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BACKGROUND: The efficacy of transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) is limited. There are insufficient data on TACE-lenvatinib sequential therapy for HCC with PVTT. We aimed to assess the efficacy and safety of TACE-lenvatinib sequential therapy for the treatment of HCC and PVTT. METHODS: We retrospectively reviewed 12 consecutive patients with HCC and PVTT who underwent TACE-lenvatinib sequential therapy between July 2018 and May 2021. Lenvatinib treatment was started 1 week after TACE at a dose of 8 or 12 mg daily depending on the patient weight. Follow-up examinations were performed at 4 week and then every 8 weeks after the first TACE procedure. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and adverse events (AEs) were calculated. Survival curves of PFS and OS were estimated using the Kaplan-Meier method. RESULTS: The median OS and PFS were 16.9 and 6.15 months, respectively. The ORR and DCR were 75% and 91.7%, respectively. The most common lenvatinib-related AE was hypertension (33.3%), and the most common TACE-related AE was elevated liver enzymes (100%). No treatment-related deaths or grade 4 events were observed. CONCLUSIONS: TACE-lenvatinib sequential therapy may be safe and well tolerated, and may improve OS and PFS for HCC patients with PVTT. Further randomized controlled trials with larger cohorts are needed to confirm its efficacy and safety.

Cache-enabled small base stations (SBS) are capable of relieving the heavy burden of the backhaul link and reducing the transmission latency. The hit probability depends on the coverage probability and caching placement probabilities. However, the interference in the small-cell networks may significantly degrade the coverage probability. In this paper, for MIMO small-cell networks consisting of SBS and users, where both of them are equipped with multiple antennas, a joint interference alignment (IA) and probabilistic caching (JIA-ProbC) scheme is proposed. Using tools from stochastic geometry, the $K$ -th order Voronoi cells are constructed to form clusters, where $K$ SBSs cooperatively serve users within each of the $K$ -th order Voronoi cells. Then, the IA scheme for MIMO interference channel (IC) is employed to cancel the intra-cluster interference within each $K$ -th order Voronoi cell. By exploiting the advantage of multiples antennas at users, the IA scheme can simultaneously support more users interference-free than both the zero forcing (ZF) based interference cancellation scheme for MISO systems and SISO systems without interference management, as more interference can be canceled. Furthermore, the coverage probability is analytically approximated by the a closed-form expression. Moreover, the optimal caching placement probability is analytically derived. Numerical Simulation results show that the proposed JIA-ProbC can significantly outperform the existing joint ZF and probabilistic caching (JZF-ProbC) scheme for MISO systems and SISO probabilistic caching (SISO-ProbC) scheme as well as the joint IA and most popular caching (JIA-MPC) caching scheme.

Despite its high antitumor activity, the clinical application of chemotherapy is greatly impeded by lacking of specific accumulation and poor solubility. To address the above challenges, we designed a AS1411 aptamer modified nanoparticles based on molecular recognition of nucleobases. Firstly, a redox sensitive Paclitaxel-SS-Zidovudine (PZ) prodrug was synthesized. Then PZ/β-lapachone/AS1411/DSPE-PEG nanoparticles were prepared and AS1411 aptamer was connected through molecular recognition between the nucleoside analogue Zidovudine (ZDV) and the thymine on aptamer. DSPE-PEG (DP) was incorporated into nanoparticles to prolong the residence time of nanoparticles in the blood circulation. Furthermore, to realize the combination treatment, β-lapachone (LAP) has been incorporated into nanoparticles with high drug loading efficiency through the interaction of π-π stacking force and H-bonding between LAP and Paclitaxel (PTX). LAP can generate abundant exogenous reactive oxygen species (ROS) via the bioactivation of NAD(P)H: quinone oxidoreductase-1 (NQO1). Moreover, the connection of Zidovudine (ZDV) and AS1411 through molecular recognition of nucleobases further optimized the nanoparticles with high affinity to nucleolin which overexpressed on tumor cell membrane, thereby inducing the specific accumulation of nanoparticles in tumor sites. In vivo and in vitro studies showed that the obtained nanoparticles of PZ/LAP/AS1411/DP exhibited better tumor growth inhibition and lower systemic side effects. Herein, we have rationally conducted a novel self-codelivery system for effectively synergistic antitumor treatment.

In this paper, a novel redox-responsive nanoparticles has been designed for targeted delivery of docetaxel (DTX). Chondroitin sulfate (CS) was used to construct the nanoparticles due to the ability of tumor targeting through binding with CD44 receptor that overexpresses on the surfaces of various tumor cells. A redox-responsive small-molecular DTX prodrug was prepared through modifying with cystamine containing disulfide bonds (Cys-DTX). Then the DTX prodrug was grafted to the CS to construct the amphiphilic polymer (CS-ss-DTX). Further, Cys-DTX/CS-ss-DTX nanoparticles were formed by self-assembly of amphiphilic polymer and incorporation of free Cys-DTX prodrug. This category of nanosized DTX delivery system was expected for not only exhibiting high permeability and cytotoxicity of Cys-DTX prodrug, but also targeting transportation of encapsulated redox-responsive Cys-DTX prodrug. According to results of related researches on physicochemical properties and biological evaluation, the novel redox-responsive Cys-DTX/CS-ss-DTX nanoparticles increased amount of DTX released from the nanoparticles in reductive environment, improved permeability in tumor tissues, enhanced cytotoxicity and decreased side effects compared with free DTX. All of these results showed that this kind of Cys-DTX/CS-ss-DTX nanoparticles were worthy of being expectation in tumor chemotherapy in future.

Stimuli-responsive polymeric micelles, a novel category of polymeric micelles with response to endogenous or exogenous environments, show variable physicochemical properties as the variation of endogenous or exogenous circumstances. Because of differences between tumour tissues and normal tissues in physicochemical properties and sensitivity to variation of endogenous or exogenous environments, the application of chemotherapeutic agents loaded stimuli-responsive polymeric micelles are regarded as promising strategies for tumour treatment. In this article, the recent developments of chemotherapeutic agents loaded stimuli-responsive polymeric micelles, for example the preparation of novel stimuli-responsive polymeric micelles and the research progresses of action mechanisms of chemotherapeutic agents loaded micelles, were reviewed and discussed in detail. The advantages of stimuli-responsive chemotherapeutic agents loaded polymeric micelles in practical tumour treatment were also illustrated with the assistance of examples of stimuli-responsive polymeric micelles for antitumor agents delivery.

In the present study, polyion complex micelles based on pluronic F127-chitosan (F127-CS) and sodium deoxycholate (NaDC) were prepared to improve the oral absorption of tacrolimus (FK506) by increasing its aqueous solubility and enhancing its absorption in the gastrointestinal (GI) tract. FK506-loaded F127-CS/NaDC micelles were prepared by the thin film hydration method and had a high drug-loading capacity (8.93±1.47%) and a small particle size (55.77±2.23 nm). The low critical micelle concentration (2.65 × 10-3 mol/L) and the stability test results indicated that F127-CS/NaDC micelles have an enhanced stability against the dilution of GI fluid or blood. Tests of cell uptake showed that F127-CS/NaDC micelles exerted a comparable P-glycoprotein inhibition to verapamil. Compared with FK506 solution, the time to peak (tmax) of FK506 in F127-CS/NaDC micelles decreased from 3 to 1 h and the half-life was prolonged from 16.09 h to 18.00 h. Moreover, drug-time area under the curve was increased by 39.3%, from 533.79 to 742.11 ng/mL·h, which indicated enhanced oral absorption of FK506 in FK506-loaded F127-CS/NaDC micelles. Furthermore, the immunosuppressive effect of FK506-loaded F127-CS/NaDC micelles in a rat liver transplantation model was better than that of FK506 solution. All these results showed that FK506-loaded F127-CS/NaDC micelles are a promising approach for oral delivery of FK506.

Nanogel-based multifunctional drug delivery systems, especially hybrid nanogels and multicompartment nanogels have drawn more and more extensive attention from the researchers in pharmacy because it can result in achieving a superior functionality through the synergistic property enhancement of each component. The unique hybrid and compartmentalized structures provide the great potential for co-delivery of multiple agents even the multiple agents with different physicochemical properties. Otherwise the hybrid nanogel encapsulating optical and magnetic resonance imaging contrast can be utilized in imaging technique for disease diagnosis. More importantly through nanogel-based multifunctional drug delivery systems the stimuli-responsive features might be easily employed for the design of targeted release of drug. This review summarizes the construction of diverse hybrid nanogels and multicompartment nanogels. The application in co-delivery of multiple agents and imaging agents for diagnosis as well as the application in the design of stimuli-responsive multifunctional nanogels as drug delivery are also reviewed and discussed. The future prospects in application of multifunctional nanogels will be also discussed in this review.

Single drug therapy that leads to the multidrug resistance of cancer cells and severe side-effect is a thing of the past. Combination therapies that affect multiple signaling pathways have been the focus of recent active research. Due to the successful development of prodrug-based nano-drug delivery systems (P-N-DDSs), their use has been extended to combination therapy as drug delivery platforms. In this review, we focus specifically on the P-N-DDSs in the field of combination therapy including the combinations of prodrugs with different chemotherapeutic agents, other therapeutic agents, nucleic acid or the combination of different types of therapy (e.g. chemotherapy and phototherapy). The relevant examples of prodrug-based nanoparticulate drug delivery strategy in combination cancer therapy from the recent literature are discussed to demonstrate the feasibilities of relevant technology.

Dendrimers as a new class of polymeric materials have a highly ordered branched structure, exact molecular weight, multivalency and available internal cavities, which make them extensively used in biology and drug-delivery. Concurrent with the development of dendrimers, much more attention is drawn to a novel block copolymer which combines linear chains with dendritic macromolecules, the linear-dendritic block copolymer (LDBC). Because of the different solubility of the contrasting regions, the amphiphilic LDBCs could self-assemble to form aggregates with special core-shell structures which exhibit excellent properties different from traditional micelles, such as lower critical micelle concentration, prolonged circulation in the bloodstream, better biocompatibility, and lower toxicity. The present review briefly describes the type of LDBC, the self-assembly behavior in solution, and the application in delivery system including the application as drug carriers and gene vectors. The interactions between block copolymers and drugs are also summarized to better understand the release mechanism of drugs from the linear-dendritic block copolymers.

Tumor-responsive nanocarriers are highly valuable and demanded for smart anticancer drug delivery, where a quick release of chemotherapeutic drugs in tumors is preferred. Herein, a redox and MMP-2 sensitive nanoparticle has been designed for targeted delivery of PTX. Bovine serum albumin as a targeting ligand and gelatin as a hydrophilic carrier and MMP-2 sensitive reagent were used to construct the nanoparticles. Disulfide containing prodrug (PTX-SS-COOH) was grafted to the sulfhydryl modified gelatin to form the redox sensitive amphiphilic polymer. The nanoparticles were formed by self-assembly of amphiphilic polymer and BSA covering. Furthermore the modified sulfhydryl group on the gelatin can form a disulfide bond by self-crosslinking in the air, which endows the nanoparticle with a stable structure. The nanoparticle was sensitive to changes in MMP-2 concentration and redox potential, resulting in multiple responsive drug delivery to the tumor microenvironment. We further verified the anticancer effect of the nanoparticles both in vitro and in vivo, the nanoparticle (BSA/Gel-SS-PTX/PTX-SS-COOH NPs) demonstrated an excellent anticancer efficiency.

A strategy of preparing mixed micelles containing both DOX prodrug and PTX prodrug was developed, i.e., synthesizing a DOX conjugate and a PTX conjugate started with the same biocompatible amphiphilic copolymer, TPGS and DTDPA, a linker containing disulfide bond. The mixed micelles were prepared by co-assembling the two conjugates with a particle size about 98.5 nm. The mixed micelles could release anticancer drug DOX and PTX upon cellular reduction once they came into the cancerous cells. Moreover, the mixed micelles displayed synergistic effect in vitro and the combination therapy in micellar dosage-form led to reduced systematic toxicity and enhanced antitumor efficacy in vivo.

In this paper, to achieve the targeted ability of anti-tumor drug doxorubicin (DOX), enhance the treatment effect and reduce the side effect, a novel pH-sensitive and charge-convertible prodrug nanogel was prepared. Firstly, cis-aconitic anhydride-doxorubicin prodrug (CAD) and Pluronic F127-chitosan-CAD (F127-CS-CAD) conjugates were synthesized. Then the DOX loaded polyion complex micelles (F127-CS-CAD/CAD) were prepared by self-assembling, thus CAD was incorporated into micelles via electrostatic interactions between electronegative CAD and positively charged F127-CS-CAD and hydrophobic interactions. Finally a pH-responsive charge-convertible copolymer, folic acid modified gelatin (Gel-FA) was shielded on the surface of micelles and the Gel-FA/F127-CS-CAD/CAD nanogel was formed, the charge-convertible capability was evaluated through changes of the morphology and Zeta potential under different pH value environment by transmission electron microscopy (TEM) and Zeta potential analyzer. And in vitro pH-dependent and two-phase drug release from nanogel was also evaluated. In vitro anti-tumor activity of Gel-FA/F127-CS-CAD/CAD nanogel was performed on HeLa cells and HepG2 cells to prove the strong cell toxicity of nanogels. Finally, the in vivo safety experiments showed that the nanogel achieved the reducing the toxic side effects of DOX significantly.

In present study, two types of micelles based on sodium cholate (NaC) were prepared through non-covalent bonding interaction and the potential of micelles as oral drug delivery systems for paclitaxel (PTX) was evaluated. Pluronic–chitosan (F127–CS) and Pluronic–poly (acrylic acid) (F127–PAA) copolymers were synthesized. Electrostatic interaction and hydrogen bond were used to prepare F127–CS/NaC micelles and F127–PAA/NaC micelles, respectively. The physicochemical characteristics of micelles were determined. An average diameter of 67.5 nm and unimodal pattern of size distribution were observed for F127–CS/NaC micelles. While for F127–PAA/NaC micelles, an average diameter of 85.89 nm and non-unimodal pattern of size distribution were observed. The results revealed that F127–CS/NaC micelles were more integrated than F127–PAA/NaC micelles. Further experiments showed that the F127–CS/NaC micelles had a higher drug-loading content of 12.8% and a lower critical micelle concentration (CMC) of 2.5 × 10−3 ...

The aim of the present study is to construct a cysteine modified polyion complex micelles made of Pluronic F127-chitosan (PF127-CS), Pluronic F127-cysteine (PF127-cysteine) and sodium cholate (NaC) and to evaluate the potential of the micelles as an oral drug delivery system for paclitaxel. Systematic studies on physicochemical properties including size distribution, zeta-potential and morphology were conducted to validate the formation of micelle structure. Compared with Pluronic micelles, drug-loading capacity of PF127-CS/PF127-cysteine/NaC micelles was increased from 3.35% to 12.77%. Both the critical micelle concentration and the stability test confirmed that the PF127-CS/PF127-cysteine/NaC micelles were more stable in aqueous solution than sodium cholate micelles. Pharmacokinetic study demonstrated that when oral administration the area under the plasma concentration-time curve (AUC0-∞) and the absolute bioavailability of paclitaxel-loaded micelles were five times greater than that of the paclitaxel solution. In general, PF127-CS/PF127-cysteine/NaC micelles were proven to be a potential oral drug delivery system for paclitaxel.

In this study, novel paclitaxel (PTX) loaded hybrid liposomes for oral PTX delivery were prepared through incorporating PTX loaded polyion complex micelles comprised of positively charged Pluronic F127-Polyethylenimine (PF127-PEI) copolymer and negatively charged sodium cholate (CA) into liposomes consisted of phospholipid molecules. According to the results, this kind of PTX-loaded hybrid liposomes showed improved PTX encapsulation efficiency, sustained PTX release, and enhanced PTX absorption in intestine. The mechanism for enhancing absorption was demonstrated in connection with inhibition of the efflux mediated by multidrug resistance protein, intestinal P-gp. In pharmacokinetic study, the absolute oral bioavailability of PTX loaded in hybrid liposomes had reached to 37.91%. All of these results demonstrated that the application of this novel PTX loaded hybrid liposomes is a strategy with great potential for highly effective oral PTX delivery.

The aim of the present study is to construct a type of polyion complex micelles made of PF127-PEI copolymer and cholic acid (CA) and to evaluate the potential of this type of micelles as a targeted drug delivery system for paclitaxel (PTX). To further improve the targeting capability of micelles, folate was also incorporated into micelles. The characteristics and anti-tumour activity in vitro were investigated. Enhanced solubility of PTX was achieved by incorporating into the micelles. The capability of the polyion complex micelles containing rhodamine 123 to increase the level of intracellular delivery was also observed using fluorescence microscopy. The cytotoxicity of PTX-loaded micelles against cancer cell in vitro was remarkably higher than that of free drug and was better when folate was incorporated into the micelles. These properties such as specificity towards the folate receptor and the low toxicity render folate-modified polyion complex micelles promising candidate for targeted PTX delivery.

The aim of the study is to synthesize a thiolated Pluronic copolymer, Pluronic-poly (acrylic acid)-cysteine copolymer, to construct a mixed micelle system with the Pluronic-poly (acrylic acid)-cysteine copolymer and Pluronic L121 (PL121) and to evaluate the potential of these mixed micelles as an oral drug delivery system for paclitaxel. Compared with Pluronic-poly (acrylic acid)-cysteine micelles, drug-loading capacity of Pluronic-poly (acrylic acid)-cysteine/PL121 mixed micelles was increased from 0.4 to 2.87%. In vitro release test indicated that Pluronic-poly (acrylic acid)-cysteine/PL121 mixed micelles exhibited a pH sensitivity. The permeability of drug-loaded micelles in the intestinal tract was studied with an in situ perfusion method in rats. The presence of verapamil and Pluronic both improved the intestinal permeability of paclitaxel, which further certified the inhibition effect of thiolated Pluronic on P-gp. In pharmacokinetic study, the area under the plasma concentration-time curve (AUC0→∞) of paclitaxel-loaded mixed micelles was four times greater than that of the paclitaxel solution (p 0.05). In general, Pluronic-poly (acrylic acid)-cysteine/PL121 micelles were proven to be a potential oral drug delivery system for paclitaxel.

The objective of this study was to prepare apigenin-loaded polymeric micelles to improve the solubility of apigenin in water. The polymeric micelles composed of Pluronic P123 and Solutol HS 15 were prepared by a thin-film dispersion method and the formulation was optimized with a central composite design (CCD). The obtained micelles were spherical under transmission electron microscope (TEM) with an average diameter of 16.9 nm, the entrapment efficiency and drug loading was 96.36% and 1.32%, respectively. The in vitro drug release study showed nearly 84% of apigenin was released from micelles within 36 h, showing the sustained release property. Cell toxicity assay indicated that the cytotoxicity of apigenin-loaded polymeric micelles against HepG2 and MCF-7 cancer cell in vitro was remarkably higher than that of the free drug. All the results provided the evidence for the great potential of polymeric micelles as nanocarrier for apigenin as a poorly water soluble drug.

The aim of this study was to construct novel targeting polymeric micelles. Folate-Poly (ethylenimine)-Pluronic copolymers were synthesized. A paclitaxel (PTX)-loaded mixed micelles consisting of Folate-Poly (ethylenimine)-Pluronic and Pluronic L121 copolymers have been developed. The mixed micelles showed nano-sized spherical morphology. The solubilization capacity of the mixed micelles was higher than Folate-Poly (ethylenimine)-Pluronic micelles because L121 has high solubilization capacity. MTT colorimetric test revealed that PTX in Folate-Poly (ethylenimine)-Pluronic micelles demonstrated the maximum anticancer activity. Pluronic-poly (ethylenimine) micelles and folate-modified Pluronic-poly(ethylenimine) micelles showed a marked increase of cellular accumulation compared with Pluronic P123 micelles. The biodistribution and retention of intravenously (i.v.) administered micelles to rats were determined. Folate-Poly (ethylenimine)-Pluronic micelles demonstrated enhanced pulmonary retention in rats after injection when compared to Pluronic P123 micelles.

Two types of novel nanogels were prepared using shell cross-linking of Pluronic F127 micelles with polyethylenimine (PEI) (F127/PEI nanogel), and penetrating network of poly(butylcyanoacrylate) (PBCA) in Pluronic F127 micelles (F127/PBCA nanogel). Poorly soluble anticancer drug, paclitaxel (PTX) and 10-hydroxycamptothecin (HCPT), were used as model drugs and incorporated into nanogels. The results obtained from FT-IR spectroscopy confirmed that the drugs were molecularly dispersed in the nanogels. DLS measurements demonstrated that the nanogel size distribution was narrow with average diameter less than 200 nm. TEM images indicated that the nanogels were spherical in shape and had smooth surfaces. The drug-loaded nanogels showed sustained release profiles compared with the free drugs as revealed by in vitro release experiments. Cytotoxicity tests showed that the cytotoxicity of drug-loaded nanogels against cancer cell in vitro was much higher than that of the free drug. The data demonstrate that these novel nanogels improved stability towards dilution, increased solubility and showed better cellular uptake by cells compared with free drug.

New reverse thermo-responsive polymers, poly(ethylene oxide)-poly(propylene oxide) multiblock copolymers (poly(ether-carbonate)s) were synthesized. The micelles made of new reverse thermo-responsive polymers were also prepared loaded with the poorly soluble anticancer drug, hydroxycamptothecin (HCPT). The structure characterization of poly(ether-carbonate)s was determined by (1)H NMR and FT-IR analysis. The critical micelle concentration (CMC), critical micelle temperature (CMT), size distribution and drug release in vitro were determined. The pharmacokinetics and tissue distribution in vivo for novel copolymer micelles were studied. The experimental results showed that the micelles was spherical in appearance and dispersed well. The process of HCPT release from micelles in vitro was composed of two steps, abrupt release and sustained release. After i.v. administration (2h), the drug concentration of poly(ether-carbonate) micelles group in liver in mice was 3.46microg/g, while that of HCPT injection group was 0.401microg/g. Compared with HCPT injection, the elimination half-life of poly(ether-carbonate) micelles group was prolonged remarkably from 1.3 to 12.5h. The poly(ether-carbonate) micelles showed a combination of liver targeting and sustained drug release in experiments on animals.

Mixed micelles made of Pluronic P105 (P105) and poly(ethylene glycol)-phosphatidyl ethanolamine conjugate (PEG-PE) were prepared. The interaction of Pluronic and PEG-PE was studied and the interaction parameter beta and critical micelle concentration (CMC) were used to evaluate the micellar stability toward dilution. The results showed that certain mixed micelles were more stable than pure Pluronic micelles upon dilution. The mixed micelles were used to trap the poorly soluble anticancer drug camptothecin (CPT). The cytotoxicity of the CPT-loaded mixed micelles against MCF-7 cancer cell was higher than that of CPT-loaded P105 micelles and much higher than that of the free drug.

A doxorubicin conjugated prodrug incorporated acid-sensitive linkage between drug and Pluronic F127-chitosan (F127-CS) polymer was successfully synthesized. Subsequently a pH-sensitive polymeric micelle system was designed based on the conjugated prodrugs (F127-CS-DOX) to co-deliver doxorubicin and paclitaxel. Paclitaxel (PTX) was physically entrapped in the hydrophobic inner core of the micelles simultaneously. The structures of conjugates were analyzed by means of (1)H NMR and UV-vis spectrum. Size distribution and morphology of the micelles were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The results indicated that obtained micelles had good dispersity and the diameter was between 56.3 and 403.4 nm. The loading of PTX into the micelle increased with higher DOX content. DOX and PTX release from polymeric micelles followed an acid-triggered manner. Furthermore, in vivo pharmacokinetic study also showed that the area under the plasma concentration time curve (AUC0-∞) values of PTX and DOX for PTX-loaded F127-CS-DOX micelles in rats were 3.97 and 4.38-fold higher than those for PTX plus DOX solution. These results suggested the PTX-loaded F127-CS-DOX micelles would be a promising carrier for co-delivering DOX and PTX.

Based on the advantages of adhesion preparations and the application status of microspheres (MSs) in mucous delivery, this paper primarily reviews the bioadhesive MSs via transmucosal administration routes, including the mucosa in alimentary tract and other lumens. Particularly, the detailed researches about of celladhesive MSs and some new-style bioadhesive MSs are mentioned. Furthermore, this review attempts to reveal the advances of bioadhesive MSs as cell-selective bioadhesion systems and the stimuli-responsive MSs as location-specific drug delivery systems. Although these MSs show powerful strength, some far-sighted ideas should be brought on agendas. In the future, mechanisms should be put under tight scrutiny and more attention should be focused on the excellent bioadhesive materials and the 'second generation mucoadhesives'. Meaningful clinical applications of these novel MSs are also of current concerns and need more detailed researches.

Lung-targeting cisplatin-loaded poly(lactic-co-glycolic) acid microspheres (CDDP-PLGA-MS) were prepared by a solvent evaporation method. The uniform design was used to optimize the technology of preparation, the appearance and size distribution were examined by scanning electron microscope, and the aspects such as in vitro release characteristics, stability, drug loading, loading efficiency, pharmacokinetics and tissue distribution in rabbit were studied. The experimental results showed that the microspheres were globular in appearance and dispersed well. The average particle size was 12.8 microm with 98% of the microspheres being in the range of 5-30 microm. The drug loading and loading efficiency were 17.68 and 53.2%, respectively. The in vitro release behavior could be expressed by the following equation: 1-Q=0.424e(-0.360t)+0.474e(-0.001t). After i.v. administration (15 min), the drug concentration of microspheres group in lung in rabbits was 212 microg/g, while that of controlled group was 1.37 microg/g. CDDP-PLGA-MS showed a combination of lung-targeting and sustained drug release in experiments on rabbits.

The aim of this study is to prepare a stable phosphatidylcholine/bile salt micelles with Pluronic F127-polyethylenimine conjugates (F127-PEI), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), soybean phosphatidylcholine (SPC) and sodium cholate (NaC) and to elucidate the effects and possible mechanism of micelle components on the intestinal absorption of paclitaxel (PTX) in rats. The results of intestinal absorption revealed that the PTX in SPC/NaC micelles displayed superior permeability across intestinal barrier than free drug and PTX in TPGS/SPC/NaC and F127-PEI/TPGS/SPC/NaC mixed micelles exhibited the strongest permeability across intestinal barrier. These results were also proved by the studies on cell uptake tests. The mechanism was demonstrated in connection with inhibition of the efflux mediated by intestinal P-gp and enhancement of the drug transportation across the unstirred water layer to the endothelial lining, thereby promoting the permeation across the intestinal wall. Pharmacokinetic study demonstrated that the area under the plasma concentration-time curve (AUC0→∞) of paclitaxel in F127-PEI/TPGS/SPC/NaC micelles was much greater than that in TPGS/SPC/NaC micelles. This phenomenon deviated from the results of uptake studies by cells and permeability experiments through rat intestine and revealed that the micelle stability had a great effect on intestinal absorption of paclitaxel.

The aim of the present study is to synthesize Pluronic F127-polyethylenimine-folate (PF127-PEI-FA) copolymer, construct a mixed micelle system with PF127-PEI-FA copolymer and Pluronic P123 (PP123) and to evaluate the potential of these mixed micelles as an oral drug delivery system for paclitaxel (PTX). The results of intestinal absorption revealed that the PTX-loaded micelles displayed superior permeability across intestinal barrier than free drug and PF127-PEI-FA/PP123 mixed micelles exhibited the strongest permeability across intestinal barrier. These results were also proved by the studies on cytotoxicity and cell uptake tests. The mechanism was demonstrated in connection with inhibition of the efflux mediated by intestinal P-glycoprotein (P-gp) and enhancement of the electrostatic interaction of positive micelles with the negative intestinal epithelial cells, thereby promoting the permeation across the intestinal wall. The presence of verapamil and Pluronic both improved the intestinal absorption of PTX, which further certified the effect of Pluronic on P-gp inhibition. Pharmacokinetic study demonstrated that the area under the plasma concentration-time curve (AUC(0→36 h)) of PTX-loaded micelles was three times greater than the PTX solution (dissolved in a 50/50 (vol/vol) mixture of Cremophore EL/dehydrated ethanol) (p0.05). In general PF127-PEI-FA/PP123 mixed micelles were proved to be potential oral drug delivery system for PTX.

In this paper, a pharmacokinetic model to describe the tissue distribution process of nanoparticles was established. To test the possibility of the model, nanoparticles composed of poly(butylcyanoacrylate) and hydroxypropyl-β-cyclodextrins (HP-β-CD) was prepared with a poorly soluble anticancer drug, hydroxycamptothecin (HCPT). Characteristics were determined including particle's size, morphology and in vitro release. The tissue distribution of nanoparticles was also studied. Further, mathematical equation was fitted to the curve of drug concentration-time in liver of hydroxycamptothecin-loaded nanoparticles and the pharmacokinetic parameters of liver were obtained. The effectiveness of hydroxycamptothecin-loaded nanoparticles for liver targeting was evaluated. The results showed that nanoparticles composed of poly(butylcyanoacrylate) and hydroxypropyl-β-cyclodextrins (HP-β-CD) exhibited enhanced liver targeting in rats after i.v. injection. More importantly, the pharmacokinetic parameters (transport constant from blood to target organ KT, drug release rate from nanoparticles Kr and drug elimination constant in target organ Ke) provided some quantitative measure of liver distribution and were useful guidelines for development of targeted drug delivery systems.

The aim of this study was to assess the potential of new copolymeric micelles to modify the pharmacokenetics and tissue distribution of Curcumin (CUR), a hydrophobic drug. In the present study, a poly ( d , l -lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly( d , l -lactide-co-glycolide) (PLGA-PEG-PLGA) copolymer was synthesized and characterized by 1 H NMR, gel permeation chromatography and FTIR analysis. The CUR-loaded PLGA-PEG-PLGA micelles were prepared by dialysis method and the physicochemical parameters of the micelles such as zeta potential, size distribution and drug encapsulation were characterized. The pharmacokinetics and biodistribution of CUR-loaded micelles in vivo were evaluated. The results showed that the zeta potential of CUR-loaded micelles was about −0.71 mV and the average size was 26.29 nm. CUR was encapsulated into PLGA-PEG-PLGA micelles with loading capacity of 6.4 ± 0.02% and entrapment efficiency of 70 ± 0.34%. The plasma AUC (0– ∞ ) , t 1/2α , t 1/2β and MRT of CUR micelles were increased by 1.31, 2.48, 4.54 and 2.67 fold compared to the CUR solution, respectively. The biodistribution study in mice showed that the micelles decreased drug uptake by liver and spleen and enhanced drug distribution in lung and brain. These results suggested that PLGA-PEG-PLGA micelles would be a potential carrier for CUR.

Nanoparticles consisting of a cross-linked cationic polymer network were prepared using Pluronic F127 and poly(ethylenimine) (PEI) and suggested as a drug delivery system for the anticancer drug Paclitaxel (PTX). In order to further improve the targeting capability of nanoparticles, folic acid (folate) was conjugated to the surface of nanoparticles. The characteristics were determined by various methods such as FT-IR for drug state in nanoparticles and DLS and TEM for particle size and morphology. The results found that the drug-loading content was increased when folate was connected to the surface of these nanoparticles. In vitro release experiments indicated that the PTX-loaded nanoparticles showed sustained release profiles compared to PTX solution, especially when nanoparticles were modified by folate. The cytotoxicity of PTX-loaded nanoparticles against cancer cell in vitro was remarkably higher than that of free drug and was better when folate, whose receptor was highly expressed in various tumors, was conjugated to the surface of these nanoparticles. The data demonstrated that this carrier-based approach to delivery of cytotoxic drugs may enhance tumor specificity and significantly reduce side effects related to systemic toxicity usually observed during cancer chemotherapy.

Multi-compartment linear circulation mathematical model for targeted drug delivery systems was established on the bases of compartment theory and mass conservation theory. The function formulas of drug concentration-time in blood and target organ were established. According to this model, the drug concentration-time curve for the target organ can be plotted with reference to the data on blood. Based on the target organ drug concentration-time curve,the pharmacokinetics parameters of the target organ can also be calculated by the statistical moment. We further detected the practicability of the models by using the experimental data of drug concentration-time curve in blood and target organ of microspheres. The drug concentration-time curve in blood and in target organ predicted by mathematical model was agreed with that observed.

Sugar-containing monomer vinylbenzylglycosylallyamide (VBG) was synthesized by vinylbenzyl amine and delta-gluconolactone in dimethylformamide(DMF) solution. The sugar-based hydrogel was prepared by free radical crosslinking copolymerization of VBG, itaconic acid (IA) and acrylamide (AM). The release properties of Aspirin from xerogels matrices and from hydrogel in different pH solutions and different concentration NaCl solutions were studied respectively. The release mechanism of Aspirin was further confirmed by evaluating the n value in Peppas equation. The results indicated that the drug release increased with the increase of pH values and with the decrease of NaCl concentration.

Sugar-containing monomer glycosylallylamide (AAG) was synthesized by allyl amine and delta-gluconolactone in dimethylformamide (DMF) solution. The sugar-based hydrogels were prepared by free radical crosslinking copolymerization of AAG and acrylamide (AM). The release properties of Aspirin from xerogels matrices were studied and the release mechanism of Aspirin was further identified by evaluating the n value in Peppas equation. The results indicate that the drug release decreases with the increase of the sugar content of hydrogel.

The mechanism of drug release from swellable polymer was studied. The model which can explain the drug release from glassy polymer was developed by coupling drug diffusion equation and solvent diffusion equation. The effect of viscoelastic stress of polymer was also considered. The Deborah number and swelling interface number were used to describe the mechanism of drug release, especially relax controlled mechanism.