Evaluation of the Antitumor Effect and Immune Response of Micelles Modified with a Polysialic Acid-D-α-Tocopheryl Polyethylene Glycol 1000 Succinate Conjugate.

D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) has shown potential applications in cancer therapy owing to its attractive properties, including reversal of multi-drug resistance and synergistic effects with antitumor drugs. However, its associated shortcomings cannot be underestimated, including activation of the body's immune response and acceleration of blood clearance of polyethylene glycolylated preparations. Polysialic acid (PSA) is a polysaccharide homopolymer, with the dual function of immune camouflage and tumor targeting. PSA and TPGS conjugates (PSA-TPGS) were synthesized to weaken the immune risks of TPGS. We developed PSA-TPGS and TPGS self-assembled mixed micelles and encapsulated the classical antineoplastic, docetaxel. The particle size of docetaxel-loaded mixed micelles was 16.3 ± 2.0 nm, with entrapment efficiency of 99.0 ± 0.9% and drug-loading efficiency of 3.20 ± 0.03%. Antitumor activity studies revealed that the mixed micelles showed better tumor inhibition than Tween 80 and TPGS micelles. Detection of the accelerated blood clearance (ABC) phenomenon demonstrated that insertion of PSA-TPGS into the micelles weakened the ABC phenomenon induced by TPGS. In summary, PSA-TPGS could be a potential nanocarrier to improve antitumor activity and weaken immune responses.

The antitumor efficacy of docetaxel is enhanced by encapsulation in novel amphiphilic polymer cholesterol-coupled tocopheryl polyethylene glycol 1000 succinate micelles.

Tocopheryl polyethylene glycol 1000 succinate (TPGS) is considered a promising surfactant, but its high critical micelle concentration (CMC) limits its application. Cholesterol is hydrophobic, can act as a tumor-targeting ligand, and has strong binding ability with taxoids. Based on this information, we coupled cholesterol with TPGS to synthesize cholesterol-coupled TPGS (TPGS-CHMC), which had a lower CMC than pure TPGS. The TPGS-CHMC was used to prepare micelles loading with docetaxel (DTX) by a self-assembly method. DTX-loaded TPGS-CHMC micelles were globule-shaped, 13.3 ± 2.0 nm in size, and had a zeta potential of -4.66 ± 0.41 mv. In vitro release studies demonstrated the delayed release property of the micelles, which also had a relatively high encapsulation efficiency and drug loading content of 99.2 and 3.20%, respectively. Furthermore, the micelles were stable in vitro at a dilution of 100-fold. In vivo antitumor studies showed that the DTX-loaded TPGS-CHMC micelles significantly enhanced the antitumor activity of DTX in S180 tumor-bearing mice. Interestingly, the blank TPGS-CHMC micelles also showed antitumor activity. Our results demonstrate that TPGS-CHMC is a promising system for DTX delivery that may be suitable for other hydrophobic antitumor drugs.

Mixed PEGylated surfactant modifying system decrease the accelerated blood clearance phenomenon of nanoemulsions in rats.

The accelerated blood clearance (ABC) phenomenon which is induced by repeated injection of poly (ethylene glycol) (PEG)-coated colloidal carriers gives clinical challenge to the promising drug delivery system. It is necessary to decrease this unexpected immunological response. A novel 4-arm poly (ethylene glycol-5000)4-cholesteryl methyl amide (4-arm PEG5000-CHMA) has been synthesized. The structure of 4-arm PEG5000-CHMA was confirmed by IR and 1H-NMR spectrum. The pharmacokinetics of the tocopheryl nicotinate (TN)-loaded nanoemulsions modified with 4-arm PEG5000-CHMA or/and 1, 2-distearoyl-Sn-glycero-3-phosphoethanolamine-n-[methoxy(poly-ethyleneglycol)-2000] (mPEG2000-DSPE) have been studied. Furthermore, the ABC phenomenon has been detailed investigated in rats by TN-loaded nanoemulsions modified with 4-arm PEG5000-CHMA and mPEG2000-DSPE (CPNE). The plasma levels of TN and anti-PEG IgM antibody were determined by HPLC and ELISA, respectively. The circulation time of the CPNEs were comparable to the mPEG2000-DSPE coated nanoemulsions. Moreover, the ABC phenomenon can be decreased by CPNEs. This study designs a method to decrease the ABC phenomenon and develops a clinical promising nanoemulsion for therapeutic or imaging purpose.

The 12-3-12 cationic gemini surfactant as a novel gastrointestinal bioadhesive material for improving the oral bioavailability of coenzyme Q10 naked nanocrystals.

To improve the oral bioavailability of nanocrystalline drug preparations, the cationic 12-3-12 quaternary ammonium surfactant gemini was introduced into nanocrystals as a novel gastrointestinal bioadhesive material. Coenzyme Q10 (CoQ10), a typical Biopharmaceutics Classification System (BCS) class II drug, was used as a model drug. The 12-3-12 gemini surfactant was added to the preparation at a low concentration and imbued the particles with abundant positive charges. In vitro and in vivo gastrointestinal adhesion tests confirmed that the gemini-modified nanocrystals were prone to adhere to the upper gastrointestinal tract (GIT), thereby prolonging retention time in the GIT and enhancing absorption. In the distribution study in rats, the use of nanocrystals modified with gemini led to greater drug distribution to the heart and the liver than that achieved with the naked nanocrystals. A pharmacokinetic study in beagle dogs showed that the gemini-modified CoQ10 nanocrystals improved the oral bioavailability of CoQ10 in a dose-dependent manner, and the smaller size produced a much better effect with the same gemini modification. These results demonstrate that the cationic surfactant gemini is a promising oral bioadhesive material with applications in nanoscale drug delivery systems.

Are PEGylated liposomes better than conventional liposomes? A special case for vincristine.

Cancer poses a significant threat to human health worldwide, and many therapies have been used for its palliative and curative treatments. Vincristine has been extensively used in chemotherapy. However, there are two major challenges concerning its applications in various tumors: (1) Vincristine's antitumor mechanism is cell-cycle-specific, and the duration of its exposure to tumor cells can significantly affect its antitumor activity and (2) Vincristine is widely bio-distributed and can be rapidly eliminated. One solution to these challenges is the encapsulation of vincristine into liposomes. Vincristine can be loaded into conventional liposomes, but it quickly leak out owing to its high membrane permeability. Numerous approaches have been attempted to overcome this problem. Vincristine has been loaded into PEGylated liposomes to prolong circulation time and improve tumor accumulation. These liposomes indeed prolong circulation time, but the payout characteristic of vincristine is severer, resulting in a compromised outcome rather than a better efficacy compared to conventional sphingomyelin (SM)/cholesterol (Chol) liposomes. In 2012, the USA Food and Drug Administration (FDA) approved SM/Chol liposomal vincristine (Marqibo®) for commercial use. In this review, we mainly focus on the drug's rapid leakage problem and the potentially relevant solutions that can be applied during the development of liposomal vincristine and the reason for conventional liposomal vincristine rather than PEGylated liposomes has access to the market.

The application of EDTA in drug delivery systems: doxorubicin liposomes loaded via NH4EDTA gradient.

The applications of ethylenediaminetetraacetic acid (EDTA) have been expanded from the treatment of heavy metal poisoning to chelation therapies for atherosclerosis, heart disease, and cancers, in which EDTA reduces morbidity and mortality by chelating toxic metal ions. In this study, EDTA was used in a drug delivery system by adopting an NH4EDTA gradient method to load doxorubicin into liposomes with the goal of increasing therapeutic effects and decreasing drug-related cytotoxicity. The particle size of the optimum NH4EDTA gradient liposomes was 79.4±1.87 nm, and the entrapment efficiency was 95.54%±0.59%. In vitro studies revealed that liposomes prepared using an NH4EDTA gradient possessed long-term stability and delayed drug release. The in vivo studies also showed the superiority of the new doxorubicin formulation. Compared with an equivalent drug dose (5 mg/kg) prepared by (NH4)2SO4 gradient, NH4EDTA gradient liposomes showed no significant differences in tumor inhibition ratio, but cardiotoxicity and liposome-related immune organ damage were lower, and no drug-related deaths were observed. These results show that use of the NH4EDTA gradient method to load doxorubicin into liposomes could significantly reduce drug toxicity without influencing antitumor activity.

Self-assembled micelles of novel amphiphilic copolymer cholesterol-coupled F68 containing cabazitaxel as a drug delivery system.

Despite being one of the most promising amphiphilic block copolymers, use of Pluronic F68 in drug delivery is limited due to its high critical micelle concentration (CMC). In this study, we developed a novel F68 derivative, cholesterol-coupled F68 (F68-CHMC). This new derivative has a CMC of 10 µg/mL, which is 400-fold lower than that of F68. The drug-loading capacity of F68-CHMC was investigated by encapsulating cabazitaxel, a novel antitumor drug. Drug-loaded micelles were fabricated by a self-assembly method with simple dilution. The optimum particle size of the micelles was 17.5±2.1 nm, with an entrapment efficiency of 98.1% and a drug loading efficiency of 3.16%. In vitro release studies demonstrated that cabazitaxel-loaded F68-CHMC micelles had delayed and sustained-release properties. A cytotoxicity assay of S180 cells showed that blank F68-CHMC was noncytotoxic with a cell viability of nearly 100%, even at a concentration of 1,000 µg/mL. The IC50 revealed that cabazitaxel-loaded F68-CHMC micelles were more cytotoxic than Tween 80-based cabazitaxel solution and free cabazitaxel. In vivo antitumor activity against S180 cells also indicated better tumor inhibition by the micelles (79.2%) than by Tween 80 solution (56.2%, P<0.05). Based on these results, we conclude that the F68-CHMC copolymer may be a potential nanocarrier to improve the solubility and biological activity of cabazitaxel and other hydrophobic drugs.