Surfactant Assisted Rapid-Release Liposomal Strategies Enhance the Antitumor Efficiency of Bufalin Derivative and Reduce Cardiotoxicity.

BACKGROUND: BF211, a derivative of bufalin (BF), shows significantly improved solubility and potent antitumor efficiency compared to BF. Unfortunately, the unwanted toxicity such as cardiotoxicity caused by unspecific distribution has hindered its clinical use. METHODS: PEGylated BF211 liposomes (BF211@Lipo) were designed and optimizely prepared based on the pre-prescription research. In vitro and in vivo cardiotoxicity was evaluated. In vivo pharmacokinetics and biodistribution of BF211@Lipo were investigated. In vivo antitumor activity and toxicity were evaluated in HepG2 cell xenograft models. The rapid-release triggered by Poloxamer 188 (P188) was assessed in vitro and in vivo. RESULTS: The optimized BF211@Lipo displayed a spherical morphology with a size of (164.6 ± 10.3) nm and a high encapsulation efficiency of (93.24 ± 2.15) %. The in vivo concentration-time curves of BF211 loaded in liposomes showed a prolonged half-life in plasma and increased tumor accumulation. No obvious abnormality in electrocardiograms was observed in guinea pigs even at 9 mg/kg. Moreover, to improve the efficient release of BF211@Lipo, a surfactant-assisted rapid-release strategy was developed, and the release-promoting mechanism was revealed by the fluorescence resonance energy transfer (FRET) and fluorescence nanoparticle tracking analysis (fl-NTA) technology. Sequential injection of BF211@Lipo and P188 could ignite the "cold" liposomes locally in tumor regions, facilitating the burst release of BF211 and enhancing the therapeutic index. CONCLUSION: Our progressive efforts that begin with preparation technology and dosage regimen enable BF211 to like a drug, providing a promising nano platform to deliver the cardiac glycosides and alleviate the side effects by decreasing unspecific biodistribution.

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.

The enhancement of N-acetylcysteine on intestinal absorption and oral bioavailability of hydrophobic curcumin.

To solve the low oral bioavailability of curcumin (CUR) due to the limits imposed by gastrointestinal (GI) barrier, we constructed a nano delivery system to evaluate the effect of N-acetyl-L-cysteine (NAC) on intestinal absorption and oral bioavailability of CUR. CUR was first encapsulated in bovine serum albumin nanoparticles (CUR-BSA-NPs), and then was further modified by NAC (CUR-NBSA-NPs). In situ single-pass intestinal perfusion assay demonstrated that CUR-NBSA-NPs displayed excellent permeation and absorption rates in GI tract. Additionally, the distribution study in GI tract revealed that more NBSA-NPs were absorbed by intestinal segments compared to the BSA nanoparticles. Plasma concentration-time curves in rats showed that AUC0-t, Cmax and MRT0-t values of CUR after oral administration of CUR-NBSA-NPs were increased to 3.25-, 4.42-, and 1.43-fold compared with that of CUR suspension. In conclusion, NAC promotes oral absorption of CUR, thereby improving its oral bioavailability.

Incorporation of ion exchange functionalized-montmorillonite into solid lipid nanoparticles with low irritation enhances drug bioavailability for glaucoma treatment.

Montmorillonite-loaded solid lipid nanoparticles with good biocompatibility, using Betaxolol hydrochloride as model drug, were prepared by the melt-emulsion sonication and low temperature-solidification methods and drug bioavailability was significantly improved in this paper for the first time to application to the eye. The appropriate physical characteristics were showed, such as the mean particle size, Zeta potential, osmotic pressure, pH values, entrapping efficiency (EE%) and drug content (DC%), all showed well suited for possible ocular application. In vitro release experiment indicated that this novel system could continuously release 57.83% drugs within 12 h owing to the dual drug controlled-release effect that was achieved by ion-exchange feature of montmorillonite and structure of solid lipid nanoparticles. Low irritability and good compatibility of nanoparticles were proved by both CAM-TBS test and cytotoxicity experiment. We first discovered from the results of Rose Bengal experiment that the hydrophilicity of the drug-loaded nanoparticles surface was increased during the loading and releasing of the hydrophilic drug, which could contribute to prolong the ocular surface retention time of drug in the biological interface membrane of tear-film/cornea. The results of in vivo pharmacokinetic and pharmacodynamics studies further confirmed that increased hydrophilicity of nanoparticles surface help to improve the bioavailability of the drug and reduce intraocular pressure during administration. The results suggested this novel drug delivery system could be potentially used as an in situ drug controlled-release system for ophthalmic delivery to enhance the bioavailability and efficacy.

Co-Encapsulation of Mitoxantrone and ß-Elemene in Solid Lipid Nanoparticles to Overcome Multidrug Resistance in Leukemia.

Multidrug resistance (MDR) due to P-glycoprotein (P-gp) overexpression is a major obstacle to successful leukemia chemotherapy. The combination of anticancer chemotherapy with a chemosensitizer of P-gp inhibitor is promising to overcome MDR, generate synergistic effects, and maximize the treatment effect. Herein, we co-encapsulated a chemotherapeutic drug of mitoxantrone (MTO) and a P-gp inhibitor of ß-elemene (ßE) in solid lipid nanoparticles (MTO/ßE-SLNs) for reversing MDR in leukemia. The MTO/ßE-SLNs with about 120 nm particle size possessed good colloidal stability and sustained release behavior. For the cellular uptake study, doxorubicin (DOX) was used as a fluorescence probe to construct SLNs. The results revealed that MTO/ßE-SLNs could be effectively internalized by both K562/DOX and K562 cells through the pathway of caveolate-mediated endocytosis. Under the optimized combination ratio of MTO and ßE, the in vitro cytotoxicity study indicated that MTO/ßE-SLNs showed a better antitumor efficacy in both K562/DOX and K562 cells than other MTO formulations. The enhanced cytotoxicity of MTO/ßE-SLNs was due to the increased cellular uptake and blockage of intracellular ATP production and P-gp efflux by ßE. More importantly, the in vivo studies revealed that MTO/ßE-SLNs could significantly prolong the circulation time and increase plasma half-life of both MTO and ßE, accumulate into tumor and exhibit a much higher anti-leukemia effect with MDR than other MTO formulations. These findings suggest MTO/ßE-SLNs as a potential combined therapeutic strategy for overcoming MDR in leukemia.

BSA Nanoparticles Modified with N-Acetylcysteine for Improving the Stability and Mucoadhesion of Curcumin in the Gastrointestinal Tract.

A major obstacle to the clinical use of curcumin (CUR) is its reduced bioavailability because of the drug's hydrophobic nature, low intestinal absorption, and rapid metabolism. In this study, a novel oral drug delivery system was constructed for improving the stability and enhancing mucoadhesion of CUR in the gastrointestinal (GI) tract. First, CUR was encapsulated in the bovine serum albumin nanoparticles (CUR-BSA-NPs). Then, N-acetyl cysteine (NAC)-modified CUR-BSA-NPs (CUR-NBSA-NPs) were obtained. The average particle size and zeta potential of CUR-NBSA-NPs were 251.6 nm and -30.66 mV, respectively; encapsulation efficiency and drug loading were 85.79 and 10.9%, respectively. CUR-NBSA-NPs exhibited a sustained release property and prominently enhanced stability in simulated GI conditions. Additionally, enhanced mucoadhesion of CUR-NBSA-NPs was also observed. An MTT study showed that the CUR-NBSA-NPs were safe for oral administration. Overall, NAC-modified BSA-NPs may potentially serve as an oral vehicle for improving CUR stability in the GI tract and enhancing mucoadhesion.

The enhancing effect of N-acetylcysteine modified hyaluronic acid-octadecylamine micelles on the oral absorption of paclitaxel.

A micelle system based on hyaluronic acid (HA)-octadecylamine (OA) conjugate (HOA) functionalized with N-acetylcysteine (NAC) was constructed to yield NAC modified HOA conjugate (NHOA) for improving oral paclitaxel (PTX) delivery (PTX-NHOA). The average size of spherical PTX-NHOA micelles was 162.7 nm with a zeta potential of -27.6 mv. The encapsulation efficiency (EE) and drug loading (DL) of PTX-NHOA micelles were 92.64% and 6.96%, respectively. Additionally, NHOA micelles exihibited significantly higher cellular uptake in comparison with HOA micelles by caveolin-mediated and clathrin-mediated endocytosis. Higher permeation ability of NHOA micelles (2.75-fold and 1.32-fold, respectively) through cell monolayers of Caco-2/HT29 cells than that of Taxol and HOA micelles were also observed. The intestinal biodistribution result showed that NAC-modified micelles could enhance its adhesion to the intestinal surface and permeate deeply within the intestinal villi. The NHOA micelles were better absorbed in the duodenum, followed by the jejunum and the ileum. In vivo pharmacokinetic studies showed that AUC0-t value of PTX-NHOA micelles was about 5.92-fold and 2.47-fold higher compared to that of Taxol and PTX-HOA micelles, respectively. In a word, NHOA micelles is a promising drug delivery system in improving the oral absorption of insoluble drugs.

Camouflaging Nanoparticles for Ratiometric Delivery of Therapeutic Combinations.

Combination therapy is a common clinical practice in the management of malignancies. Synergistic therapeutic outcomes are achieved only when tumor cells are exposed to drugs in an optimal ratio and sequence; therefore, carriers coencapsulating multiple drugs are widely pursued for their coordinated delivery. However, it is challenging to coload drugs with different physicochemical properties in a single carrier with specific ratios. It is not even beneficial to load them in one carrier if they need to be released at different times. We propose to load drugs into chemically compatible carriers separately, equalize different carriers by a simple, rapid, and versatile camouflage technique based on natural polyphenol tannic acid (TA), and administer them in desirable ratios and sequences. To demonstrate this potential, different nanoparticles (NPs) with different charges and material basis, such as polymeric (carboxyl-terminated or amine-terminated cationic polystyrene NPs or poly(lactic- co-glycolic acid (PLGA) NPs), inorganic (mesoporous silica NPs (MSNs)), and liposomal NPs, are camouflaged with TA layers and further modified with folate-conjugated polyethylene glycol to aid in the delivery to tumors. The camouflaged NPs show similar physicochemical properties and interactions with KB cells despite the difference in core platforms, and their mixtures interact with common cell targets in a ratiometric manner. In KB-tumor-bearing mice, the camouflaged PLGA NPs and MSNs show near-perfect colocalization in tumors. These results support that TA helps equalize different NPs with high versatility and enables their ratiometric delivery to common targets. This approach can relieve technical challenges in ratiometric codelivery or sequential delivery of therapeutic agents with distinct physicochemical properties.

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.

N-acetylcysteine modified hyaluronic acid-paclitaxel conjugate for efficient oral chemotherapy through mucosal bioadhesion ability.

N-acetylcysteine modified hyaluronic acid-paclitaxel (NAC-HA-PTX) conjugate was designed to improve the water solubility and oral bioavailability of PTX through mucosal bioadhesion ability. The average size of spherical NAC-HA-PTX micelles was 187 nm with a zeta potential of -25.38 mV. Mucin adhesion study showed that the amount of mucin adhered to NAC-HA-PTX micelles was 1.98-fold greater than that of hyaluronic acid-paclitaxel (HA-PTX) micelles. The fluorescence micrographs showed that the biodistribution sequence of coumarin 6-loaded micelles in the gastrointestinal tract was duodenum > jejunum > ileum, and NAC-modified micelles significantly exhibited better mucoadhesive properties than the corresponding unmodified ones. The pharmacokinetic study showed that the area under the curve (AUC0-24h) of NAC-HA-PTX micelles was 2.32-fold and 2.56-fold higher compared to that of HA-PTX micelles and PTX solution (Taxol) after oral administration, respectively. NAC-HA-PTX micelles appear to be a promising drug delivery system to improve the bioavailability of insoluble drugs for efficient tumor therapy via oral administration.

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.

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.

Montmorillonite/chitosan nanoparticles as a novel controlled-release topical ophthalmic delivery system for the treatment of glaucoma.

BACKGROUND: To date, the rapid clearance from ocular surface has been a huge obstacle for using eye drops to treat glaucoma, since it has led to the short preocular residence time and low bioavailability. METHODS: The novel nanoparticles (NPs) were designed for topical ophthalmic controlled drug delivery system through intercalating the BH into the interlayer gallery of Na-montmorillonite (Na+Mt) and then further enchasing chitosan nanoparticles. The resulting nanoparticles had a positive charge (+29±0.18 mV) with an average diameter of 460±0.6 nm. RESULTS: In vitro study of drug release profiles suggested controlled release pattern. The irritation experiment analysis on both human immortalized cornea epithelial cell (iHCEC) and chorioallantoic membrane-trypan blue staining (CAM-TBS) showed good tolerance for ocular tissues. It was interestingly found that the nanoparticles could enter into iHCEC from the result of cellular uptake experiment measured by confocal layer scan microscopy (CLSM). Meanwhile, multilayered iHCEC was used to simulate the barrier of corneal epithelial cells for in vivo preocular retention capacity study, which suggested that BH-Mt/CS NPs could prolong the retention time in comparison with BH solution. The ocular pharmacokinetics studied by microdialysis sampling technique showed that AUC0-t and MRT0-t of BH-Mt/CS NPs were 1.99-fold and 1.75-fold higher than those of BH solution, indicating higher bioavailability. Moreover, the study of blood drug concentration, few researchers have reported, showed that low level drug could enter into blood, suggesting lower systematic side effect. Importantly, pharmacodynamics studies suggested that BH-Mt/CS NPs could make a significant decreased intraocular pressure on glaucomatous rabbits. CONCLUSION: Inspired by these advance of montmorillonite/chitosan nanoparticles, we envision that the BH-Mt/CS NPs will be a potential carrier for BH, opening up the possible applications in glaucoma therapy.

Quantitative Assessment of Nanoparticle Biodistribution by Fluorescence Imaging, Revisited.

Fluorescence-based whole-body imaging is widely used in the evaluation of nanoparticles (NPs) in small animals, often combined with quantitative analysis to indicate their spatiotemporal distribution following systemic administration. An underlying assumption is that the fluorescence label represents NPs and the intensity increases with the amount of NPs and/or the labeling dyes accumulated in the region of interest. We prepare DiR-loaded poly(lactic- co-glycolic acid) (PLGA) NPs with different surface layers (polyethylene glycol with and without folate terminus) and compare the distribution of fluorescence signals in a mouse model of folate-receptor-expressing tumors by near-infrared fluorescence whole-body imaging. Unexpectedly, we observe that fluorescence distribution patterns differ far more dramatically with DiR loading than with the surface ligand, reaching opposite conclusions with the same type of NPs (tumor-specific delivery vs predominant liver accumulation). Analysis of DiR-loaded PLGA NPs reveals that fluorescence quenching, dequenching, and signal saturation, which occur with the increasing dye content and local NP concentration, are responsible for the conflicting interpretations. This study highlights the critical need for validating fluorescence labeling of NPs in the quantitative analysis of whole-body imaging. In light of our observation, we make suggestions for future whole-body fluorescence imaging in the in vivo evaluation of NP behaviors.

The effect of the molecular weight of hyaluronic acid on the physicochemical characterization of hyaluronic acid-curcumin conjugates and in vitro evaluation in glioma cells.

In this study, a redox-sensitive glioma-targeting micelle system was designed to deliver curcumin (CUR) by conjugating it to hyaluronic acid (HA-s-s-CUR, HSC) via disulfide linkage. The effect of the molecular weight of HA on the physicochemical characteristics of HSC conjugates and their in vitro effects in glioma cells were also explored. These conjugates formed nano-scale micelles (209-926 nm) independently in aqueous solution. The micelles greatly increased the solubility of CUR and improved its stability, which is crucial for harnessing the therapeutic potential of this active molecule. The redox sensitivities of different HSC micelles were measured by using a dynamic light scattering method and in vitro release assay, which showed that the low (50 kDa) and medium molecular weight (200 kDa and 500 kD) HA-based conjugates were sensitive to GSH, whereas higher molecular weights (1000 kDa and 2000 kDa) did not show redox-sensitivity. Increased cytotoxicity and uptake of low and medium molecular weight-modified HSC conjugates by the glioma cells further confirmed that the sensitive micelles are more effective for intracellular drug delivery compared to the high molecular weight-modified HSC conjugates or the plain CUR. In summary, the molecular weight of HA affects the physicochemical attributes of HSC conjugates. Only HSC micelles made with HA molecules less than 500 kDa exhibit redox sensitivity.

Nanostructured Peptidotoxins as Natural Pro-Oxidants Induced Cancer Cell Death via Amplification of Oxidative Stress.

Melittin (Mel), one of the host defense peptides derived from the venom of honeybees, demonstrates substantial anticancer properties, which is attributed to augmenting reactive oxygen species (ROS) generation. However, little has been reported on its pro-oxidation capacity in cancer oxidation therapy. In this study, an ROS amplifying nanodevice was fabricated through direct complexation of two natural pro-oxidants, Mel and condensed epigallocatechin gallate (pEGCG). The obtained nanocomplex (NC) was further covered with phenylboronic acid derivatized hyaluronic acid (pHA) through the ROS-responsive boronate ester coordination bond to produce pHA-NC. Upon undergoing receptor-mediated endocytosis into cancer cells, the inner cores of pHA-NC will be partially uncovered once pHA corona is degraded by hyaluronidase and will then escape from the lysosome by virtue of cytolytic Mel. The elevated ROS level in the tumor cytoplasm can disrupt the boronate ester bond to facilitate drug release. Both Mel and pEGCG could synergistically amplify oxidative stress and prolong ROS retention in cancer cells, leading to enhanced anticancer efficacy. This ROS cascade amplifier based on selective coordination bond and inherent pro-oxidation properties of natural ingredients could detect and elevate intracellular ROS signals, potentiating to move the tumor away from its homeostasis and make the tumor vulnerable. Compared to previously reported chemosynthetic pro-oxidants, the ROS self-sufficient system, fully composed of natural medicine, from this study provides a new insight in developing cancer oxidation therapy.

N-acetyl-L-cysteine functionalized nanostructured lipid carrier for improving oral bioavailability of curcumin: preparation, in vitro and in vivo evaluations.

The application of orally administered nanoparticles in the circulation system is limited by the secretion and shedding of intestinal tract mucous layer. In order to enhance mucoadhesion and mucus penetration of curcumin (Cur)-loaded nanostructured lipid carrier (NLC) after oral administration, a new multifunctional conjugate, N-acetyl-L-cysteine-polyethylene glycol (100)-monostearate (NAPG), was synthesized. Functionalized nanocarriers (Cur-NAPG-NLC) modified by different amounts of NAPG (the amounts of NAPG were 20, 50, and 100 mg) were prepared and investigated for in vitro and in vivo behavior. Mean particle sizes of 89-141 nm with negative zeta potential (-15 to -11 mV) and high encapsulation efficiency (EE, >90%) possessing spherical and stable nanocarriers were observed. Sustained drug release was also observed for the NAPG-NLC. In situ intestinal perfusion studies showed that with increasing the amount of NAPG increase absorption of Cur. In vivo oral pharmacokinetic evaluation suggested that the bioavailability of Cur in rats was proportional to the degree of functionalization of NLCs with NAPG. AUC0-t of Cur-NAPG100-NLC was improved by 499.45 and 116.89 folds as compared to that of Cur solution and unmodified Cur-NLC, respectively. In conclusion, NAPG modified NLC could be a promising drug delivery system for improving oral performance of BCS class IV drugs.

Polysaccharide-based nanoparticles for co-loading mitoxantrone and verapamil to overcome multidrug resistance in breast tumor.

The aim of this study was to evaluate the potential of polyelectrolyte complex nanoparticles (PENPs) based on hyaluronic acid/chitosan hydrochloride (HA/HCS) for co-loading mitoxantrone (MTO) and verapamil (VRP) to overcome multidrug resistance in breast tumors. PENPs co-loaded with MTO and VRP (MTO-VRP-PENPs) were affected by the method of preparation, molecular weight of HA, mass ratios and initial concentrations of HA/HCS, pH, and drug quantities. Optimized MTO-VRP-PENPs were ~209 nm in size with a zeta potential of approximately -24 mV. Encapsulation efficiencies (%) of MTO and VRP were 98.33%±0.27% and 44.21%±8.62%, respectively. MTO and VRP were successfully encapsulated in PENPs in a molecular or amorphous state. MTO-VRP-PENPs showed significant cytotoxicity in MCF-7/ADR cells in contrast to MTO-loaded PENPs (MTO-PENPs). The reversal index of MTO-VRP-PENPs was 13.25 and 10.33 times greater than that of the free MTO and MTO-PENPs, respectively. In conclusion, MTO-VRP-PENPs may serve as a promising carrier to overcome tumor drug resistance.

Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence.

Cell-mediated drug-delivery systems have received considerable attention for their enhanced therapeutic specificity and efficacy in cancer treatment. Neutrophils (NEs), the most abundant type of immune cells, are known to penetrate inflamed brain tumours. Here we show that NEs carrying liposomes that contain paclitaxel (PTX) can penetrate the brain and suppress the recurrence of glioma in mice whose tumour has been resected surgically. Inflammatory factors released after tumour resection guide the movement of the NEs into the inflamed brain. The highly concentrated inflammatory signals in the brain trigger the release of liposomal PTX from the NEs, which allows delivery of PTX into the remaining invading tumour cells. We show that this NE-mediated delivery of drugs efficiently slows the recurrent growth of tumours, with significantly improved survival rates, but does not completely inhibit the regrowth of tumours.

Nanoparticles based on chitosan hydrochloride/hyaluronic acid/PEG containing curcumin: In vitro evaluation and pharmacokinetics in rats.

Nanoparticles based on chitosan hydrochloride (CSH)-hyaluronic acid (HA)-PEG were prepared for delivering curcumin (CUR) (CUR-PNPs) to brain tumor. CUR-PNPs of 245.9nm and spherical morphology were obtained at optimized CSH/HA/PEG20000/CUR ratios with negative charge of about -27.2mV and EE of approximately 93.3%. Cytotoxicity studies showed that CUR-PNPs improved drug's anticancer activity in rat glioma cells (C6). The cellular uptake mechanism study showed active targeting of CUR-PNPs into C6 cells by HA mediated endocytosis. Clathrin-coated pit mediated endocytosis, clathrin-mediated endocytosis and macropincytosis were also identified as the entry pathways of PNPs into C6 cells. Pharmacokinetics of preparations in rats after i.v. administration further proved the superiority of CUR-PNPs (3.98 times greater than the area under the curve of CUR solution). In conclusion, CUR-PNPs might be a promising carrier for the therapy of brain tumors.