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Albumin has been regarded as the ideal drug carrier for delivering hydrophobic agents into cancer cells over decades. Combination therapy of paclitaxel (PTX) with resveratrol (RES) could enhance the sensitivity of multidrug resistance (MDR) cancer cell lines to PTX. In this study, novel paclitaxel/resveratrol co-loaded albumin nanoparticles (PTX/RES NPs) were developed to achieve synergistic anticancer efficacy and conquer paclitaxel resistance. The hybrid NPs had an average diameter of about 150 nm and an apparent negative surface charge of about −33 mV. PTX/RES NPs could be efficiently internalized by cells and exert synergistic combination efficacy of the two drugs, thus resulting in dramatically in vitro cytotoxicity even against MDR cancer cells. In vivo antitumor assay demonstrated that the antitumor effect of the hybrid NPs was superior to that of single drug-loaded NPs or free drug combination. Molecular docking analysis disclosed that the binding of PTX and RES to bovine serum albumin (BSA) was noncompetitive but the binding free energy of BSA/PTX dockings was significantly lower than BSA/RES dockings, which resulted in high encapsulation efficiency and sustained drug release profiles of PTX. In summary, the PTX/RES co-delivery system might be a promising strategy for combined anticancer therapy to overcome tumor drug resistance.

Combinatorial chemo-photodynamic therapy is regared as effective cancer therapy strategy, which could be realized via multiple nano-drug delivery system. Herein, novel high payload nanoparticles stabilized by amphiphilic block polymer cholesterol-b-poly(ethylene glycol) (PEG)2000 (Chol-PEG2000) were fabricated for loading chemotherapeutic drug 10-hydroxycamptothecin (HCPT) and photosensitizer chlorin e6 (Ce6). The obtained HCPT/Ce6 NPs showed uniform rod-like morphology with a hydration diameter of 178.9 ± 4.0 nm and excellent stability in aqueous solution. HCPT and Ce6 in the NPs displayed differential release profile, which was benefit for preferentially exerting the photodynamic effect and subsequently enhancing the sensitivity of the cells to HCPT. Under laser irradiation, the NPs demonstrated fantastic in vitro and in vivo anticancer efficiency due to combinational chemo-photodynamic therapy, enhanced cellular uptake effectiveness, and superb intracellular ROS productivity. Besides, the NPs were proved as absent of systemic toxicity. In summary, this nanoparticle delivery system could be hopefully utilized as effective cancer therapy strategy for synergistically exerting combined chemo-photodynamic therapy in clinic., Graphical Abstract

The co-encapsulation of multiple bioactive components in a carrier may produce synergistic effects and improve health benefits. In this study, the interactions of β-lactoglobulin (β-LG) with epigallocatechin-3-gallate (EGCG) and/or piceatannol (PIC)/oxyresveratrol (OXY) were investigated by multispectroscopic techniques, isothermal titration calorimetry, and molecular docking. The static quenching mechanism of β-LG by EGCG, PIC and OXY was confirmed by fluorescence spectroscopy and UV-vis absorption difference spectroscopy. The binding sites of these three polyphenols in β-LG were identified by site marking fluorescence experiments and molecular docking. The thermodynamic parameters of the β-LG + EGCG/PIC/OXY binary complex and β-LG + EGCG + PIC/OXY ternary complex were obtained from fluorescence data and used to analyze the main driving force for complex formation. The exothermic binding process was further confirmed by isothermal titration calorimetry. The α-helical content, particle size and morphology of free and ligand-bound β-LG were determined by circular dichroism spectroscopy, dynamic light scattering and transmission electron microscopy, respectively. The effect of EGCG, PIC and OXY on the conformation of β-LG was studied by Fourier transform infrared spectroscopy. In addition, the maximum synergistic antioxidant activity between EGCG and PIC/OXY was obtained by response surface analysis. The effects of β-LG in the binary and ternary systems on the antioxidant activity, stability, solubility and cytotoxicity of the polyphenols were also studied. Finally, the different cytotoxicities of the complexes and nanoparticles of the binary and ternary systems were compared. The results of this study are expected to provide a theoretical basis for the development of β-LG-based carriers co-encapsulating a variety of bioactive components.

Background The combination of chemo-photodynamic therapy based on nano-technology has emerged as a preferable and promising measure for synergetic antitumor therapy. Purpose The aim of this study was expected to overcome most of the safety concerns from nano-carriers and improve the chemo-photodynamic synergistic antitumor efficacy. Methods Herein, we reported a facile and effective approach based on the self-assembly of chemotherapeutic agent 10-hydroxycamptothecin (HCPT) and photosensitizer chlorin e6 (Ce6) for preparing stably dual-functional nanorods (NRs). Results The chemical thermodynamic parameters obtained from isothermal titration calorimeter (ITC) and the microcosmic configuration snapshots acquired by molecular dynamics (MD) simulations verified that HCPT and Ce6 molecules tended to assemble with each other through various intermolecular forces. The as-prepared HCPT/Ce6 NRs possessed a relatively uniform size of around 165 nm and zeta potential of about -29 mV, together with good stability in aqueous solution and freeze-dried state. In addition, both the extra- and intracellular reactive oxygen species (ROS) generation capacity of the NRs under laser irradiation was significantly enhanced compared with Ce6 injections. Moreover, the dual-functional HCPT/Ce6 NRs exhibited a substantial in vitro/in vivo synergistic antitumor efficacy under laser irradiation due to the integration of the two therapeutic modalities into one drug delivery system. Besides, no obvious hepatic or renal toxicity was observed in the NRs treatment groups. Conclusion Taken together, HCPT/Ce6 NRs demonstrated a powerful efficacy in chemo-photodynamic therapy for breast cancer. Therefore, the carrier-free dual-functional NRs prepared in a facile and effective strategy might give inspiration for the development of combined antitumor therapy.

In this study, novel ritonavir solid dispersion (RTV SD) formulations were prepared with copovidone (PVPVA 64) and optimized plasticizers via hot-melt extrusion (HME) at different extrusion temperature to evaluate the effect of plasticizers on the process of HME. The optimized drug-loading content of RTV SD formulations was around 15% and RTV was converted to the amorphous state and integrated through physical interactions (possibly hydrogen bonding) with the polymeric carrier. Using Span 20 or HSPC as plasticizer, the HME extrusion temperature of RTV SD formulations suggested a decrease of 10 °C or 20 °C. Furthermore, the in vitro release and the in vivo pharmacokinetics analyses both showed that RTV SD formulations using Span 20 or HSPC as plasticizer possessed better release profiles and bioavailability over RTV bulk powder but showed equal physicochemical characteristics compared to RTV SD formulations without plasticizer. According to the increased drug solubility, enhanced dissolution profiles, superior bioavailability, but decreased extrusion temperature in HME process, the RTV SD formulation using HSPC as plasticizer could be potentially applied in the clinic as an efficient drug delivery system, and HSPC is recommended as an efficient plasticizer for manufacturing RTV SD formulations via HME.

In current study, a novel nimodipine solid dispersion (NM-SD) was prepared by hot-melt extrusion (HME) with Hypromellose methylcellulose acetate succinate (H type and fine grades, HPMCAS-HF) for its excellent recrystallization inhibition effects. NM was confirmed to exist as an amorphous state in NM-SD by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), hot stage microscopy (HSM) and scanning electron micrographs (SEM). FT-IR analysis illustrated hydrogen bond interaction between drugs and excipients in NM-SD. The release behavior of NM-SD tablets was investigated in the dissolution medium of pH 6.8 for the in vitro study, which showed that the release of nimodipine could be realized in vitro without recrystallization within two hours. The in vivo pharmacokinetic profiles study in Sprague-Dawley rats was also determined. It was obvious that the Cmax value of NM-SD tablets made by dry granulation was slightly higher than Nimotop®, while the area under the curve, AUC(0-t) exhibited no significant difference between them. In conclusion, the solubility of NM and dissolution rate of NM-SD tablets were greatly improved by HME due to the recrystallization inhibition characteristic of HPMCAS-HF.

The quality control of drug products during manufacturing processes is important, particularly the presence of different polymorphic forms in active pharmaceutical ingredients (APIs) during production, which could affect the performance of the formulated products. The objective of this study was to investigate the phase transformation of fexofenadine hydrochloride (FXD) and its influence on the quality and performance of the drug. Water addition was key controlling factor for the polymorphic conversion from Form I to Form II (hydrate) during the wet granulation process of FXD. Water-induced phase transformation of FXD was studied and quantified with XRD and thermal analysis. When FXD was mixed with water, it rapidly converted to Form II, while the conversion is retarded when FXD is formulated with excipients. In addition, the conversion was totally inhibited when the water content was &lt, 15% w/w. The relationship between phase transformation and water content was studied at the small scale, and it was also applicable for the scale-up during wet granulation. The effect of phase transition on the FXD tablet performance was investigated by evaluating granule characterization and dissolution behavior. It was shown that, during the transition, the dissolved FXD acted as a binder to improve the properties of granules, such as density and flowability. However, if the water was over added, it can lead to the incomplete release of the FXD during dissolution. In order to balance the quality attributes and the dissolution of granules, the phase transition of FXD and the water amount added should be controlled during wet granulation.

Hydrogel formulations are considered to be promising dosage forms for clinical delivery of antibiotics but suffer from many limitations such as polymers selection and crosslinking methods. Herein, dynamic Schiff base reaction crosslinked hydrogels (denoted as CO) with 'switchable' channels were designed based on Chitosan and Salecan. Chitosan maintains the pH sensitive property while providing functional groups for the reversible bond formation. Equilibrium water content, swelling and degradation behavior, dynamic rheology and cytotoxicity assay were investigated to characterize the hydrogels' properties. By simulating and comparing four classic models, the drug release kinetics and mechanism were studied in detail. HeLa cells were encapsulated to further exploring the feasibility of 3D cell culture. All the results revealed CO hydrogels possessed excellent biological functions to maintain cell growth. Therefore, CO hydrogels can be served as a promising carrier for drug delivery and also expected to apply in many other medical fields.

To improve the ultraviolet resistance and thermal stability of waterborne polyurethane, stable waterborne polyurethane/nano-cerium oxide hybrid dispersions were obtained by adding nano-cerium colloids to previously synthesized waterborne polyurethane dispersions. The dried ceria colloid was characterized by X-ray diffraction (XRD) and high resolution transmission electron microscopy (HRTEM). The XRD results indicated the prepared CeO2 was a face-centered cubic structure. The prepared polyurethane/CeO2 dispersions were studied by dynamic light scattering (DLS), transmission electron microscopy (TEM), UV–Vis spectroscopy and accelerated weathering test. The dried polyurethane/CeO2 films were characterized using thermogravimetric analysis (TGA). The DLS analysis indicated the particles average diameter of hybrids emulsion was bigger than that of the pure waterborne polyurethane dispersion. TG analysis and accelerated weathering test suggested the hybrid latex films had better thermal stability and mechanical properties than those of the pure waterborne polyurethane. The UV–Vis absorption capacity of the dispersions prepared was increasing with the amount of CeO2 colloid increased.

Self-assembled DNA nanostructures, as a novel type of nano-biomaterials, are widely used for smart and targeted drug delivery due to their precise structures and versatile functions. The binding affinity of drugs to DNA nanostructures plays an important role in drug loading, release and efficacy. The interaction of mithramycin (MTR) with AS1411-tethered DNA nanotrains (AS1411NTrs) in the presence of different divalent metal ions (Mg2+, Zn2+, and Mn2+) was studied by fluorescence spectroscopy, differential scanning calorimetry and viscosity measurement. The binding mode between the MTR dimers and AS1411NTrs was determined by viscosity experiment and melting temperature measurement. The thermodynamic parameters of the binding process (binding stoichiometry, binding constant, enthalpy change, entropy change and Gibbs free energy change) were determined by fluorescence spectroscopy and differential scanning calorimetry, and the effect of different metal ions on the binding was compared. The release of the MTR dimers loaded by AS1411NTrs in the absence and presence of DNase I was analyzed. The in vitro cytotoxicity of the MTR dimers to HepG2 cancer cells and L02 normal cells and their intracellular uptake efficiency were evaluated. The binding parameters were correlated with the loading, release and cytotoxicity of the MTR dimers. These studies showed that AS1411NTrs had high drug loading and sustained release effect on (MTR)2Mg2+, (MTR)2Zn2+ and (MTR)2Mn2+. This drug loading system improved the lethality to cancer cells and reduced the side effects on normal cells. This study may provide a theoretical basis for the clinical application of MTR loaded by DNA nanostructures.

The quality control of drug products during manufacturing processes is important, particularly the presence of different polymorphic forms in active pharmaceutical ingredients (API) during production, which could affect the performance of the formulated products. In this study, Fexofenadine Hydrochloride (FXD) Form I (anhydrous) was used as the starting material for pharmaceutical formulation, while FXD exhibited a polymorphic conversion to hydrate Form II in presence of water. It is necessary to monitor phase transition from Form I to Form II during wet granulation. The aim of this paper was to quantify the polymorphic forms of FXD during wet granulation process by NIR and DSC technique. Calibration models were developed and validated in binary mixtures of FXD polymorphs forms and multicomponent mixtures of FXD formulation. The NIR and DSC can be successfully employed to evaluate and quantify Form I during wet granulation. The Form I % determined was similar by NIR and DSC. The relationship between phase transition of FXD and water content was determined. In addition, the effect of various excipients on the phase transition of FXD was also evaluated by NIR. The understanding of the phase transition in wet granulation process of pure FXD, formulation and FXD-excipient mixtures provided directions for optimization of FXD manufacturing processes.

Nanoparticles based on dendrimers were explored as excellent candidates for nanoscale drug delivery system. In this study, the fluorescently labeled amphiphilic codendrimer PGC from PAMAM G4.0 and oligoethylene glycol dendron was utilized as a carrier to prepare honokiol-loaded nanoparticles (HK NPs) via an evaporation method augmented by ultrasonication with an optimized drug-loading content (∼60%, wt%). The release of HK NPs showed a sustained release manner and was completed within 120 h. The HK NPs presented higher cytotoxicity against 4T1 cells, and the cellular uptake mechanism was proven to be caveolae-mediated endocytosis and clathrin-mediated endocytosis. Importantly, the HK NPs resulted in a strong antitumor efficacy on the 4T1 breast tumor model in vivo, and no significant adverse effects were observed. In addition, in vivo studies also showed that the HK NPs possessed better tumor accumulation over HCPT injection. According to the higher drug-loading content, enhanced antitumor efficacy, and appropriate particle size, HK NPs were shown to be safe and efficient drug delivery systems and could have potential application in cancer chemotherapy.

Mild crosslinking methods, which have a strong influence on biomedical hydrogels and scaffolds, have attracted wide attention in recent years. In this project, native chemical ligation (NCL) was utilized to prepare biocompatible and biodegradable hydrogels using naturally derived poly(glutamic acid) (PGA) with no additives or by-products. Firstly, thiolactone-grafted poly(glutamic acid) (PGA-HC) and cysteine-grafted poly(glutamic acid) (PGA-C) precursors were synthesized. Their structure was confirmed by nuclear magnetic resonance (NMR). Then, hydrogels crosslinked by NCL were formed by blending buffered solutions of PGA-HC and PGA-C with no additives under physiological conditions. After that, the equilibrium water content, morphology, degradation rate and mechanical properties of the hydrogels were characterized in detail. The data showed that the PGA hydrogels had gelation times, water contents and mechanical properties that were tunable by adjusting the precursor composition. Furthermore, the biocompatibility of the hydrogels was confirmed by an MTT assay. These characteristics provide a potential opportunity for the NCL hydrogels as wound dressings, skin fillings, drug delivery vehicles and tissue regeneration matrices.

Nanorods based on dendrimers were explored as excellent candidates for nanoscale drug delivery system. In this study, fluorescently labeled PAMAM-b-oligoethylene glycols codendrimer (POC) was utilized as carrier to prepare 10-hydroxycamptothecin (HCPT) loaded nanorods (HCPT NRs) via antisolvent precipitation method augmented by ultrasonication with the optimized drug-loading content (∼90.6%) and positive charged surface. The nanorods presented high stability, and the release of HCPT nanorods showed a sustained release manner and was completed within 48 h. The nanorods presented higher cytotoxicity against HepG2 and 4T1 cells than HCPT injections, and the cellular uptake mechanism was proved to involve clathrin-mediated endocytosis and macropincytosis-dependent endobytosis. Importantly, the HCPT nanorods resulted in strong antitumor efficacy on the H22 liver tumor model, and no significant adverse effects was observed. Besides, in vivo studies also showed that HCPT NRs possessed better tumor accumulation over HCPT injection at the equivalent concentration. According to the high drug-loading content, enhanced antitumor efficacy, and appropriate particle size, HCPT NRs as the safe and efficient drug delivery systems could have potential application for cancer chemotherapy in clinic.

The combination therapy strategy based on both chemotherapy and photodynamic therapy (PDT) exhibits great potential for advanced cancer treatment. Multimodal nanodrug delivery systems based on both chemotherapeutic drug and photodynamic agent have been proven to possess excellent synergistic efficacy. In this study, 7-ethyl-10-hydroxycamptothecin (SN38) and chlorin e6 (Ce6) were co-assembled into novel carrier-free nanoparticles (SN38/Ce6 NPs) via simple antisolvent precipitation method. As expected, SN38/Ce6 NPs exhibited uniform morphology with a particle size of around 150 nm and a zeta potential of about -30 mV, good stability in aqueous solution/at lyophilized state and high cellular uptake efficiency against murine mammary carcinoma (4T1) cell lines. Besides, enhanced singlet oxygen generation capacity of the nanoparticles was both observed in test-tube and in 4T1 cell lines in contrast with Ce6 injection. Moreover, a ∼85 % inhibition rate of SN38/Ce6 NPs with laser was detected, which was significantly higher (P 0.05) than those without laser (∼65 %) and injections (less than 20 %), verified the excellent synergistic antitumor efficacy of the nanoparticles due to combined chemo-photodynamic therapy, enhanced tumor accumulation and higher cellular internalization. Notably, chemical thermodynamic method and molecular dynamics (MD) simulations supplied solid data and visual images to estimate the driving forces for the self-assembly process of the carrier-free nanoparticles as primary hydrophobic interactions (π-π stacking) and subordinate hydrogen bonds. Conclusively, the above self-assembled carrier-free nanoparticles represented a promising synergistic anticancer strategy capable of maximal therapeutic efficacy and minimal systemic toxicity. Moreover, the application of thermodynamic method together with MD simulations in the investigation of NPs self-assembly process also provided new ideas for the assembly mechanism exploration of more complicated nanodrug delivery system.

Celecoxib (CLX), a selective COX-2 inhibitor, is a biopharmaceutics classification system (BCS) class II drug with its bioavailability being limited by thepoor aqueoussolubility. The purpose of this study was to develop and optimize CLX nanocrystalline(CLX-NC) solid dispersion prepared by the wet medium millingtechnique combined with lyophilizationto enhance oral bioavailability. In formulation screening, the resulting CLX-NC usingpolyvinylpyrrolidone (PVP) VA64 and sodiumdodecyl sulfate (SDS) as combined stabilizers showed the minimum particle size and a satisfactory stability. The formulation and preparation processwere further optimized by central composite experimentaldesign with PVP VA64 concentration (X1), SDS concentration (X2) and milling times (X3) as independent factors and particle size (Y1), polydispersity index (PDI, Y2) and zeta potential (Y3) as response variables. The optimal condition was determined as a combination of 0.75% PVP VA64, 0.11% SDS with milling for 90 min.The particle size, PDI and zeta potential of optimized CLX-NC were found to be 152.4 &plusmn, 1.4 nm, 0.191 &plusmn, 0.012 and &minus, 34.4 &plusmn, 0.6 mV, respectively. The optimized formulation showed homogeneous rod-like morphology as observed by scanning electron microscopy and was in a crystalline state as determined by differential scanning calorimetry and powder X-ray diffraction. In a storage stability study, optimized CLX-NC exhibited an excellent physical stability during six months&rsquo, storage at both the refrigeration and room conditions. In vivo pharmacokinetic research in Sprague-Dawley ratsdisplayed that Cmax and AUC0&ndash, &infin, of CLX-NC were increased by 2.9 and 3.1 fold, compared with physical mixture. In this study, the screening and optimizing strategy of CLX-NC formulation represents a commercially viable approach forenhancing the oral bioavailability of CLX.

The oral bioavailability of bisdemethoxycurcumin, one of the main active compounds of curcuminoids, can be improved by the encapsulation of surfactant micelles. The interaction of bisdemethoxycurcumin with Tween 20 and Tween 60 micelles was investigated by spectroscopic techniques and molecular dynamics simulation. The binding parameters were obtained from temperature-dependent fluorescence and absorption spectra. The main driving forces were inferred from the enthalpic and entropic contributions. The binding site and surrounding microenvironment of bisdemethoxycurcumin in Tween micelles were evaluated. Coarse-grained molecular dynamics simulations confirmed the binding of bisdemethoxycurcumin with Tween micelles from the microscopic perspective. The influence of different alkyl chains of Tween 20 and Tween 60 on their interaction with bisdemethoxycurcumin and their solubilization capability toward bisdemethoxycurcumin was discussed. These results suggested that Tween 20 and Tween 60, especially Tween 60, can be used as carriers for encapsulating bisdemethoxycurcumin to increase its aqueous solubility.

Combined chemo-photodynamic therapy strategy is regarded as a potential strategy for advanced cancer treatments. Herein, novel high payload 7-ethyl-10-hydroxycamptothecin (SN38)/chlorin e6 (Ce6) NPs based on the collaborative assembly of the pre-obtained SN38–Ce6 complex and biocompatible amphiphilic block polymer DSPE-PEG2000 were successfully constructed. The self-assembly mechanism of the NPs was corporately disclosed as static quenching resulted from complex formation between DSPE-PEG2000 and the pre-acquired SN38–Ce6 complex via fluorescence quenching experiment. The high payload SN38/Ce6 NPs exhibited uniform rod-like morphology with a hydrodynamic radius of about 200 nm, a zeta potential of around −25 mV, and excellent storage stability. The high payload NPs showed efficient singlet oxygen generation capacity both in tube and in murine mammary carcinoma (4T1) cells under laser irradiation. Moreover, the in vitro cytotoxicity and in vivo antitumor efficacy of the NPs (with laser) against 4T1 cell lines model were proved to be statistically significant compared to CPT-11 injection and single-drug NPs due to synergistic chemo-photodynamic therapy and high cellular uptake efficiency. Meanwhile, the systemic toxicity of the NPs was basically absent. Conclusively, the high payload dual-functional nanoparticles could be served as a promising strategy for cancer treatment in clinic.

DNA nanostructures-based chemotherapy-phototherapy (CTPT) combination therapy can achieve targeted release and effectively overcome multidrug resistance (MDR). The therapeutic effect of CTPT combination drugs loaded in DNA nanostructures is related to the interactions among them. Herein, based on our previous research on AS1411NTrs loading with a single drug of DOX, the interactions between a single drug (toluidine blue O, TBO) or combination drugs (doxorubicin and toluidine blue O, DOX + TBO) and AS1411 aptamer-tethered DNA nanotrains (AS1411NTrs) were investigated. By fluorescence spectroscopy and isothermal titration calorimetry technique, the corresponding thermodynamic parameters were obtained, including the number of binding sites, binding constant, enthalpy change and entropy change. By combining with the differential scanning calorimetry and ferrocyanide ion quenching analysis, the binding mode-thermodynamic parameters were correlated. In addition, the effect of the binding affinity of DOX and TBO to AS1411NTrs on the drugs release rate was studied. Finally, the in vitro cytotoxicity and confocal laser scanning microscopy imaging of AS1411NTrs + TBO + DOX was investigated. The results showed that this drug delivery system could increase its in vitro cytotoxicity and overcome drug resistance in DOX-resistant human breast cancer cells (MCF-7/ADR). The work would provide important information for the combination therapy of DOX and TBO to overcome MDR effectively.

An amphiphilic dendron–drug conjugate was synthesized via oligoethylene glycol (OEG) dendrons coupled with anticancer drug doxorubicin (DOX). The amphiphilic conjugate OEG–DOX (GD) self-assembled into spherical nanoparticles in aqueous solution, with mean diameters of approximately 212.5 nm. As an effective drug carrier, DOX was entrapped into GD to form drug-loaded nanoparticles (GD/D) with high drug loading content (24%, wt%), due to the enhanced hydrophobic/aromatic interactions between the DOX moiety in GD and free DOX. Besides, GD nanoparticles exhibited thermo-induced collapse and aggregation, therefore, the temperature-dependent drug release profiles of DOX from GD/D nanoparticles were measured and the possible mechanism was proposed. Moreover, hemolytic activity of GD/D revealed the good blood compatibility, and the cytotoxicity of DOX in GD/D was enhanced significantly in vitro against HepG2 cells. Overall, amphiphilic conjugate GD was considered to be potentially feasible to overcome formulation challenges for drug delivery and to be used in clinic.

The combined application of polyphenols and anticancer drugs may be of great help to current cancer treatment. In this paper, the individual and combined interactions of oxyresveratrol (OXY)/piceatannol (PIC) and mitoxantrone (MIT) with human serum albumin (HSA) in phosphate buffer of pH 7.4 were studied by multi-spectroscopic techniques and molecular docking. The quenching mechanism of HSA by OXY, PIC and MIT was determined by fluorescence quenching experiments and UV difference spectra. The binding location of the three ligands on HSA was identified by site marking fluorescence spectra, synchronous fluorescence spectra, and molecular docking. For the OXY/PIC/MIT + HSA binary system and the OXY/PIC + MIT + HSA ternary system, the thermodynamic parameters were obtained. The results indicated the competitive binding of OXY/PIC and MIT to HSA. The driving forces in the binding process were discussed. The circular dichroism spectroscopy and dynamic light scattering were employed to investigate the effects of OXY/PIC/MIT single drug and OXY/PIC + MIT combined drugs on the secondary structure and particle size of HSA. The effects of drug combination and HSA interaction on the in vitro cytotoxicity against HeLa cells were determined by MTT assay. The results would provide a theoretical basis for the combined application of polyphenols and traditional anticancer drugs.

As one of the most promising drug delivery carriers, self-assembled DNA nanostructures are characterized of well-defined sizes, excellent biocompatibility, high drug loading and ability to control drug release. Studying the interactions between anticancer drugs and DNA nanostructures can help to associate microstructure-drug loading-release rate-therapeutic effect. Herein AS1411 aptamer-tethered DNA nanotrains (AS1411NTrs) were constructed and used as anthracyclines carrier with high payload for targeted delivery. The bindings of doxorubicin (DOX), epirubicin (EPI), and daunorubicin (DAU) to AS1411NTrs were investigated by isothermal titration calorimetry and fluorescence spectroscopy, and thermodynamic parameters were obtained. The high drug payload capacity of AS1411NTrs was verified by the large number of binding sites (~20). The binding mode was determined by differential scanning calorimetry and potassium iodide (KI) quenching experiments. The release experiment data showed that DNase I facilitated drug release and the release followed the first-order kinetic model. MTT cell viability assay demonstrated that the drug-loaded AS1411NTrs had significantly higher cytotoxicity against target HeLa cells than normal human liver L02 cells. These findings revealed that AS1411NTrs had high payload and targeted release capacity for DOX, EPI, and DAU. This result can provide a theoretical basis for constructing reasonable DNA nanostructures based on drug carriers.

It was reported that the shape of nanocarriers played an important role in achieving a better therapeutic effect. To optimize the morphology and enhance the antitumor efficacy, in this study based on the amphiphilic PAMAM- b-OEG codendrimer (POD), docetaxel-loaded spherical and flake-like nanoparticles (DTX nanospheres and nanosheets) were prepared via an antisolvent precipitation method with similar particle size, surface charge, stability, and release profiles. The feed weight ratio of DTX/POD and the branched structure of OEG dendron were suggested to influence the shapes of the self-assembled nanostructures. As expected, DTX nanospheres and nanosheets exhibited strong shape-dependent cellular internalization efficiency and antitumor activity. The clathrin-mediated endocytosis and macropincytosis-dependent endocytosis were proven to be the main uptake mechanism for DTX nanospheres, while it was clathrin-mediated endocytosis for DTX nanosheets. More importantly, DTX nanosheets presented obviously superior antitumor efficacy over nanospheres, the tumor inhibition rate was increased 2-fold in vitro and 1.3-fold in vivo. An approximately 2-fold increase in pharmacokinetic parameter (AUC, MRT, and T

Organic solvents have been reported to exert certain influence on the structure and drug loading efficiency of albumin. It is urgent to develop organic solvent-free albumin-based paclitaxel nanoparticles for effective anticancer therapy. In this study, novel PTX liposome-albumin composite nanoparticles (Lip-PTX/BSA NPs) aimed at avoiding the direct contact of albumin with toxic organic solvents and enhancing the colloidal stability of the formulation were prepared. To methodically evaluate the impacts of multifarious factors on the critical characteristics of the nanoparticles, Box-Behnken design was applied in the formulation optimized process. Ratio of drug-phosphatidylcholine (EPC), ratio of drug-BSA and pH of the media were chosen as the independent variables, while particle size and drug-loading content (DLC) loss rate were applied as the selected response variables. A quadratic model fitted best to describe the data with maximal lack-of-fit p-value and minimum sequential p-value. Three-dimension surface figures were utilized to describe the correlation of independent variables with response variables. Optimized formulation of the nanoparticles with size of 116.2 ± 2.0 nm and zeta potential of -18.4 ± 1.01 mV were obtained with a high encapsulation efficiency of 99.8%. PTX was involved physical interaction with the excipient during the preparation process of the nanoparticles. The release of PTX from Lip-PTX/BSA NPs exhibited a sustained release manner compared to albumin-bound PTX (nab-PTX) and Taxol. Besides, Lip-PTX/BSA NPs presented enhanced in vitro cytotoxicity against 4T1 cells due to highly nonspecific internalization in the cytoplasm. Simultaneously, Lip-PTX/BSA NPs showed effective in vivo antitumor efficacy against 4T1 bearing BALB/c mice, while no apparent adverse effect was observed by histological section and blood biochemical analysis. In conclusion, the novel Lip-PTX/BSA NPs could be applied as a promising drug delivery system for PTX to exert efficient cancer curative effects in clinic.

The interactions of (−)-epigallocatechin-3-Gallate (EGCG) and anthracycline drugs (doxorubicin, DOX and epirubicin, EPI) alone or in combination with human serum albumin (HSA) under physiological condition were studied by fluorescence spectroscopy, UV–vis absorption spectroscopy, circular dichroism (CD) spectroscopy, and dynamic light scattering (DLS). The cytotoxic activity of the single drug, combined drugs, and their complexes with HSA against human cervical cancer HeLa cell line was determined by MTT assay. Fluorescence quenching result and difference spectra of UV absorption revealed the formation of static complex between EGCG, DOX, or EPI and HSA. The binding of EGCG with HSA was driven by both enthalpy and entropy while the binding of DOX or EPI was mainly entropy driven. The nature of binding was expounded based on the effect of sodium chloride, tetrabutylammonium bromide, and sucrose which interfere in electrostatic, hydrophobic, and hydrogen bonding interactions, respectively. Site marker competitive experiments combined with synchronous fluorescence spectra showed that these three ligands mainly bound to subdomain IIA of HSA and were closer to tryptophan residues. In EGCG + DOX/EPI + HSA ternary system, the effect of one drug on the binding ability of another drug was discussed. The influences of the individual and combined binding of EGCG and DOX/EPI on the secondary structure and particle size of HSA were investigated by CD spectroscopy and DLS, respectively. Moreover, the synergistic cytotoxicity of EGCG and DOX/EPI as well as their complexes with HSA were discussed. Obtained results would provide beneficial information on the combination of EGCG and anthracyclines in clinic.

The novel methotrexate-loaded nanoparticles (MTX/PGD NPs) prepared with amphiphilic codendrimer PGD from polyamidoamine and oligothylene glycol dendrons were obtained via antisolvent precipitation method augmented by ultrasonication. Based on the excellent hydrophility of PGD, the drug-loaded nanoparticles could be investigated easily with the high drug-loading content (~85.2%, w/w). The MTX/PGD NPs possessed spherical morphology, nanoscaled particle size (approximately 182.4 nm) and narrow particle size distribution. Release of MTX from MTX/PGD NPs showed a sustained release manner and completed within 48 h. Hemolytic evaluation indicated MTX/PGD NPs presented good blood compatibility and the cytotoxicity of nanoparticles against breast cancer cells in vitro, biodistribution in tumor tissue and antitumor efficacy in vivo were enhanced significantly compared to MTX injection. According to the higher drug-loading content, enhanced antitumor efficacy and appropriate particle size, MTX/PGD NPs as the drug delivery systems could have potential application for cancer chemotherapy in clinic.

Xiaofeng Yang,1 Yingying Liu,1,2 Yanna Zhao,1 Meihua Han,1 Yifei Guo,1 Haixue Kuang,2 Xiangtao Wang1 1Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 2School of Pharmacy, Heilongjiang University of Traditional Chinese Medicine, Harbin, People’s Republic of China Abstract: 10-Hydroxycamptothecin (10-HCPT) is a promising anticancer drug with a wide spectrum of antitumor activities. Due to its poor solubility, the carboxylate form that shows high water solubility but minimal anticancer activity and pharmacokinetic defects is used in the marketed 10-HCPT injections, resulting in its limited clinical application. To develop a simple, safe, and highly effective drug delivery system, a modified acid–base microprecipitation combined with a high-pressure homogenization technique was adopted to prepare 10-HCPT nanocrystals. Neither organic solvents nor stabilizers were employed throughout the preparation process. The in vitro and in vivo performances of the resulting10-HCPT nanocrystals were investigated systematically. The nanocrystals were spherical with a small size of ~130 nm, and the actual drug-loading content was as high as 75%. The nanocrystals displayed a sustained release pattern and were proven to have a higher cell uptake and antiproliferative activity than the 10-HCPT injections. The 10-HCPT nanocrystals also showed enhanced drug accumulation in tumors and better anticancer efficacy in 4T1-bearing mice. In summary, the 10-HCPT nanocrystals prepared in this study seem to be a promising delivery system for a new form of 10-HCPT dosages. Keywords: 10-hydroxycamptothecin, drug delivery, poloxamer 188, high drug payload, 4T1cells