Yanzhi Song

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.

In vitro–in vivo study of CoQ10-loaded lipid nanoparticles in comparison with nanocrystals

The present work described the effect of CoQ10 dissolution characteristics in nanocrystals and lipid nanoparticles (LNs) on its oral absorption in rats. Nanocrystals and LNs were prepared by melt-high pressure homogenization and sucrose monolaurate was used as a stabilizer in all formulations. Witepsol(®)W35 and medium-chain triglycerides (MCT) were selected as lipid additives to form LN(CoQ10+W35) and LN(CoQ10+MCT), respectively. From the results obtained, the particle size of CoQ10 nanocrystals was 285 nm, while it was reduced to 150 nm by mixture with an equal amount of lipid additives due to their lower melting points. In vitro dissolution results indicated that the drug release from two LNs was delayed compared with that from nanocrystals, and LN(CoQ10+W35) exhibited the highest drug release over 4h. Finally, in vivo evaluation demonstrated that the oral absorption of CoQ10 was markedly increased by using nanocrystals and LNs compared with a coarse suspension. A good relationship was found between the in vitro dissolution and in vivo evaluation. The enhanced oral absorption of CoQ10 by nanocrystals and LNs was due to improved dissolution. In conclusion, Witepsol(®)W35 was shown to be a better lipid additive for the preparation of LNs to increase the oral absorption of CoQ10.

Accelerated blood clearance phenomenon upon cross-administration of PEGylated nanocarriers in beagle dogs

The cross-administration of nanocarriers modified by poly(ethylene glycol) (PEG), named PEGylated nanocarriers, a type of combination therapy, is becoming an increasingly important method of long-term drug delivery, to decrease side effects, avoid multidrug resistance, and increase therapeutic efficacy. However, repeated injections of PEGylated nanocarriers induces the accelerated blood clearance (ABC) phenomenon, prevents long circulation, and can cause adverse effects owing to alterations in the biodistribution of the drug. Although the nature of the ABC phenomenon that is induced by repeated injections of PEGylated nanocarriers has already been studied in detail, there are few reports on the immune response elicited by the cross-administration of PEGylated nanocarriers. In this study, we investigated the ABC phenomenon induced by the intravenous cross-administration of various PEGylated nanocarriers, including PEGylated liposomes (PL), PEG micelles (PM), PEGylated solid lipid nanoparticles (PSLN), and PEGylated emulsions (PE), in beagle dogs. The results indicated that the magnitude of the immune response elicited by the cross-administration was in the following order (from the strongest to the weakest): PL, PE, PSLN, PM. It is specifically PEG in the brush structure that elicits a significant immune response, in both the induction phase and the effectuation phase. Furthermore, the present study suggests that there is a considerable difference between the effect of repeated injections and cross-administration, depending on the colloidal structure. This work is a preliminary investigation into the cross-administration of PEGylated nanocarriers, and our observations can have serious implications for the design of combination therapies that use PEGylated vectors.

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

Abstract 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) Vincristines 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 drugs 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.

Targeted delivery of epirubicin to tumor-associated macrophages by sialic acid-cholesterol conjugate modified liposomes with improved antitumor activity

With the knowledge that the receptors of sialic acid are overexpressed on the surface of tumor-associated macrophages (TAMs), which play a crucial role in the tumors progression and metastasis, a sialic acid-cholesterol conjugate (SA-CH) was synthesized and modified on the surface of epirubicin (EPI)-loaded liposomes (EPI-SAL) to improve the delivery of EPI to the TAMs. The liposomes were developed using remote loading technology via a pH gradient. The liposomes were evaluated for particle size, encapsulation efficiency, in vitro release, stability, in vitro cytotoxicity and pharmacokinetics. And the in vitro and in vivo cellular uptake studies demonstrated EPI-SAL achieved enhanced accumulation of EPI into TAMs. The antitumor studies indicated that EPI-SAL provided the strongest antitumor activity compared with the other formulations (EPI-S, EPI-CL and EPI-PL represent EPI solution, conventional liposomal EPI, PEGylated liposomal EPI, respectively), and the survival percent of tumor-bearing mice was 83.3%. The superior antitumor efficacy was probably attributed to the killing of TAMs by EPI-SAL, and modulating the tumor microenvironment with the depletion of TAMs. These findings suggested that SA-CH decorated EPI-loaded liposomes may present an effective strategy to eradicate TAMs, which may be a promising approach for cancer therapy.

Polysialic acid-modifying liposomes for efficient delivery of epirubicin, in-vitro characterization and in-vivo evaluation

Polysialic acid (PSA) serves as a hydrophilic polymer and affords conjugated biologically active molecules a longer circulation time in vivo. Furthermore, PSA could potentially target tumor tissues and help achieve better curative effects. In this study, PSA was conjugated with octadecyl dimethyl betaine (BS18) to yield a PSA-BS18 conjugate. The PSA-BS18 modified liposomal epirubicin (EPI-SL), had a particle size of 133.63±0.92nm, a zeta potential of -26.23±1.50mV and an encapsulation efficiency (%EE) of 96.23±1.16%. In vitro release studies showed that PSA-BS18 could delay EPI release from the modified liposomes. The MTT assay suggested that EPI-SL led to stronger cytotoxic activity than that exhibited by common and PEGylated liposomes. The pharmacokinetic study showed that EPI-SL prolonged the residence time of the EPI in the blood compared with that observed from common liposomes. Bio-distribution results obtained from tumor-bearing mice clearly demonstrated that PSA-BS18 increased the accumulation of modified liposomes in tumors compared with that of common liposomes. In the antitumor efficacy study, EPI-SL showed the best antitumor and life-prolonging effects among all of the tested formulations. These findings strongly indicate EPI-SL might have great potential as an effective approach for anticancer therapy.

Polysialic acid and Pluronic F127 mixed polymeric micelles of docetaxel as new approach for enhanced antitumor efficacy

Abstract In our previous study, polysialic acid-octadecyl dimethyl betaine (PSA-BS18) was synthesized and modified to liposomal EPI. Preliminary experiments revealed that the PSA-BS18 was a potential material for targeting tumor site with superior curative effects. In this study, PSA-BS18 and Pluronic F127 (F127) mixed polymeric micelles encapsulated docetaxel (DTX) (FP/DTX) were prepared by a self-assembly method. The FP/DTX was found to have a diameter of 34.83 ± 0.50 nm with a narrow polydispersity, the entrapment efficiency was 99.12 ± 1.17%, and the drug loading efficiency of 1.40 ± 0.01%. The storage and dilution stability of FP/DTX was fine. In vitro release studies demonstrated that FP/DTX had delayed the drug release from the micelles. In vitro cytotoxicity assay on B16 cells presented that FP/DTX led to a stronger cytotoxic activity in comparison to F127 micelles based DTX (F127/DTX) and Tween80-based DTX (Taxotere®). The in vivo imaging study showed that the accumulation of FP/DTX at tumor sites was more than F127/DTX. The in vivo antitumor activity of FP/DTX against B16 tumor xenograft model showed a significant higher inhibition and a lower toxicity compared with F127/DTX and Taxotere®. Taken together, the results obtained above showed that PSA-BS18 and F127 mixed polymeric micelles may be a promising strategy for antitumor delivery of DTX.

Neutrophil-mediated delivery of pixantrone-loaded liposomes decorated with poly(sialic acid)–octadecylamine conjugate for lung cancer treatment

Abstract Poly(sialic acid) (PSA) is a natural hydrophilic biodegradable and non-immunogenic biopolymer, receptors for its monomer are expressed on peripheral blood neutrophils (PBNs), which plays important roles in the progression and invasion of tumors. A poly(sialic acid)–octadecylamine conjugate (PSA–ODA) was synthesized and then anchor it on the surface of liposomal pixantrone (Pix-PSL), to achieve an improved anticancer effect. The liposomes were prepared using a remote loading method via a pH gradient, and then assessed for particle size, zeta potential encapsulation efficiency, in vitro release, and in vitro cytotoxicity. Simultaneously, in vitro and in vivo cellular uptake studies confirmed that PSA-decorated liposomes provided an enhanced accumulation of liposomes in PBNs. An in vivo study presented that the anti-tumor activity of Pix-PSL was superior to that of other Pix formulations, probably due to the efficient targeting of PBNs by Pix-PSL, after which PBN containing Pix-PSL (Pix-PSL/PBNs) in the blood circulation are recruited by the tumor microenvironment. These findings suggest that PSA-decorated liposomal Pix may provide a neutrophil-mediated drug delivery system (DDS) for the eradication of tumors, which represents a promising approach for the tumor targeting of chemotherapeutic treatments.

A novel nanosuspension of andrographolide: Preparation, characterization and passive liver target evaluation in rats

Abstract Andrographolide (Andro) is an excellent anti‐inflammatory bicyclic diterpene &ggr;‐lactone. However, the poor solubility limits its application as injection for the treatment of acute inflammation. To meet the clinical needs for emergency, the Andro nanosuspensions injection was first prepared by the wet milling technique. The Andro nanosuspensions were composed of 3% Andro, 5% poloxamer 188 as the non‐ionic stabilizer, 0.05% sodium deoxycholate or 0.1% sodium tauroursodeoxy cholate as the ionic stabilizer, and prepared by 350 rpm speed and 12 cycles of grinding with 0.4 mm zirconium oxide pearls. The nanosuspensions showed hexagonal morphology with particle size of 300 nm, and no change in crystalline state of Andro after milling. The nanosuspensions had a significant increase in saturation solubility, and could completely release within 0.25 h (bulk Andro within 24 h). The lyophilized product of Andro nanosuspensions with mannitol (5%) as lyoprotectant had good physical and chemical stability during the 6‐month storage period. The pharmacokinetic and tissue distribution results showed that it was rapidly eliminated from the blood and largely distributed in the liver. Overall, the Andro nanosuspensions may be used as a potential formulation for the treatment of liver infections owing to its passive liver targeting function. Graphical abstract Figure. No Caption available.