Distribution Of Doxorubicin Research Articles

Controlled release of doxorubicin from Poly-(D,L-lactide-co-glycolide) (PLGA) nanoparticles prepared by coaxial electrospraying

Enhancing the efficacy and reducing the toxicity of chemotherapeutic agents like doxorubicin (DOX) is crucial in cancer treatment. Core-shell nanoparticles (NPs) fabricated by coaxial electrospraying offer controlled release of anticancer agents with the polymer shell protecting drug molecules from rapid degradation, prolonging therapeutic effect. This study developed DOX-loaded poly(lactic-co-glycolic acid) (PLGA) NPs. NPs were fabricated with matrix or core–shell structure via single needle or coaxial electrospraying, respectively. Core-shell NPs exhibited high encapsulation efficiency (>80 %) with controlled DOX distribution. Compared to matrix NPs, core–shell NPs demonstrated slower sustained release (69 % in 144 h) after reduced initial burst (22 % in 8 h). Release kinetics followed a diffusion mechanism when compared to free drug and matrix DOX-loaded NPs. In vitro assays showed core–shell NPs’ enhanced cytotoxicity against breast cancer cells MCF-7, with higher uptake observed by fluorescence microscopy and flow cytometry. The IC50 for core-shell NPs displayed a significant drop (0.115 μg/mL) compared to matrix NPs (0.235 μg/mL) and free DOX (1.482 μg/mL) after 72 h. Coaxial electrospraying enables the production of therapeutically advantageous core–shell NPs, offering controlled drug release with high encapsulation efficiency, potentially improving clinical anticancer chemotherapy.

A multi-nozzle nebuliser does not improve tissue drug delivery during PIPAC

BackgroundMulti-nozzle nebulisers for pressurised intraperitoneal aerosol chemotherapy (PIPAC) are implemented in clinical practice to improve the homogeneity of tissue drug delivery. Nonetheless, the advantages of such devices over one-nozzle nebulisers have not been demonstrated thus far. In this study, we compared the performance of multi- and one-nozzle nebulisers by conducting physical and ex vivo pharmacological experiments.MethodsThe one-nozzle nebuliser Capnopen® and the multi-nozzle nebuliser were the subjects of this study. In physical experiments, the aerosol droplet size was measured by laser diffraction spectroscopy. Spatial spray patterns were depicted on blotting paper. Pharmacological experiments were performed on the enhanced inverted bovine urinary bladder model, demonstrating real-time tissue drug delivery, aerosol sedimentation and homogeneity of doxorubicin and cisplatin tissue distribution.ResultsThe multi-nozzle nebuliser had a sixfold greater aerosolisation flow and a threefold greater angle of aerosolisation than Capnopen®. The aerosol particle size and distribution range were higher than that of Capnopen®. Spray patterns on blotting paper were more extensive with the multi-nozzle nebuliser. Real-time tissue drug delivery with the multi-nozzle nebuliser was over 100 ml within 1 min, and the aerosol sedimentation was 48.9% ± 21.2%, which was not significantly different from that of Capnopen®. The doxorubicin and cisplatin tissue concentrations were greater with Capnopen®. Although there was no significant difference in the homogeneity of doxorubicin distribution between the two devices, the homogeneity of cisplatin distribution was significantly higher with Capnopen®.ConclusionThe multi-nozzle PIPAC nebuliser did not fulfil expectations. Even though the surface spray patterns were broader with the multi-nozzle nebuliser, the tissue drug homogeneity and concentration were greater with Capnopen®.Graphical

Determination of doxorubicin in plasma and tissues of mice by UPLC-MS/MS and its application to pharmacokinetic study

A rapid and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was established for the simultaneous determination of doxorubicin (DOX) in mouse plasma and tissues, including the heart, liver, spleen, lung, kidney and tumor, and to investigate the pharmacokinetics and distribution in mice. In this study, daunorubicin (DNR) was used as an internal standard, and the mobile phase consisted of ammonium formate 2 mM containing 0.1 % formic acid (A) and acetonitrile (B), the chromatographic column was ACQUITY UPLC BEHTM C18 with a gradient elution at a flow rate of 0.2 mL/min. Electrospray ionization (ESI) in positive ion pattern was utilized for the ion separation of DOX, with the ions used for quantitative analysis being DOX m/z 544.28 → 397.10 and DNR m/z 528.35 → 321.08, respectively. The results showed that a good linear relationship in the calibration curve range of 1–800 ng/mL in mouse plasma and 1–2500 ng/g in tissues (R2 > 0.99) with the limits of quantification of 1 ng/mL in plasma and tissues. The method exhibited good matrix effect and extraction recovery, with the intra-day and inter-day precision of plasma and tissue were less than 10.3 % and 15.4 %, and the relative error (RE) were both less than ±14.8 % and ±18.9 %, respectively. The stability results under different conditions were found to be accurate. It also revealed the distribution of DOX in various tissues of mice, with the concentration ranking as liver > heart > kidney > spleen > lung > tumor. This method was successfully used to the study for the pharmacokinetics in plasma and drug distribution in tissues of BALB/c mice.

Pharmacokinetic-Pharmacodynamic Analysis of pH-Responsive Doxorubicin-Releasing Micelles with Anticancer Activity.

This study aimed to investigate the effect of in vivo pH-responsive doxorubicin (DOX) release and the targetability of pilot molecules in folic acid (FA)-modified micelles using a pharmacokinetic-pharmacodynamic (PK-PD) model. The time profiles of intratumoral DOX concentrations in Walker256 tumor-bearing rats were monitored using a microdialysis probe, followed by compartmental analysis, to evaluate intratumoral tissue pharmacokinetics. Maximal DOX was released from micelles 350 min after the administration of pH-responsive DOX-releasing micelles. However, FA modification of the micelles shortened the time to peak drug concentration to 150 min. Additionally, FA modification resulted in a 27-fold increase in the tumor inflow rate constant. Walker256 tumor-bearing rats were subsequently treated with DOX, pH-responsive DOX-releasing micelles, and pH-responsive DOX-releasing FA-modified micelles to monitor the tumor growth-time profiles. An intratumoral threshold concentration of DOX (55-64 ng/g tumor) was introduced into the drug efficacy compartment to construct a PD model, followed by PK-PD analysis of the tumor growth-time profiles. Similar results of threshold concentration and drug potency of DOX were obtained across all three formulations. Cell proliferation was delayed as the drug delivery ability of DOX was improved. The PK model, which was developed using the microdialysis method, revealed the intratumoral pH-responsive DOX distribution profiles. This facilitated the estimation of intratumoral PK parameters. The PD model with threshold concentrations contributed to the estimation of PD parameters in the three formulations, with consistent mechanisms observed. We believe that our PK-PD model can objectively assess the contributions of pH-responsive release ability and pilot molecule targetability to pharmacological effects.

Correlative Fluorescent Scanning Probe Nanotomography Used to Study the Intracellular Distribution of Doxorubicin in MCF-7 Human Breast Adenocarcinoma Cells

Developing technologies for efficient targeted drug delivery for oncotherapy requires new methods to analyze the features of micro- and nanoscale distributions of antitumor drugs in cells and tissues. A new approach to three-dimensional analysis of the intracellular distribution of cytostatics was developed using fluorescence scanning optical-probe nanotomography. A correlative analysis of the nanostructure and distribution of injected doxorubicin in MCF-7 human breast adenocarcinoma cells revealed the features of drug penetration and accumulation in the cell. The technology is based on the principles of scanning optical probe nanotomography and is applicable to studying the distribution patterns of various fluorescent or fluorescence-labelled substances in cells and tissues.

Sustained-release behavior and the antitumor effect of charge-convertible poly(amino acid)s drug-loaded nanoparticles.

Enhancing tissue permeability and achieving drug aggregation is the key to targeted tumor therapy. A series triblock copolymers of poly(ethylene glycol)-poly(L-lysine)-poly(L-glutamine) were synthesized by ring-opening polymerization, and charge-convertible nano-delivery system was constructed by loading doxorubicin (DOX) with 2-(hexaethylimide) ethanol on side chain. In normal environment (pH = 7.4), the zeta potential of the drug-loaded nanoparticle solution is negative, which is conducive to avoiding the identification and clearance of nanoparticles by the reticulo-endothelial system, while potential-reversal can be achieved in the tumor microenvironment, which effectively promotes cellular uptake. Nanoparticles could effectively reduce the distribution of DOX in normal tissues and achieve targeted aggregation at tumor sites, which can effectively improve the antitumor effect, while would not causing toxicity and damage to normal body.

Effect of paclitaxel priming on doxorubicin penetration in a multicellular layer model of human colorectal cancer cells

Tumor priming is considered a promising strategy for improving drug distribution in malignant tissues. Multicellular layers (MCLs) of human cancer cells are potentially useful models for evaluating tumor-priming agents. We evaluated the priming effects of paclitaxel (PTX) on doxorubicin (DOX) penetration using MCLs of the human colorectal cancer cell lines including DLD-1, HCT-116, and HT-29. The penetration of DOX treated at 50 μM for 3 h was highly limited in all three MCLs. The penetration of the priming agent PTX into MCLs was determined using rhodamine-labeled PTX and appeared to be cell line-dependent: full penetration was observed in HCT-116 and HT-29 MCLs, whereas only limited penetration occurred in DLD-1 MCLs. PTX pretreatment at 20 μM for 24 or 48 h induced a tumor-priming effect in DOX distribution, with a 3 to 5.6-fold-increase in HCT-116 and HT-29 MCLs but a less than two-fold increase in DLD-1 MCLs. PTX treatment decreased fibronectin expression in HCT-116 and HT-29 MCLs but not in DLD-1, suggesting that the prominent priming effect of PTX in HCT-116 and HT-29 MCLs may be associated with the downregulation of fibronectin expression. Our study demonstrated that MCLs of human cancer cells are a useful model not only for the study of drug penetration into tumor tissues but also for screening and evaluating tumor-priming agents.

Safety, Efficacy and Distribution of Doxorubicin Loaded Radiopaque Beads in Chemoembolization in Intermediate Stage Hepatocellular Carcinoma (HCC) with Correlation with Local Response.

The primary objectives of this study were to evaluate safety, and efficacy of Transarterial Chemoembolization (TACE) using doxorubicin-loaded radiopaque microspheres (DC Bead LUMI™) for the treatment of early and intermediate stage Hepatocellular Carcinoma (HCC) not amenable for curative treatments. Distribution of the microspheres was correlated with results post embolization. This was a prospective, single arm, open label study. The primary outcome measures were distribution of the radiopaque microspheres as showed by computerized tomography (CT) and local response measured by modified Response Evaluation Criteria (mRECIST) after Magnetic Resonance Imaging (MRI). Secondary measures were Time to Progression (TTP) and Overall Survival (OS). Fifty patients were enrolled over 36months. Median age was 69.0years; mean sum of target lesions diameters was 78.6 ± 36.8mm. There were no Grade 4 or 5 adverse events (AEs). At 6months Complete Response (CR) (18%), Partial Response (PR) (62%), Objective Response OR (80%) and Stable Disease (SD) (20%) were recorded. Before embolization, Diffusion Weighted Imaging (DWI) showed high signal (restricted diffusion). Post procedure, patients with dense deposition (< 5mm distance of microsphere aggregations) showed 100% absence of enhancement and no restriction in 30.6%. Median TTP was 8.3months. TTP for patients with CR was 13.3months and 7.2 and 5.6 for PR and SD, respectively. At 6 and 36months, survival was 94% and 34%, respectively. DC Bead LUMI™ is well tolerated and effective in early and intermediate stage HCC with maximal necrosis obtained in dense deposition in the target.

Nebulization is less effective than aerosolization, in PIPAC live animal drug delivery testing

IntroductionPressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is a new drug delivery approach to treat peritoneal metastasis. This study evaluated two different devices, one based on aerosolization, the Capnopen ® (CAPNOMED – company) and a second, a prototype named Nebulo ® (GAMIDA - company), based on nebulization. The performance of the two devices were tested for PIPAC distribution and cell penetration of doxorubicin in a sheep model. MethodsDoxorubicin was aerosolized for 30 min, using PIPAC into 6 ewes, 3 with Capnopen ® and 3 with Nebulo ®. The number of doxorubicin positive cells was determined using the ratio between doxorubicin fluorescence-positive cell nuclei (DOXO+) over total number of DAPI positive cell nuclei (DAPI+). Penetration depth (μm) was defined as the distance between the luminal surface and the location of the deepest DOXO+ nuclei. ResultsDOXO+ nuclei were identified in 46% of the samples. All omental samples, directly localized in front of the nebulizer head, had DOXO+ nuclei except one in the Nebulo group. There was no significant difference in penetration depth between the 2 groups. Concerning the peritoneum, 40% showed by microscope analysis a depth > 100 μm in the Capnopen group, versus 5% in the Nebulo group (p = 0.06). ConclusionsOur results and limitations observed imposes a change in developing technic. A smaller size of PIPAC droplet is not an efficient option to increase significantly the tissue penetration and concentration of drugs in chemotherapy.

In vivo distribution characteristics and anti-tumor effects of doxorubicin encapsulated in PEG-modified niosomes in solid tumor-bearing mice

Niosomes, non-ionic surfactant-based vesicles, are capable of encapsulating various drugs, and surface modifications by polyethylene glycol (PEG) are expected to facilitate the passive targeting of encapsulated drugs to solid tumors due to the longer blood circulation time. However, the niosomalization of drugs may also enhance the delivery of drugs to specific tissues at which free drugs do not normally accumulate. Therefore, in the present study, we prepared several doxorubicin (DOX)-encapsulated niosomes composed of different non-ionic surfactants, and examined their in vitro stability, in vivo biodisposition, and anti-tumor effects in solid tumor-bearing mice. In vitro DOX release from Brij 72 niosomes and Span 20 niosomes in the presence of serum was significantly suppressed by their PEGylation. Moreover, the PEGylation of Brij 72 niosomes and Span 20 niosomes markedly increased the plasma level of DOX encapsulated in each niosome after their intravenous injection into tumor-bearing mice. The liver, spleen, and heart distributions of DOX encapsulated in PEG Brij 72 niosomes and Span 20 niosomes were markedly lower and their tumor dispositions were markedly larger than each naked counterpart. These two DOX-encapsulated PEG niosomes exerted strong anti-tumor effect and prolonged the survival time of tumor-bearing mice. On the other hand, PEGylation did not significantly affect the in vitro stability, in vivo biodisposition, or anti-tumor effects of Tween 60 niosomes. These results demonstrate that the PEGylation of Brij 72 and Span 20 niosomes improved the biodisposition of encapsulated anti-cancer drugs, thereby increasing their therapeutic efficacies.

Hypoxia-alleviating hemoglobin nanoclusters for sensitizing chemo-photodynamic therapy of cervical cancer

Hypoxia-alleviating hemoglobin (Hb) nanoclusters (NCs) have been developed for sensitizing combined chemo-photodynamic therapy (chemo-PDT) of cervical cancer. Hb was conjugated with chlorin e6 and biotinylated polyethylene glycol and adsorbed with doxorubicin (DOX), resulting in the self-assembly of 220 nm diameter protein NCs. These oxygen-carrying NCs, namely DOX@HPBC, exhibited improved colloidal stability in the serum compared to that of native Hb and pH-responsive drug release favorable for cancer treatment. DOX@HPBC alleviated hypoxia by 64.8% in HeLa cells cultured under hypoxia and normalized the levels of related biomarkers, HIF-1α and MDR1, with enhanced cellular uptake via biotin–receptor interactions. Moreover, antitumor efficacy tests performed in HeLa monolayer and spheroid cultures revealed that DOX@HPBC possessed 3.8-fold improved therapeutic efficacy compared to DOX and chlorin e6 physical mixture, showing synergism between chemotherapy and PDT. DOX@HPBC-mediated chemo-PDT significantly suppressed tumor growth in heterotopic (96.6% reduction in tumor volume compared to no-intervention) and orthotopic (comparable uterus weight to the normal group) HeLa-xenografted mice with no significant toxicity. These results showed the hypoxia amelioration effect, which lowered HIF-1α and MDR1 levels in tumor tissues, and efficient DOX distribution to hypoxic regions of the tumor, suggesting that DOX@HPBC could be a promising chemo-PDT strategy for cervical cancer treatment.

Mesoscopic Simulations of Diselenide-Containing Crosslinked Doxorubicin-Loaded Micelles and Their Tumor Microenvironment Responsive Release Behaviors

There is currently limited research on the structure-property relationship of reduction stimuli-responsive polymeric crosslinked micelles using mesoscopic simulations. Herein, dissipative particle dynamics (DPD) simulations were used to simulate the self-assembly process of the blank non-crosslinked micelle, the structure and doxorubicin (DOX) distribution of diselenide crosslinked micelle with different crosslinker contents (CCs) based on the nearest-neighbor bonding principle. The results revealed that the formation of a three-layer spherical micelle and the loaded DOX mainly distributed in the polycaprolactone (PCL) core and hydroxyethyl methacrylate (HEMA) mesosphere. The larger the dosage of DOX, the more DOX encapsulated, but the encapsulation of DOX in the hydrophobic domain would reach saturation when the dosage increased to 6.0 %. In micelles with lower CCs or crosslinking levels (CLs), DOX entered the middle layer and the inner core faster. Then, based on the nearest media-bead bond breaking principle and subsequently DPD simulation, the effects of different CCs on the micelle structure and DOX release properties were investigated. Low CC could cause fast drug release. With the increase of CCs, the micelle showed a slower DOX release trend. The multilayer crosslinked network system also affected the DOX release rate. Hence, this work can provide some mesoscale guidance for the structural design and structure-property relationship of stimuli-responsive reversible crosslinked micelles for drug delivery.

Extracellular matrix degrading enzyme with stroma-targeting peptides enhance the penetration of liposomes into tumors.

Various anti-tumor nanomedicines have been developed based on the enhanced permeability and retention effect. However, the dense extracellular matrix (ECM) in tumors remains a major barrier for the delivery and accumulation of nanoparticles into tumors. While ECM-degrading enzymes, such as collagenase, hyaluronidase, and bromelain, have been used to facilitate the accumulation of nanoparticles, serious side effects arising from the current non-tumor-specific delivery methods limit their clinical applications. Here, we report targeted delivery of bromelain into tumor tissues through its covalent attachment to a hyaluronic acid (HA)-peptide conjugate with tumor ECM targeting ability. The ECM targeting peptide, collagen type IV-binding peptide (C4BP), was chosen from six candidate-peptides based on their ability to bind to frozen sections of triple-negative breast cancer, 4T1 tumor ex vivo. The HA- C4BP conjugate showed a significant increase in tumor accumulation in 4T1-bearing mice after intravenous administration compared to unmodified HA. We further demonstrated that the systemic administration of bromelain conjugated C4BP-HA (C4BP-HA-Bro) potentiates the anti-tumor efficacy of liposomal doxorubicin. C4BP-HA-Bro decreased the number and length of collagen fibers and improved the distribution of doxorubicin within the tumor. No infusion reaction was noted after delivery of C4BP-HA-Bro. C4BP-HA thus offers a potential for effective and safe delivery of bromelain for improved intratumoral delivery of therapeutics.

Effect of Collagen Matrix on Doxorubicin Distribution and Cancer Cells' Response to Treatment in 3D Tumor Model.

The extracellular matrix (ECM) plays an important role in regulation of many aspects of tumor growth and response to therapies. However, the specifics of the interaction of chemotherapeutic agents with cancer cells in the presence of collagen, the major component of ECM, is still poorly investigated. In this study, we explored distribution of doxorubicin (DOX) and its effects on cancer cells' metabolism in the presence of collagen with different structures in 3D models. For this, a combination of second harmonic generation imaging of collagen and multiphoton fluorescence microscopy of DOX, and metabolic cofactor NAD(P)H was used. It was found that collagen slowed down the diffusion of DOX and thus decreased the cellular drug uptake. Besides nuclei, DOX also targeted mitochondria leading to inhibition of oxidative phosphorylation, which was more pronounced in the cells growing in the absence of collagen. As a result, the cells in collagen displayed better viability upon treatment with DOX. Taken together, our data illustrate that tumor collagen contributes to heterogeneous and sub-optimal response to DOX and highlight the challenges in improving drug delivery and efficacy.

Investigation of the Antitumor Activity and Toxicity of Tumor-Derived Exosomes Fused with Long-Circulating and pH-Sensitive Liposomes Containing Doxorubicin.

Exosome-liposome hybrid nanocarriers containing chemotherapeutic agents have been developed to enhance drug delivery, improve the efficacy of the treatment of metastatic cancer, and overcome chemoresistance in cancer therapy. Thus, the objectives of this study were to investigate the toxicological profiles of exosomes fused with long-circulating and pH-sensitive liposomes containing doxorubicin (ExoSpHL-DOX) in healthy mice and the antitumor activity of ExoSpHL-DOX in Balb/c female mice bearing 4T1 breast tumors. The acute toxicity was determined by evaluating the mortality and morbidity of the animals and conducting hematological, biochemical, and histopathological analyses after a single intravenous administration of ExoSpHL-DOX. The results of the study indicated that the ExoSpHL-DOX treatment is less toxic than the free doxorubicin (DOX) treatment. ExoSpHL-DOX showed no signs of nephrotoxicity, even at the highest dose of DOX, indicating that the hybrid nanosystem may alter the distribution of DOX and reduce the kidney damage. Regarding the antitumor activity, ExoSpHL-DOX showed an antitumor effect compared to the control group. Furthermore, the hybrid nanocarrier of tumor-derived exosomes fused with long-circulating and pH-sensitive liposomes reduced the number of metastatic foci in the lungs. These results indicate that ExoSpHL-DOX may be a promising nanocarrier for the treatment of breast cancer, reducing toxicity and inhibiting metastasis, mainly in the lungs.

Dynamic drug release state and PEG length in PEGylated liposomal formulations define the distribution and pharmacological performance of drug

To optimize the therapeutic efficacy of active pharmaceutical ingredients, various lipid-based drug delivery systems have been developed. In particular, due to the various advantages, most of the lipid-based nanoformulation products on the market contain the poly(ethylene glycol) (PEG) block on the carrier. However, the effect of PEG length on pharmacokinetic (PK) profile, nanoparticle distribution, and pharmacological efficacy of the encapsulated drug have not been explored fully. Here, we assessed the effects of PEG length on the distribution and pharmacological efficacy of doxorubicin (Dox)-loaded liposomal formulations. Compared to PEG-Lipo 2 K, PEG-Lipo 10 K increased the drug concentration in blood at 24 and 48 h and the extent of particle accumulation at the tumor site due to the enhanced blood circulation time of the nanoparticles having higher PEG length. However, as the drugs begin to be released from the carrier at the point of administration, the drug concentration at that later time point drops to 4% or less compared to that of the initial time points. Thus, the pharmacological efficacy among the PEG-Lipo formulations did not differ significantly, which could be attributed to their dynamic drug-releasing characteristics during circulation in the blood. These findings suggest that although PEG length plays a critical role in the particle and drug distribution of the formulations, it does not affect the therapeutic efficacy of the incorporated drug because of the dynamic character of drug-loaded PEG-Lipo structures.

Plasma Pharmacokinetics and Tissue Distribution of Doxorubicin in Rats following Treatment with Astragali Radix.

Doxorubicin (DOX) is an essential component in chemotherapy, and Astragali Radix (AR) is a widely used tonic herbal medicine. The combination of DOX and AR offers widespread, well-documented advantages in treating cancer, e.g., reducing the risk of adverse effects. This study mainly aims to uncover the impact of AR on DOX disposition in vivo. Rats received a single intravenous dose of 5 mg/kg DOX following a single-dose co-treatment or multiple-dose pre-treatment of AR (10 g/kg × 1 or × 10). The concentrations of DOX in rat plasma and six tissues, including heart, liver, lung, kidney, spleen, and skeletal muscle, were determined by a fully validated LC-MS/MS method. A network-based approach was further employed to quantify the relationships between enzymes that metabolize and transport DOX and the targets of nine representative AR components in the human protein–protein interactome. We found that short-term (≤10 d) AR administration was ineffective in changing the plasma pharmacokinetics of DOX in terms of the area under the concentration–time curve (AUC, 1303.35 ± 271.74 μg/L*h versus 1208.74 ± 145.35 μg/L*h, p > 0.46), peak concentrations (Cmax, 1351.21 ± 364.86 μg/L versus 1411.01 ± 368.38 μg/L, p > 0.78), and half-life (t1/2, 31.79 ± 5.12 h versus 32.05 ± 6.95 h, p > 0.94), etc. Compared to the isotype control group, DOX concentrations in six tissues slightly decreased under AR pre-administration but only showed statistical significance (p < 0.05) in the liver. Using network analysis, we showed that five of the nine representative AR components were not localized to the vicinity of the DOX disposition-associated module. These findings suggest that AR may mitigate DOX-induced toxicity by affecting drug targets rather than drug disposition.

Congo Red as a Supramolecular Carrier System for Doxorubicin: An Approach to Understanding the Mechanism of Action.

The uptake and distribution of doxorubicin in the MCF7 line of breast-cancer cells were monitored by Raman measurements. It was demonstrated that bioavailability of doxorubicin can be significantly enhanced by applying Congo red. To understand the mechanism of doxorubicin delivery by Congo red supramolecular carriers, additional monolayer measurements and molecular dynamics simulations on model membranes were undertaken. Acting as molecular scissors, Congo red particles cut doxorubicin aggregates and incorporated them into small-sized Congo red clusters. The mixed doxorubicin/Congo red clusters were adsorbed to the hydrophilic part of the model membrane. Such behavior promoted transfer through the membrane.

Near-Infrared Light-Remote Localized Drug Delivery Systems Based on Zwitterionic Polymer Nanofibers for Combination Therapy.

Localized drug delivery systems (LDDS) have gained great interests because they can directly treat the tumors and minimize systematic toxicity, and maximize drug action by controlling release precisely at the tumor site. However, the resistance of the non-specific adsorption of biomolecules is also important to alleviate the inflammatory reactions and avoid the decrease in performance of LDDS. In this study, we develop a near infrared (NIR) light-triggered nanofibrous delivery system consisting of zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine)-b-poly(ε-caprolactone) (PMPC-b-PCL) encapsulated with indocyanine green (ICG) and doxorubicin (DOX) for dual photothermal therapy and chemotherapy. The nanofibrous mat shows hydrophilic characteristics and good antifouling performance. Under mild NIR irradiation, ICG could convert NIR light into thermal energy that elevates the surrounding temperature above 45 °C. This thermal energy also markedly accelerates the DOX release from the nanofibrous mat due to softening of the nanofibers, indicating the drug release could be controlled and switched on/off by light-triggering. Moreover, this light-triggered thermal energy and releasing behavior contribute to enhancing the cell lethality. Intracellular DOX distribution confirms the more drugs release upon light irradiation. All results demonstrate the developed light-triggered drug release nanofibers as LDDS are biocompatible and antifouling as well as has the superior combinational chemotherapy/photothermal therapy.

Nanomicelle-Microsphere Composite as a Drug Carrier to Improve Lung-Targeting Specificity for Lung Cancer.

Lung cancer is the second-most common cancer and has the highest mortality among all cancer types. Nanoparticle (NP) drug delivery systems have been used to improve the therapeutic effectiveness of lung cancer, but rapid clearance and poor targeting limit their clinical utility. Here, we developed a nanomicelle-microsphere composite, in which doxorubicin (DOX) was loaded with spermine (Spm) modified poly (ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) micelles, and then the nanomicelles were noncovalently adsorbed on the surface of poly (lactic-co-glycolic acid) (PLGA) microspheres. The attachment was confirmed by scanning electron microscopy and confocal microscopy. In vitro cell experiments, MTT assays and intracellular uptake assays were used to demonstrate the cytotoxicity and the cellular uptake of micelles in A549 cells. In vivo biodistribution studies were conducted, an orthotopic lung cancer implantation model based on C57BL/6 mice was established, and then real-time fluorescence imaging analysis was used to study the targeted efficacy of the complex. A nanomicelle-microsphere composite was successively constructed. Moreover, Spm-modified micelles significantly enhanced cytotoxicity and displayed more efficient cellular uptake. Notably, an orthotopic lung cancer implantation model based on C57BL/6 mice was also successively established, and in vivo biodistribution studies confirmed that the complex greatly improved the distribution of DOX in the lungs and displayed notable tumor targeting. These results suggested that the nanomicelle-microsphere composite has potential application prospects in the targeted treatment of lung cancer.