Soluplus/TPGS mixed micelles for dioscin delivery in cancer therapy

Background: Dioscin has shown cytotoxicity against cancer cells, but its poor solubility and stability have limited its clinical application. In this study, we designed mixed micelles composed of TPGS and Soluplus^® copolymers entrapping the poorly soluble anticancer drug dioscin.

Method: In order to improve the aqueous solubility and bioactivity of dioscin, TPGS/Soluplus^® mixed micelles with an optimal ratio were prepared using a thin-film hydration method, and their physicochemical properties were characterized. Cellular cytotoxicity and uptake of the dioscin-loaded TPGS/Soluplus^® mixed micelles were studied in MCF-7 breast cancer cells and A2780s ovarian cancer cells. The pharmacokinetics of free dioscin and dioscin-loaded TPGS/Soluplus^® mixed micelles was studied in vivo in male Sprague-Dawley rats via a single intravenous injection in the tail vein.

Results: The average size of the optimized mixed micelle was 67.15?nm, with 92.59% drug encapsulation efficiency and 4.63% drug loading efficiency. The in vitro release profile showed that the mixed micelles presented sustained release behavior compared to the anhydrous ethanol solution of dioscin. In vitro cytotoxicity assays were conducted on human cancer cell lines including A2780s ovarian cancer cells and MCF-7 breast cancer cells. The mixed micelles exhibited better antitumor activity compared to free dioscin against all cell lines, which may benefit from the significant increase in the cellular uptake of dioscin from mixed micelles compared to free dioscin. The pharmacokinetic study showed that the mixed micelle formulation achieved a 1.3 times longer mean residual time (MRT) in circulation and a 2.16 times larger area under the plasma concentration–time curve (AUC) than the free dioscin solution.

Conclusion: Our results suggest that the dioscin-loaded mixed micelles developed in this study might be a potential nano drug-delivery system for cancer chemotherapy.     

Synthesis,in vitro characterization,and anti-tumor effects of novel polystyrene-poly(amide-ether-ester-imide) co-polymeric micelles for delivery of docetaxel in breast cancer in Balb/C mice

Objective: The goal of the present work was to make novel co-polymeric micellar carriers for the delivery of docetaxel (DTX).

Significance: Co-polymeric micelles can not only solubilize DTX and eliminate the need for toxic surfactants to dissolve it, but also cause passive targeting of the drug to the tumor and reduce its toxic side effects.

Methods: Poly(styrene-maleic acid) (SMA) was conjugated to poly (amide-ether-ester-imide)-poly ethylene glycol (PAEEI-PEG). Copolymer synthesis was proven by Fourier transform infrared (FTIR) and ¹H-nuclear magnetic resonance (¹H-NMR). The SMA-PAEEI-PEG micelles loaded with DTX were prepared and their critical micelle concentration (CMC), zeta potential, particle size, entrapment efficiency, and their release efficiency were studied. MCF-7 and MDA-MB231 breast cancer cells were used to evaluate the cellular uptake and cytotoxicity of the micelles. The antitumor activity of the DTX-loaded nanomicelles was measured in Balb/c mice.

Results: The FTIR and HNMR spectroscopy confirmed successful conjugation of SMA and PAEEI-PEG. The drug loading efficiency was in the range of 34.01–72.75% and drug release lasted for 120?h. The CMC value of the micelles was affected by the SMA/PAEEI-PEG ratio and was in the range of 29.85–14.28?µg/ml. The DTX-loaded micelles showed five times more cytotoxicity than the free drug. The DTX loaded micelles were more effective in tumor growth suppression in vivo and the animals showed an enhanced rate of survival.

Conclusion: The results show that the SMA-PAEEI-PEG micelles of DTX could potentially provide a suitable parenteral formulation with more stability, higher cytotoxicity, and improved antitumor activity.     

One‐Step Microfluidic Synthesis of Nanocomplex with Tunable Rigidity and Acid‐Switchable Surface Charge for Overcoming Drug Resistance

Multidrug resistance (MDR), is the key reason accounting for the failure of cancer chemotherapy, remains a dramatic challenge for cancer therapy. In this study, the one‐step microfluidic fabrication of a rigid pH‐sensitive micellar nanocomplex (RPN) with tunable rigidity and acid‐switchable surface charge for overcoming MDR by enhancing cellular uptake and lysosome escape is demonstrated. The RPN is composed of a poly(lactic‐co‐glycolic acid) (PLGA) core and a pH‐sensitive copolymer shell, which is of neutral surface charge during blood circulation. Upon internalization of RPN by cancer cells, the pH‐responsive shell dissociates inside the acidic lysosomes, while the rigid and positively charged PLGA core improves the lysosomal escape. The cellular uptake and nuclear uptake of doxorubicin (Dox) from Dox‐loaded RPN are 1.6 and 2.4 times higher than that from Dox‐loaded pH‐sensitive micelles (PM) using a Dox‐resistant cancer model (MCF‐7/ADR, re‐designated NCI/ADR‐RES) in vitro. Dox‐loaded RPN significantly enhances the therapeutic efficacy (92% inhibition of tumor growth) against MCF‐7/ADR xenograft tumor in mice, while Dox‐loaded PM only inhibits the tumor growth by 36%. RPN avoids the use of complicated synthesis procedure of nanoparticle and the necessary to integrate multiple components, which can facilitate the clinical translation of this novel nanostructure.     

Doxorubicin- and cisplatin-loaded nanostructured lipid carriers for breast cancer combination chemotherapy

Context: Combination anticancer therapy is promising to generate synergistic anticancer effects, to maximize the treatment effect and to overcome multi-drug resistance. Nanostructured lipid carriers (NLCs), composed of solid and liquid lipids, and surfactants are potentially good colloidal drug carriers.

Objective: The aim of this study is to construct novel NLCs as nanocarriers for co-delivery of doxorubicin (DOX) and cisplatin (CDDP) to treat breast cancer.

Methods: DOX and CDDP loaded NLCs (D–C-NLCs) were prepared by the solvent diffusion method. The in vitro cytotoxicity and synergistic studies of different formulations were evaluated on human breast cancer cells (doxorubicin resistant) (MCF-7/ADR cells). In vivo anti-tumor effects were observed on the murine bearing MCF-7/ADR cells model.

Results: D–C-NLCs showed the highest cytotoxicity and synergistic effect of two drugs in tumor cells in vitro. The in vivo study revealed the greatest anti-tumor activity than the other formulations in the breast cancer model.

Conclusion: The constructed NLCs could be used as a novel carrier for co-delivery of DOX and CDDP for breast cancer therapy. D–C-NLCs could be a promising targeted and combinational therapy nanomedicine.     

Combination of doxorubicin with harmine-loaded liposomes exerting synergistic antitumor efficacy

Context: Long-circulation (PEGLip), pH-sensitive (PEOzLip), and active targeted liposomes (PEG-TATLip)-loading doxorubicin (DOX) and harmine (HM) were prepared. Their physicochemical properties and antitumor effect were investigated.

Objectives: The aims of the present study were to evaluate synergistic antitumor efficacy.

Materials and methods: Liposomes were prepared by using thin-film dispersion, active drug-loading and target post-insertion method. Subsequently physiochemical properties including particle size distribution, zeta potential, entrapment efficiency (EE), drug-loading content and in-vitro release were determined. Besides, the in vitro cytotoxicity of free drugs and drug-loaded liposomes was explored by using a Sulforhodamine-B Staining assay and the combination index values (CI Value) were calculated. Finally, the cellular uptake experiments by MCF-7cells were carried out via flow cytometry.

Results and discussion: All liposomes enhanced the antitumor effect significantly compared to free drugs. Among liposomes, PEG-TATLip enhanced the antitumor effect significantly compared to others. DOX and HM had moderate synergism with CI Value 0.85 for free drugs, 0.81 for PEGLip, 0.72 for PEOzLip, and 0.84 for PEG-TATLip respectively when the weight ratio of two drugs was 1:2. Moreover, the similarity between DOX and HM such as physicochemical properties, in vitro release modes and in vitro uptake kinetics characteristics when they were in the same formulations proved it possible for them to be delivered together.

Conclusion: Active targeting liposomes were the most effective delivery system as compared with pH-sensitive and long circulation liposomes. Additionally, DOX and HM could be co-delivered in liposomes and they could play moderate synergism effect in antitumor efficacy.     

Development and evaluation of a novel drug delivery: Soluplus®/TPGS mixed micelles loaded with piperine in vitro and in vivo

Background: Although piperine can inhibit cells of tumors, the poor water solubility restricted its clinical application. This paper aimed to develop mixed micelles based on Soluplus^® and D-α-tocopherol polyethylene glycol succinate (TPGS) to improve the aqueous solubility and anti-cancer effect.

Methods: Piperine-loaded mixed micelles were prepared using a thin-film hydration method, and their physicochemical properties were characterized. The cellular uptake of the micelles was confirmed by confocal laser scanning microscopy in A549 lung cancer cells and HepG₂ liver cancer cells. In addition, cytotoxicity of the piperine mixed micelles was studied in A549 lung cancer cells and HepG₂ liver cancer cells. Free piperine or piperine-loaded Soluplus^®/TPGS mixed micelles were administered at an equivalent dose of piperine at 3.2?mg/kg via a single intravenous injection in the tail vain for the pharmacokinetic study in vivo.

Results: The diameter of piperine-loaded Soluplus^®/TPGS (4:1) mixed micelles was about 61.9?nm and the zeta potential –1.16?±?1.06?mV with 90.9% of drug encapsulation efficiency and 4.67% of drug-loading efficiency. Differential scanning calorimetry (DSC) studies confirmed that piperine is encapsulated by the Soluplus^®/TPGS. The release results in vitro showed that the piperine-loaded Soluplus^®/TPGS mixed micelles presented sustained release behavior compared to the free piperine. The mixed micelles exhibited better antitumor efficacy compared to free piperine and physical mixture against in A549 and HepG₂ cells by MTT assay. The pharmacokinetic study revealed that the AUC of piperine-loaded mixed micelles was 2.56 times higher than that of piperine and the MRT for piperine-loaded mixed micelles was 1.2-fold higher than piperine (p?Conclusion: The results of the study suggested that the piperine-loaded mixed micelles developed might be a potential nano-drug delivery system for cancer chemotherapy. These results demonstrated that piperine-loaded Soluplus^®/TPGS mixed micelles are an effective strategy to deliver piperine for cancer therapy.     

Overcoming multidrug resistance of breast cancer cells by the micellar doxorubicin nanoparticles of mPEG-PCL-graft-cellulose

The amphiphilic block copolymer methoxy-poly(ethylene glycol)-poly(epsilon-caprolactone) (mPEG-PCL) was grafted to 2-hydroxyethyl cellulose (HEC) to produce nano-sized micellar nanoparticles. The nanoparticles were loaded with anti-tumor drug, doxorubicin (DOX) and the size of the DOX-loaded nanoparticles were determined by dynamic light scattering (DLS) in aqueous solution to be from 197.4 to 230 nm. The nanoparticles subjected to co-culture with macrophage cells showed that these nanoparticles used as drug carrier are not recognized as foreign bodies. Overexpression of P-glycoprotein (P-gp) is an important factor in the development of multidrug resistance (MDR) in many cancer cells. In this study, Western blot and Rhodamine 123 were used to monitor the relative P-glycoprotein expression in human breast cancer cell lines MCF-7/WT and MCF-7/ADR. The endocytosis of the DOX-loaded nanoparticles by breast cancer cells is more efficient observed under a confocal laser scanning microscopy (CLSM) and a flow cytometry in MCF7/ADR cells, compared to the diffusion of the free drug into the cytoplasm of cells. Based on these findings, we concluded that the nanoparticles made from mPEG-PCL-g-cellulose were effective in overcoming P-gp efflux in MDR breast cancer cells.     

In vitro evaluation of a novel pH sensitive drug delivery system based cockle shell-derived aragonite nanoparticles against osteosarcoma

ABSTRACT

Background: Osteosarcoma (OS) is a highly malignant primary bone cancer. Severe side effects and multidrug resistance are obstacles faced with chemotherapy against OS. With the hope to overcome the obstacles of the conventional chemotherapy, various targeted drug delivery systems using nanotechnology have been explored in the past few decades. Biogenic calcium carbonate (CaCO₃) has great potential to be a smart drug delivery system.

Results: In this study, cockle shells-derived aragonite nanoparticles (ANPs) were developed and loaded with doxorubicin (DOX). The physicochemical properties of the DOX-loaded ANPs (DOX-ANPs) were characterised by various techniques. The results of drug-loading study demonstrated that DOX was loaded onto ANPs at high loading and encapsulation efficiency (11.09% and 99.58%, respectively). The pH-sensitive release of DOX from DOX-ANPs was successful. At lower pH values (4.8), the release of DOX was much quicker than that at pH 7.4. Additionally, cellular uptake study using fluorescence microscopy showed obviously cellular uptake of DOX-ANPs through endocytosis. Moreover, the flow cytometric analysis revealed DOX-ANPs-induced cell cycle arrest, which was consistent with the mechanism of DOX. DOX-ANPs also showed an efficient cytotoxicity against OS cancer cells, close to the toxicity effect of free DOX at the same concentration. Morphological observations showed microvilli disappearance, chromatin condensation, cell shrinkage, membrane blebbing, and formation of apoptotic bodies, which confirmed both DOX-ANPs- and DOX-induced apoptosis of OS cancer cells in vitro.

Conclusion: Our findings indicated that ANPs could act as a pH-sensitive drug delivery against OS.     

Efficiency against multidrug resistance by co-delivery of doxorubicin and curcumin with a legumain-sensitive nanocarrier

Multidrug resistance proteins (MDRPs), which are implicated in the mediation of multidrug resistance in tumors, represent the main obstacle to successful chemotherapy. As curcumin (Cur) exerts inhibitory effects on both the expression and function of MDRPs, a nanocarrier for the co-delivery of Cur and doxorubicin (DOX) was prepared to overcome MDR tumors through their synergistic effects. Owing to the overexpression of legumain in tumors, the release profile of DOX from this nanocarrier was designed to be legumain modulated, which was achieved by bridging DOX to a basic material (chitosan) with a legumain-sensitive peptide. Compared with nanoparticles that only contain DOX, the coadministration of DOX and Cur significantly inhibited multidrug resistance (P < 0.05) in a multidrug-resistant cancer cell model (MCF-7/ADR cell line), with cytotoxicity to normal cells (L929 cell line). Such inhibition could be ascribed to the increased DOX accumulation in the MCF-7/ADR nucleus. The co-delivery system exhibited good anticancer effects through prolonged circulation time, improved tumor-targeting efficiency, elevation of the tumor inhibition activity, and the suppression of MDRP expression. These data revealed the enormous potential of this co-delivery system for cancer therapy, especially in the later stages where multidrug resistance may develop.

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Safe and Effective Reversal of Cancer Multidrug Resistance Using Sericin‐Coated Mesoporous Silica Nanoparticles for Lysosome‐Targeting Delivery in Mice

Multidrug resistance (MDR) and adverse side effects are the major challenges facing cancer chemotherapy. Here, pH/protease dually responsive, sericin‐coated mesoporous silica nanoparticles (SMSNs) for lysosomal delivery of doxorubicin (DOX) to overcome MDR and reduce systemic toxicity are reported. Sericin, a natural protein from silkworm cocoons, is coated onto MSNs as a gatekeeper via pH sensitive imine linkages. The sericin shell prevents the premature leakage of encapsulated DOX from MSNs in extracellular environment. Once reaching drug‐resistant tumors, sericin's cell‐adhesive bioactivity enhances cellular uptake of SMSNs that are in turn transported into perinuclear lysosomes, thus avoiding drug efflux mediated by membrane‐bound pumps. Lysosomal acidity triggers cleavage of pH sensitive linkage between sericin and MSNs concurrently with lysosomal proteases deconstructing sericin shell. This pH/protease dual responsiveness leads to DOX burst release into cell nuclei, inducing effective cell death, thus reversing MDR. These DOX‐loaded SMSNs not only effectively kill drug‐resistant cells in vitro, but also significantly reduce the growth of DOX‐resistant MCF‐7/ADR (breast cancer cells) tumor by 70% in a preclinical animal model without eliciting systemic toxicity frequently encountered in current clinical therapeutic formulations. Thus, the dually responsive SMSNs are an effective, lysosome‐tropic, and bio‐safe delivery system for chemotherapeutics for combating MDR.     

Cadmium nanoclusters in a protein matrix: Synthesis,characterization, and application in targeted drug delivery and cellular imaging

Biotemplated metal nanoclusters have garnered much attention owing to their wide range of potential applications in biosensing, bioimaging, catalysis, and nanomedicine. Here, we report the synthesis of stable, biocompatible, water-soluble, and highly fluorescent bovine serum albumin-templated cadmium nanoclusters (Cd_NCs) through a facile one-pot green method. We covalently conjugated hyaluronic acid (HA) to the Cd_NCs to form a pH-responsive, tumortargeting theranostic nanocarrier with a sustained release profile for doxorubicin (DOX), a model anticancer drug. The nanocarrier showed a DOX encapsulation efficiency of about 75.6%. DOX release profiles revealed that 74% of DOX was released at pH 5.3, while less than 26% of DOX was released at pH 7.4 within the same 24-h period. The nanocarrier selectively recognized MCF-7 breast cancer cells expressing CD44, a cell surface receptor for HA, whereas no such recognition was observed with HA receptor-negative HEK293 cells. Biocompatibility of the nanocarrier was evaluated through cytotoxicity assays with HEK293 and MCF-7 cells. The nanocarrier exhibited very low to no cytotoxicity, whereas the DOX-loaded nanocarrier showed considerable cellular uptake and enhanced MCF-7 breast cancer cell-killing ability. We also confirmed the feasibility of using the highly fluorescent nanoconjugate for bioimaging of MCF-7 and HeLa cells. The superior targeted drug delivery efficacy, cellular imaging capability, and low cytotoxicity position this nanoconjugate as an exciting new nanoplatform with promising biomedical applications.

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Nanostructured lipid carriers loaded with simvastatin: effect of PEG/glycerides on characterization,stability, cellular uptake efficiency and in vitro cytotoxicity

Objective: The aim of this study is to evaluate the use of PEG/glycerides of different HLB; oleoyl macrogol-6-glycerides (Labrafil^® M 1944 CS) and caprylocaproylmacrogol-8-glycerides (Labrasol^®), compared to Labrafac lipophile^® as PEG-free glyceride in the preparation of nanostructured lipid carriers (NLCs). PEG/glycerides are suggested to perform a dual function; as the oily component, and as the PEG-containing substrate required for producing the PEGylated carriers without physical or chemical synthesis.

Methods: Lipid nanocarriers were loaded with simvastatin (SV) as a promising anticancer drug. An optimization study of NLC fabrication variables was first conducted. The effect of lyophilization was investigated using cryoprotectants of various types and concentrations. The prepared NLCs were characterized in terms of particle size (PS), size distribution (PDI), zeta potential (ZP), drug entrapment, in vitro drug release, morphology and drug–excipient interactions. The influence of glycerides?±?PEG on the cytotoxicity of SV was evaluated on MCF-7 breast cancer cells, in addition to the cellular uptake of fluorescent blank NLCs.

Results: The alteration between different oil types had a significant impact on PS, ZP and drug release. Both sucrose and trehalose showed the lowest increase in PS and PDI of the reconstituted lyophilized NLCs. The in vitro cytotoxicity and cellular uptake studies indicated that SV showed the highest antitumor effect on MCF-7 cancer cells when loaded into Labrasol^® NLCs demonstrating a high cellular uptake as well.

Conclusion: The study confirms the applicability of PEG/glycerides in the development of NLCs. Encapsulating SV in Labrasol^®-containing NLC could enhance the antitumor effect of the drug.     

pH‐ and NIR Light‐Responsive Polymeric Prodrug Micelles for Hyperthermia‐Assisted Site‐Specific Chemotherapy to Reverse Drug Resistance in Cancer Treatment

Despite the exciting advances in cancer chemotherapy over past decades, drug resistance in cancer treatment remains one of the primary reasons for therapeutic failure. IR‐780 loaded pH‐responsive polymeric prodrug micelles with near infrared (NIR) photothermal effect are developed to circumvent the drug resistance in cancer treatment. The polymeric prodrug micelles are stable in physiological environment, while exhibit fast doxorubicin (DOX) release in acidic condition and significant temperature elevation under NIR laser irradiation. Phosphorylcholine‐based biomimetic micellar shell and acid‐sensitive drug conjugation endow them with prolonged circulation time and reduced premature drug release during circulation to conduct tumor site‐specific chemotherapy. The polymeric prodrug micelles combined with NIR laser irradiation could significantly enhance intracellular DOX accumulation and synergistically induce the cell apoptosis in DOX‐resistant MCF‐7/ADR cells. Meanwhile, the tumor site‐specific chemotherapy combined with hyperthermia effect induces significant inhibition of MCF‐7/ADR tumor growth in tumor‐bearing mice. These results demonstrate that the well‐designed IR‐780 loaded polymeric prodrug micelles for hyperthermia‐assisted site‐specific chemotherapy present an effective approach to reverse drug resistance.     

pH值响应性透明质酸纳米粒的制备及作为阿霉素载体的研究

通过化学交联法合成组氨酸修饰透明质酸耦合物(His-HA),制备载阿霉素纳米粒,分析其pH值响应性和抗肿瘤特征.研究显示,随着pH值的降低(7.4～5.5),纳米粒的粒径增大(230～780nm),zeta电位升高,载药纳米粒的体外释放量增加.细胞毒性实验显示粒径＜300nm的载药纳米粒具更高的毒性.细胞摄入实验表明,阿霉素通过受体介导的胞吞和载药纳米粒的胞外释放两种途径被细胞摄入.以上研究显示组氨酸修饰透明质酸纳米粒具有显著的pH值响应性,具备作为阿霉素药物载体的应用前景.     

Preparation and characterization of galactosylated glycol chitosan micelles and its potential use for hepatoma-targeting delivery of doxorubicin

This study aimed to develop novel galactosylated cholesterol modified-glycol chitosan (Gal-CHGC) micelles for targeting delivery of doxorubicin (DOX) in live cancer cells. Three kinds of Gal-CHGC conjugates were synthesized and characterized. The mean particle size and critical aggregation concentration of these polymeric micelles increased with the increase of galactose substitution degree. The DOX-loaded micelles were prepared by an o/w method. The mean diameters of DOX-loaded galactosylated micelles were in the range of 387–497 nm. DOX released from drug-loaded micelles displayed a biphasic way. Cellular uptake studies demonstrated that DOX-loaded galactosylated micelles could enhance the uptake of DOX into HepG2 cells. Moreover, the cytotoxicity of DOX-loaded galactosylated micelles against HepG2 cells significantly improved in contrast with free DOX and DOX-loaded micelles without galactosylation. These results suggested that Gal-CHGC micelles could be a potential carrier for hepatoma-targeting drug delivery.     

Construction of glucose and H<Subscript>2</Subscript>O<Subscript>2</Subscript> dual stimuli-responsive polymeric vesicles and their application in controlled drug delivery

Herein, glucose and H₂O₂ stimuli-responsive vesicles are constructed based on host–guest interaction between a diblock copolymer, poly(ethylene glycol)-b-poly[3-acrylamidophenylboronic acid-co-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acrylate], (PEG-b-P(PBA-co-PBEM), BCP for short) and α-cyclodextrin. In the presence of glucose, the vesicles are transformed to giant swollen spherical micelles because of the formation of a negatively charged tetravalent form between phenylboronic acid and glucose. On the other hand, the vesicles are totally disassembled when they are exposed to H₂O₂, which is due to the H₂O₂-mediated degradation of the pendant phenylboronic acid pinacol ester. The glucose and H₂O₂ stimuli-responsive vesicles are then applied in the controlled release of water-soluble anticancer drug, doxorubicin hydrochloride (DOX). Upon external stimuli, the DOX displays a faster release rate than that without stimuli. Moreover, the polymeric vesicles show an excellent cytocompatibility toward MCF-7 cells, and the drug-loaded vesicles exhibit a lower cytotoxicity than free drug toward cancer cells. The drug-loaded vesicles can be taken up by MCF-7 cells and further release the DOX in cancer cells due to the high glucose and H₂O₂ concentration in tumor cells, while they have negligible effect on normal cells, which may be important for applications in the therapy of cancers as a controlled-release drug carrier.     

Programmable Codelivery of Doxorubicin and Apatinib Using an Implantable Hierarchical‐Structured Fiber Device for Overcoming Cancer Multidrug Resistance

Multiple drug resistance (MDR) of cancer cells is a major cause of chemotherapy failure. It is currently a great challenge to develop a direct and effective strategy for continuously inhibiting the P‐glycoprotein (P‐gp) drug pump of MDR tumor cells, thus enhancing the intracellular concentration of the therapeutic agent for effectively killing MDR tumor cells. Here, a new implantable hierarchical‐structured ultrafine fiber device is developed via a microfluidic‐electrospinning technology for localized codelivery of doxorubicin (DOX) and apatinib (AP). An extremely high encapsulation efficiency of ≈99% for the dual drugs is achieved through this strategy. The release of the loaded dual drugs can be controlled in a programmable release model with a rapid release of the micelles, while AP is slowly released. The sustained release of AP can continuously inhibit the P‐gp drug pump of MDR tumor cells, increasing the intracellular DOX accumulation. The in vivo DOX biodistribution displays that the DOX accumulation in the tumor tissues achieves 17.82% after implanting the fiber device for 72 h, which is 6.36‐fold higher than that of the intravenously injected DOX. Importantly, the fiber device shows an excellent antitumor effect on MDR tumor‐bearing mice with low systemic toxicity.     

A Transformable Chimeric Peptide for Cell Encapsulation to Overcome Multidrug Resistance

Multidrug resistance (MDR) remains one of the biggest obstacles in chemotherapy of tumor mainly due to P‐glycoprotein (P‐gp)‐mediated drug efflux. Here, a transformable chimeric peptide is designed to target and self‐assemble on cell membrane for encapsulating cells and overcoming tumor MDR. This chimeric peptide (C₁₆‐K(TPE)‐GGGH‐GFLGK‐PEG₈, denoted as CTGP) with cathepsin B‐responsive and cell membrane‐targeting abilities can self‐assemble into nanomicelles and further encapsulate the therapeutic agent doxorubicin (termed as CTGP@DOX). After the cleavage of the Gly‐Phe‐Leu‐Gly (GFLG) sequence by pericellular overexpressed cathepsin B, CTGP@DOX is dissociated and transformed from spherical nanoparticles to nanofibers due to the hydrophilic–hydrophobic conversion and hydrogen bonding interactions. Thus obtained nanofibers with cell membrane‐targeting 16‐carbon alkyl chains can adhere firmly to the cell membrane for cell encapsulation and restricting DOX efflux. In comparison to free DOX, 45‐time higher drug retention and 49‐fold greater anti‐MDR ability of CTGP@DOX to drug‐resistant MCF‐7R cells are achieved. This novel strategy to encapsulate cells and reverse tumor MDR via morphology transformation would open a new avenue towards chemotherapy of tumor.     

pH-responsive polymeric micelles with core–shell–corona architectures as intracellular anti-cancer drug carriers

Abstract

Polymeric micelles with core–shell–corona nanoarchitecture were designed for intracellular therapeutic anti-cancer drug carriers. Poly(styrene-b-acrylic acid-b-ethylene glycol) (PS-b-PAA-b-PEG) asymmetric triblock copolymer underwent self-assembly in aqueous solution to form spherical micelles with hydrophobic PS core, anionic PAA shell and hydrophilic PEG corona. The anti-cancer drug (doxorubicin, DOX) was successfully incorporated into the polymeric micelles. The in vitro release experiment confirmed that the release of DOX from the micelles was inhibited at pH 7.4. In contrast, an accelerated release of DOX was observed at mildly acidic conditions such as pH 4.5. The excellent biocompatibility of our PS-b-PAA-b-PEG-based micelles made the synthesized nano-carrier best suited for the delivery of anti-cancer drugs.     

Overcoming Non-Specific Interactions for Efficient Encapsulation of Doxorubicin in Ferritin Nanocages for Targeted Drug Delivery

Due to its beneficial pharmacological properties, ferritin (Ftn) is considered as an interesting drug delivery vehicle to alleviate the cardiotoxicity of doxorubicin (DOX) in chemotherapy. However, the encapsulation of DOX in Ftn suffers from heavy precipitation and low protein recovery yield which limits its full potential. Here, a new DOX encapsulation strategy by cysteine-maleimide conjugation is proposed. In order to demonstrate that this strategy is more efficient compared to the other approaches, DOX is encapsulated in Ftn variants carrying different surface charges. Furthermore, in contrast to the common belief, this data show that DOX molecules are also found to bind non-specifically to the surface of Ftn. This can be circumvented by the use of Tris(2-carboxyethyl)phosphine (TCEP) during encapsulation or by washing with acidic buffer. The biocompatibility studies of the resulting DOX Ftn variants in MCF-7 and MHS cancer cells shows a complex relationship between the cytotoxicity, the DOX loading and the different surface charges of Ftn. Further investigation on the cell uptake mechanism provides reasonable explanations for the cytotoxicity results and reveals that surface charging of Ftn hinders its transferrin receptor 1 (TfR-1) mediated cellular uptake in MCF-7 cells.