride (DOX) delivery (Lf-DOX/PBNG). Spherical Lf-DOX/PBNG with optimized physicochemical properties was obtained, and it could rapidly release the encapsulated DOX under high glutathione concentration. Moreover, enhanced cytotoxicity, superior cellular uptake efficiency, and significantly improved brain permeability of Lf-DOX/PBNG were observed in cytological studies compared with those of DOX solution, DOX-loaded PBA functionalized nanogels (DOX/PBNG), and Lf modified DOX-loaded nanogels (Lf-DOX/NG). The pharmacokinetic study exhibited that the area under the curve of DOX/PBNG, Lf-DOX/NG, and Lf-DOX/PBNG increased by 8.12, 4.20 and 4.32 times compared with that of DOX solution, respectively. The brain accumulation of Lf-DOX/PBNG was verified in biodistribution study to be 12.37 and 4.67 times of DOX solution and DOX/PBNG, respectively. These findings suggest that Lf-DOX/PBNG is an excellent candidate for achieving effective glioma targeting.

Optimization, in vitro release and toxicity evaluation of novel pH sensitive itaconic acid-g-poly(acrylamide)/sterculia gum semi-interpenetrating networks.

BACKGROUND: In recent era, pH sensitive polymeric carriers that combines the materials engineering and medicine is gaining researcher's attention as they maximizes drug concentration at site of absorption and reduces side effects for e.g. orally administered cetirizine HCl (CTZ HCl) upsets the stomach and furthermore shows high intestinal absorption. Thus, development of pH sensitive hydrogels with sufficient mechanical strength will be good candidate to address this issue. METHODS: Here, we developed pH sensitive itaconic acid-g-poly(acrylamide)/sterculia gum (IA-g-poly(AM)/sterculia gum) semi-interpenetrating network (semi-IPN) by free radical polymerization technique for intestinal delivery of CTZ HCL. RESULTS: Optimized formulation (I5) with 6% w/w IA showed negligible swelling at pH 1.2, and maximum swelling at pH 7.4. Solid state characterization of optimized formulation showed successful development of semi-IPN structure and incorporation of drug without any noticeable drug-carrier interaction. In vitro release study showed biphasic pH dependent release of CTZ HCl, where initial burst release was observed at acidic pH followed by sustained release at basic pH. Acute oral toxicity and histopathological studies confirmed the non-toxic nature of IA-g-poly(AM)/sterculia gum. CONCLUSION: Conclusively, developed biocompatible semi-IPN hydrogels with sufficient pH sensitivity and mechanical strength could serve as a potential carrier for intestinal delivery of CTZ HCL to maximize its absorption and reduce side effects.

Nanoemulgel, an Innovative Carrier for Diflunisal Topical Delivery with Profound Anti-Inflammatory Effect: in vitro and in vivo Evaluation.

PURPOSE: Rheumatoid arthritis is an autoimmune disorder that directly affects joints. However, other body organs including heart, eyes, skin, blood vessels and lungs may also be affected. The purpose of this study was to design and evaluate a nanoemulgel formulation of diflunisal (DIF) and solubility enhanced diflunisal (DIF-IC) for enhanced topical anti-inflammatory activity. METHODOLOGY: Nanoemulsion formulations of both DIF and DIF-IC were prepared and incorporated in three different gelling agents, namely carboxymethylcellulose sodium (CMC-Na), sodium alginate (Na-ALG) and xanthan gum (XG). All the formulations were evaluated in term of particle size, pH, conductivity, viscosity, zeta potential and in vitro drug release. The formulation 2 (NE2) of both DIF and DIF-IC which expressed optimum release and satisfactory physicochemical properties was incorporated with gelling agents to produce final nanoemulgel formulations. The optimized nanoemulgel formulation was subjected to three different in vivo anti-inflammatory models including carrageenan-induced paw edema model, histamine-induced paw edema model and formalin-induced paw edema model. RESULTS: DIF-IC-loaded nanoemulgel formulations yielded significantly enhanced in vitro skin permeation than DIF-loaded nanoemulgel. The nanoemulgel formulation of DIF-IC formulated with XG produced improved in vivo anti-inflammatory activity. CONCLUSION: It was recommended that DIF-IC-based nanoemulgel formulation prepared with XG could be a better option for effective topical treatment of inflammatory conditions.

Borneol and poly (ethylene glycol) dual modified BSA nanoparticles as an itraconazole vehicle for brain targeting.

Itraconazole (ITZ) can be used for the treatment of cryptococcus neoformans meningitis and aspergillus brain abscess. While, the inherent hydrophobicity of ITZ and the existence of blood brain barrier (BBB) limit its applications as a central nervous system drug. In this study, a novel brain targeting drug delivery system based on bovine serum albumin (BSA) was constructed for enhancing ITZ distribution in brain. Firstly, ITZ was loaded into BSA nanoparticles (ITZ-NPs) with 11.6% of drug loading. Subsequently, the nanoparticles were modified with borneol (BO) and polyethylene glycol (PEG) (PEG/BO-ITZ-NPs). The resulting nanoparticles retained their nanosize (186.3 nm), uniform and spherical morphology, and negative surface charge (-21.03 mV). Cell uptake studies showed that compared with ITZ-NPs, PEG/BO-ITZ-NPs had significantly increased uptake in bEnd.3 cells, and the increase in BO concentration was beneficial for the cellular uptake of NPs. Moreover, PEG/BO-ITZ-NPs displayed an approximately 3.5-fold higher area under the curve in rats and about 2-fold higher brain distribution in mice than that of Sporanox®, i.e. ITZ solubilized by hydroxylpropyl-ß-cyclodetrin, after i.v. administration. In a word, BO and PEG dual modified BSA nanoparticles may potentially serve as an ITZ vehicle for brain targeting.

Amino-decorated mesoporous silica nanoparticles for controlled sofosbuvir delivery.

The present study describes synthesis of amino-decorated mesoporous silica nanoparticles (MSNs) for sustained delivery and enhanced bioavailability of sofosbuvir. Sofosbuvir is active against hepatitis C virus and pharmaceutically classified as class III drug according to biopharmaceutics classification system (BCS). MSNs were synthesized using modified sol-gel method and the surface was decorated with amino functionalization. Drug loaded MSNs were also grafted with polyvinyl alcohol in order to compare it with the amino-decorated MSNs for sustained drug release. The prepared MSNs were extensively characterized and the optimized formulation was toxicologically and pharmacokinetically evaluated. The functionalized MSNs of 196 nm size entrapped 29.13% sofosbuvir in the pores, which was also confirmed by the decrease in surface area, pore volume and pore size. The drug-loaded amino-decorated MSNs revealed an improved thermal stability as confirmed by thermal analysis. Amino-decorated MSNs exhibited Fickian diffusion controlled sofosbuvir release as compared with non-functionalized and PVA grafted MSNs. Amino-decorated MSNs were deemed safe to use in Sprague-Dawley rats after 14-days exposure as confirmed by the toxicological studies. More interestingly, we achieved a 2-fold higher bioavailability of sofosbuvir in Sprague-Dawley rats in comparison with sofosbuvir alone, and the Tmax was delayed 3-times indicating a sustained release of sofosbuvir.

Formulation and evaluation of natural gum-based sustained release matrix tablets of flurbiprofen using response surface methodology.

BACKGROUND: This research work was done to design oral sustained release matrix tablets of water-insoluble drug, flurbiprofen, using natural gums as the matrix polymers and to evaluate the drug release characteristics using response surface methodology. The central composite design for two factors at five levels each was employed to systematically optimize drug release profile. METHOD: Matrix tablets were prepared by direct compression technique. Xanthan and acacia gums were taken as the independent variables. Fourier transform infrared spectroscopy studies were also performed to find out the stability of drug during the direct compression and to check the interactions between polymers and drug. Percent drug release in 2 hours and percent drug release in 8 hours were taken as response variables (Y1 and Y2, respectively). RESULTS: Both the polymers were found to have significant effect on the drug release. Polynomial mathematical models, generated for the response variables using multiple linear regression analysis, were found to be statistically significant (P < 0.05). Contour plots were drawn to depict the relationship between response variables and independent variables. CONCLUSION: The formulated matrix tablets followed zero-order kinetics with negligible drug release in 0.1 N HCl at pH 1.2, which was the objective of this study to produce a formulation avoiding the gastric effects of flurbiprofen.

Effects of phospholipid and polyethylene glycol monostearate (100) on the in vitro and in vivo physico-chemical characterization of poly(n-butyl cyanoacrylate) nanoparticles.

In this study, poly(n-butyl cyanoacrylate) nanoparticles (PBCA-NPs) modified with various amounts of soybean phospholipid (PC) and polyethylene glycol monostearate (S100) were prepared in order to investigate the effects of PC and S100 on the nanoparticles' physico-chemical properties, cytological properties and in vivo gastrointestinal absorption. Coumarin-6 (C6) was used as a fluorescent probe; C6-loaded PBCA-NPs modified with both PC and S100 (C6-PS-PBCA-NPs) were prepared using miniemulsion polymerization, and C6-loaded PBCA-NPs modified with either S100 (C6-S-PBCA-NPs) or PC (C6-P-PBCA-NPs) were used as references. All of the different NPs were shown to be stably dispersed and to have a small particle size. A cytotoxicity study indicated that all of the blank PBCA-NPs were safe and nontoxic. The uptake of NPs by Caco-2 cells was shown to be increased when the amount of PC was increased from 0% to 1.25% and the amount of S100 was increased from 0% to 0.725%. The use of a ligated intestinal loop model demonstrated that C6-PS-PBCA-NPs could rapidly penetrate a highly viscoelastic mucous layer, leading to an improvement in the absorption efficiency. During a pharmacokinetic study, C6-PS-PBCA-NPs improved the absorption of C6, as indicated by their higher Cmax and AUC0-t values compared with those of C6-S-PBCA-NPs or C6-P-PBCA-NPs. Overall, the results of this study indicate that PBCA-NPs modified with PC and S100 can enhance the absorption of orally administered drugs.

Local strategies and delivery systems for the treatment of malignant gliomas.

Glioma is one of the most common type of malignant tumours with high morbidity and mortality rates. Due to the particular features of the brain, such as blood-brain barrier or blood-tumour barrier, therapeutic agents are ineffective by systemic administration. The tumour inevitably recurs and devitalises patients. Herein, an overview of the localised gliomas treatment strategies is provided, including direct intratumoural/intracerebral injection, convection-enhanced delivery, and the implant of biodegradable polymer systems. The advantages and disadvantages of each therapy are discussed. Subsequently, we have reviewed the recent developments of therapeutic delivery systems aimed at transporting sufficient amounts of antineoplastic drugs into the brain tumour sites while minimising the potential side effects. To treat gliomas, localised and controlled delivery of drugs at their desired site of action is preferred as it reduces toxicity and increases treatment efficiency. Simultaneously, various drug delivery systems (DDS) have been used to enhance drug delivery to the brain. Use of non-conventional DDS for localised therapy has greatly expanded the spectrum of drugs available for the treatment of malignant tumours. Use smart DDS via localised delivery strategies, in combination with radiotherapy and multiple drug loading would serve as a promising approach to treat gliomas.

Mesenchymal stem cells-curcumin loaded chitosan nanoparticles hybrid vectors for tumor-tropic therapy.

The combination of controlled release technology and targeted drug delivery has become a promising strategy for cancer therapy. In this study, cell-nanoparticle hybrid vector was constructed using mesenchymal stem cells as the targeting cellular carrier and biotinylated chitosan polymer nanoparticles as the drug depot. Drug-loaded nanoparticles (hydrodynamic size =377.0 ±â€¯14.6 nm and zeta potential = 9.6 ±â€¯1.9 mV) were prepared by encapsulating hydrophobic model drug curcumin into biotinylated chitosan polymer. The biotin-modified nanoparticles were anchored on biotinylated mesenchymal stem cells surface by biotin-avidin binding, achieving an upload of 54.73 ±â€¯3.95 pg/cell. The anchorage of nanoparticles on mesenchymal stem cells had no effect on their viability and homing property. Biotin-avidin binding lasted over 48 h, which could be sufficient for cell-directed tumor-tropic delivery. The in vitro and in vivo anti-tumor results advocate that cell-nanoparticle hybrid vector could prove beneficial in pulmonary melanoma metastasis therapy.

Tween 80-modified hyaluronic acid-ss-curcumin micelles for targeting glioma: Synthesis, characterization and their in vitro evaluation.

Redox-sensitive micelles based onhydrophilic hyaluronic acid-ss-hydrophobic curcumin conjugate were designed as a novel delivery system for gliomas targeting. Furthermore, the obtained micelles were further functionalized with Tween 80 (CUR-THSC) for better brain penetration. Dynamic light scattering experiment and in vitro release study showed that the synthetic disulfide-linked conjugate possessed redox-sensitivity under high glutathione conditions. Spherical micelles with a mean particle size of 74.2 nm, negative zeta potential (-30.25 mV), high entrapment efficiency (94.12%) and drug loading (8.9%) were obtained. XRD analysis of micelles revealed amorphous form of the encapsulated drug. CUR-THSC micelles showed good plasma stability and did not induce any hemolysis in erythrocytes. In addition, highest cytotoxicity in G422 cells was observed compared to the free curcumin group and non-sensitive micelles group. These results indicate that the Tween 80-modified hyaluronic acid-ss-curcumin micelles could emerge as a promising platform for the delivery of curcumin in the treatment of gliomas.

In vitro and in vivo evaluation of 10-hydroxycamptothecin-loaded poly (n-butyl cyanoacrylate) nanoparticles prepared by miniemulsion polymerization.

In this paper, 10-hydroxycamptothecin (HCPT)-loaded poly (n-butyl cyanoacrylate) nanoparticles (HCPT-PBCA-NPs) co-modified with polysorbate 80, soybean phospholipids, and polyethylene glycol (100) monostearate were successfully prepared via miniemulsion polymerization, and were characterized for particle size, morphology, zeta potential, encapsulation efficiency (EE) and drug loading capacity (DL). The chemical structure of HCPT-PBCA-NPs and the state of HCPT in the PBCA-NPs were investigated by DSC, FTIR and 1H NMR. Additionally, drug release, cytotoxicity, cellular uptake capacity, cellular uptake mechanism, and in vivo behavior of NPs were investigated as well. The particles were 92.7nm in size with a high EE of 94.24%. FTIR, 1H NMR, and DSC demonstrated complete polymerization of BCA monomers and the drug was in a molecular or amorphous form inside the NPs. In vitro release of the drug from HCPT-PBCA-NPs exhibited sustained-release and less than 60% of HCPT was released from the NPs within 24h of dialysis. Cellular uptake study displayed that Caco-2 cell uptake of NPs was governed by active endocytosis, clathrin- and caveolin-mediated process, and increased with the increase of the NPs concentration and the time. The pharmacokinetic study in rats showed that encapsulation of HCPT into PBCA-NPs increased the Cmax and AUC0-t about 6.52 and 7.56 times, respectively, in comparison with the HCPT suspension. It was concluded that HCPT loaded PBCA-NPs prepared by miniemulsion polymerization could be promising in oral drug delivery.

Mitoxantrone-loaded chitosan/hyaluronate polyelectrolyte nanoparticles decorated with amphiphilic PEG derivates for long-circulating effect.

Poly (ethylene glycol) (PEG) and its derivatives are not only used to improve the stability of drug-loaded nanoparticles but also prolong their stay in blood for extended durations. We, hereby, report mitoxantrone loaded polyelectrolyte nanoparticles (MTO-PENPs) based on the hyaluronic acid (HA) and chitosan hydrochloride (HCS) complexed with amphiphilic PEG derivatives, carboxylated PEG (100) monostearate (PGMC, MTO-CPENPs) and D-tocopheryl PEG 1000 succinate (TPGS, MTO-TPENPs), to extend the in vivo circulation time. Maximum encapsulation efficiency (>95%) was observed at 40 mg/mL of PGMC or TPGS. TEM showed that PENPs preparations were spherical with an average diameter around 200 nm. Both MTO-CPENPs and MTO-TPENPs showed better stability than MTO-PENPs during storage at 4 °C, offered better control over the release of drug than simple PENPs, and showed pH-sensitivity with faster drug release in acidic conditions. MTO-CPENPs showed greater aversion from the protein adsorption and phagocytic uptake by macrophages but their cytotoxicity against the cancerous cells was poor of the all, and yet MTO-TPENPs showed good cytotoxicity against the MCF-7 cells. In the pharmacokinetic study, both MTO-CPENPs and MTO-TPENPs exhibited significant prolongation in blood circulation of drug compared to MTO-PENPs and MTO solution in rats after intravenous administration. However, MTO-TPENPs showed no statistically significant difference in plasma profile of MTO than the MTO-CPENPs. This indicates that there are underlying mechanisms that need to be explored to use the PEGylation in a way that could prolong stay of the nanoparticles in blood without compromising their interactions with target cells.