Hyperthermia/glutathione-triggered ferritin nanoparticles amplify the ferroptosis for synergistic tumor therapy.

Breast cancer is the most diagnosed malignancy in women globally, and drug resistance is among the major obstacles to effective breast cancer treatment. Emerging evidence indicates that photothermal therapy and ferroptosis are both promising therapeutic techniques for the treatment of drug-resistant breast tumors. In this study, we proposed a thermal/ferroptosis/magnetic resonance imaging (MRI) triple functional nanoparticle (I@P-ss-FRT) in which ferritin, an iron storage material with excellent cellular uptake capacity, was attached via disulfide bonds onto polydopamine coated iron oxide nanoparticle (I@P) as photothermal transduction agent and MRI probe. I@P-ss-FRT converted the near-infrared light (NIR) into localized heat which accelerated the release of ferrous ions from ferritin accomplished by glutathione reduction and subsequently induced ferroptosis. The drug-resistant cancer cell lines exhibited a more significant uptake of I@P-ss-FRT and sensitivity to PTT/ferroptosis compared with normal cancer cell lines. In vivo, I@P-ss-FRT plus NIR displayed the best tumor-killing potential with inhibitory rate of 83.46 %, along with a decline in GSH/GPX-4 content and an increase in lipid peroxides generation at tumor sites. Therefore, I@P-ss-FRT can be applied to combat drug-resistant breast cancer.

Nanoparticle-Mediated Strategies for Enhanced Drug Penetration and Retention in the Airway Mucosa.

Airway mucus is a complex viscoelastic gel composed mainly of water, glycoproteins, lipids, enzymes, minerals, etc. Among them, glycoproteins are the main factors determining mucus's gel-like rheology. Airway mucus forms a protective barrier by secreting mucin, which represents a barrier for absorption, especially for more lipophilic drugs. It rapidly removes drugs from the airway through the physiological mucus clearance mechanism so drugs cannot remain in the lungs or reach the airway epithelial tissue for a long time. Significant progress has been made in enhancing drug lung deposition recently, but strategies are still needed to help drugs break through the lung mucosal barrier. Based on the physiopathological mechanisms of airway mucus, this paper reviews and summarizes strategies to enhance drug penetration and retention in the airway mucosa mediated by nano-delivery systems, including mucosal permeation systems, mucosal adhesion systems, and enzyme-modified delivery systems. On this basis, the potential and challenges of nano-delivery systems for improving airway mucus clearance are revealed. New ideas and approaches are provided for designing novel nano-delivery systems that effectively improve drug retention and penetration in the airway mucus layer.

Enhancement of cancer immunotherapy using CRT valgus tumor cell membranes coated bacterial whole peptidoglycan combined with radiotherapy.

Immunotherapy has achieved some success in preclinical and clinical studies, but the immunosuppressive tumor microenvironment (TME) leads to a low response rate of this therapy. In this paper, we describe a calreticulin (CRT) valgus CT-26 tumor cell membranes-coated bacterial whole peptidoglycan (WPG) from P. aeruginosa (CPW/SR) with a high rate of the STING agonist loading. In the construct, WPG from P. aeruginosa (P.WPG) was used as a carrier with the immunoadjuvant function while synergistically promoting the maturation of dendritic cells (DCs) through the delivery of the STING agonist SR-717. CRT valgus tumor cell membranes were identified and internalized by DCs via CRT on the surface. In addition, this construct was able to reverse the immunosuppressive TME in vivo and achieve synergies with radiotherapy by creating a personalized tumor vaccine, therefore achieving more resultful antitumor efficacy. In conclusion, CPW/SR constructed in this paper provides a new approach for achieving efficient cancer immunotherapy and combination therapy.

Evaluation of particle size distribution of sub-visible particles in powder injections with different packaging forms - small-sized sub-visible particles should not be ignored.

OBJECTIVES: Sub-visible particle, or particulate matter, is an important indicator in the safety assessment of clinical infusions. The present study aims to evaluate the effect of the packaging formats of antibiotic on the distribution of sub-visible particles in the small particle size range (<10 µm), to provide evidence for explanation to clinical adverse reactions and guidelines for rational drug use. METHODS: The conventional light blockage and the single particle optical sensing (SPOS) technology were applied to determine the size distribution of the sub-visible particles in the redissolved injections in different packages (dual-chamber bag and vial) from different manufacturers. In order to verify our hypothesis, the influences of active pharmaceutical ingredient (API) and solvent were controlled. Further, scanning electron microscopy (SEM) was utilized to observe the morphological characteristics of sub-visible particles from different package injections. RESULTS: After redissolving, the small-sized sub-visible particles (<10 µm) in the solution of injectable powder packaged in the dual-chamber bag were significantly lower than that of the conventional injectable powder packaged in the vial, and the difference remained significant after controlling for API. The results observed by SEM also supported the differences in the amount of particulate matter between the two packaging formats, showing a higher number of sub-visible particles from sodium chloride dissolved preparations packed in vails, with irregular shapes. CONCLUSION: In our study, the differences in the distribution of sub-visible particles were mainly attributed to the packaging formats. The dual-chamber bag injection might be an effective alternative to reduce the adverse reactions caused by sub-visible particles.

Anti-CHAC1 exosomes for nose-to-brain delivery of miR-760-3p in cerebral ischemia/reperfusion injury mice inhibiting neuron ferroptosis.

Ferroptosis plays a critical role in ischemic stroke, and anti-ferroptosis strategies were regarded as potentially effective measures. Based on ferroptosis-related mechanisms, this study aims to design and prepare anti-ferroptosis exosomes from adipose-derived mesenchymal stem cells (ADSC-Exo) for treating ischemic brain injury via intranasal (IN) administration. According to the bioinformatic analysis, CHAC1 was a key gene in the progress of ferroptosis in ischemic stroke. miR-760-3p can inhibit the expression of CHAC1 and may be abundant in ADSC-Exo. Therefore, ADSC-Exo were successfully isolated and the immunofluorescence showed that they can be efficiently delivered to the brain via IN administration. Additionally, IN administration of ADSC-Exo can effectively improve the neurobehavior function of mice after I/R, and improve the ferroptosis-related outcomes. As the immunofluorescence showed the co-localization of NeuN with CHAC1 obviously, we further evaluated the systematic effect of ADSC-Exo in an oxygen-glucose deprivation (OGD) mouse neuroblastoma cell line N2a model. The results showed that miR-760-3p in ADSC-Exo contributed to their function in inhibiting ferroptosis by targeting CHAC1 in neurons. Collectively, the present study successfully designed and prepared anti-CHAC1 ADSC-Exo and suggested a promising exosome-based strategy for anti-ferroptosis therapy in cerebral ischemia/reperfusion injury.

Assessment of Irinotecan Loading and Releasing Profiles of a Novel Drug-Eluting Microsphere (CalliSpheres) In Vitro.

Background: This study investigated irinotecan loading efficiency and release profiles of CalliSpheres in vitro. Materials and Methods: CalliSpheres with size of 50-150, 100-300, and 300-500 µm and irinotecan at different amounts (20, 40, 80, and 100 mg) and concentrations (5 and 10 mg/mL) were prepared for experiments. Dynamic light scattering and Agilent 1260 high-performance liquid chromatography system were used to quantify bead diameters and the efficiency of irinotecan loading and releasing properties, respectively. Results: The diameters of CalliSpheres with all sizes were reduced after being loaded with irinotecan compared with unloaded ones with shrinkage rate ranging from 8.5% to 16.2%. Above 80% irinotecan was incorporated with CalliSpheres with all sizes when being loaded with irinotecan 20, 40, and 80 mg, while loading efficiencies were 70%-80% when being loaded with irinotecan 100 mg. Besides, elevated loading efficiency was observed at a higher concentration of irinotecan solutions (10 mg/mL) compared with a lower concentration (5 mg/mL) for CalliSpheres with all sizes. As to release profiles, irinotecan was released from CalliSpheres very quickly, and irinotecan release rate was elevated in CalliSpheres with smaller size than CalliSpheres with larger size within the first 12 h, whereas it was similar among CalliSpheres with different sizes at 24 and 48 h with maximum release rate ∼100%. In addition, fetal bovine serum seemed to have an effect on the accelerating irinotecan release. Conclusion: CalliSpheres exhibits good physical characteristics, satisfied irinotecan loading efficiency, and acceptable releasing profiles.

An In Vitro Comparative Study of Three Drug-Eluting Beads Loaded with Raltitrexed.

Background: This study investigated the raltitrexed loading method, compatible stability with contrast agent, release profiles, and morphological properties of CalliSpheres, DC Bead, and HepaSphere. Materials and Methods: The amounts of raltitrexed added, loading medium, loading condition, and drug concentrations were investigated as factors influencing drug loading efficiency. Compatible stability with iopamidol was tested. Release profiles were accessed by a flowthrough apparatus system. Morphological properties were evaluated by a scanning electron microscope (SEM). Diameters were measured by a laser diffraction particle size analyzer. Results: With the optimized method, the amount of raltitrexed loading to a marketed drug-eluting beads (DEBs) package was 2.67 mg for CalliSpheres, 2.34 mg for DC Bead, and 3.19 mg for HepaSphere. For all three DEBs, the drug leak rate was >50% within 2 h after mixing with iopamidol, and the time to reach 75% of the release plateau was within 10 min. Diameters increased after drug loading. Drug crystals were observed on the surface of DEBs in SEM. Conclusions: The amount of drug loading could meet clinical requirements by the optimized method. All three raltitrexed-loaded DEBs showed poor compatible stability with iopamidol, as well as rapid drug release performance, which should be noticed in clinical practice.

In Vitro Drug Loading, Releasing Profiles, and In Vivo Embolic Efficacy and Safety Evaluation of a Novel Drug-Eluting Microsphere (CalliSpheres).

Background: To investigate morphology, physical property, loadability, stability, and release profiles of a novel drug-eluting microsphere, CalliSpheres, in vitro and to explore its embolic efficacy and safety in vivo. Materials and Methods: CalliSpheres (50-150 µm, 100-300 µm, and 300-500 µm) and doxorubicin in different amounts (20, 40, 80, and 100 mg) and concentrations (5 and 10 mg/mL) were prepared for experiments. Dynamic light scattering and an Agilent 1260 high-performance liquid chromatography system were used to quantify bead diameters and the efficiency of drug loading and release, respectively. Twelve New Zealand rabbits were treated with catheter-aided hepatic embolization using CalliSpheres. Results: CalliSpheres displayed a red color after loading with doxorubicin, and the mean diameters decreased by 20.7-25.8%. Almost 100% of the drug was incorporated with CalliSpheres in different sizes immersed with doxorubicin 20 mg, while loading efficiency ranged from 75.8% to 100.0% with doxorubicin at 40, 80, and 100 mg dependent on CalliSpheres sizes (smaller sizes, higher loading efficiency). Elevated loading efficiency was observed at higher concentration of doxorubicin solutions. Regarding release profiles, doxorubicin was released from CalliSpheres quickly at the very beginning, and doxorubicin release percentage was increased in the 50-150 µm group (39.2% ± 1.2%) compared with the 100-300 µm group (31.3% ± 1.3%) and 300-500 µm group (31.7% ± 2.5%). Digital subtraction angiography, computed tomography, and histopathologic emanation results proved in vivo safety and embolic efficacy of CalliSpheres. Conclusions: CalliSpheres present with good physical characteristics and satisfactory loading and releasing profiles in vitro and are well tolerated and efficient in embolization in vivo.

Development and In Vivo Evaluation of a Novel Vitamin D3 Oral Spray Delivery System.

Developing drugs that are highly selective to host tissues but are the least toxic remains one of the most difficult challenges in cancer treatment. Recent studies have shown that tumor cells from a variety of sources can express vitamin D3 receptors and that the response to vitamin D3 and its analogs is prone to growth arrest and cell death. However, conventional vitamin D3 drug formulations lack dose control and cannot target specific cells or tissues. The aim of this study was to prepare vitamin D3 nanospray for inhalation delivery route. This study evaluated the physical properties of the formulation (particle size distribution and biological stability), the total number of sprays per bottle, the spray volume per spray, and the loading variance of the spray. The optimized vitamin D3 spray formula is easy to spray, has fewer drips, and has a fast drying time. It can be stored for 3 months at 37 ± 2 °C temperature, 75 ± 5% relative humidity, and away from light, and can maintain biological stability. This study showed that compared with traditional nasal sprays, the spray has a larger fan angle (82.1 degrees) and beam width (104.88 mm), more symmetrical spray on both sides of the spray column, a faster coverage of the administration site, and a wider range, which is suitable for inhalation delivery routes.

Design and Characterization of HY-038 Solid Dispersions via Spray Drying Technology: In Vitro and In Vivo Evaluations.

The aim of this study was to prepare HY-038 solid dispersions (SDs) with single carrier at high drug loading and then forming a tablet to enhance solubility, dissolution, and bioavailability via spray drying technology. At the same time, we hope to develop a more convenient in vitro method to predict the absorption behavior of different formulations in vivo. Different solid dispersions, varying in drug/polymer ratios, were prepared. Infrared spectroscopy, differential scanning calorimetry, scanning electron microscope, and X-ray diffraction were used to perform solid-state characterizations of the pure drug and SDs. Contact angle of water, dissolution in pH = 6.8 phosphate buffer, and in vivo absorption in dogs were studied. As a result, solid-state characterization demonstrated the transformation of the crystalline HY-038 to an amorphous state in the solid dispersions, and the in vivo exposure followed with the trend of the dissolution curve combined with contact angle. Compared with the prototype formulation, the Cmax and AUC0-∞ of optimized formulation SD2 (HY-038-HPMCAS 3:1) increased by about 5 ~ 9 times at the same dose. More importantly, the SD2 formulation showed approximately linear increases in Cmax and AUC0-∞ as the dose increased from 50 to 100 mg, while the prototype formulation reached absorption saturation at 50 mg. SD2 (HY-038-HPMCAS 3:1) was selected as the best formulation for the downstream development.

Nanoparticles-mediated emerging approaches for effective treatment of ischemic stroke.

Ischemic stroke leads to high disability and mortality. The limited delivery efficiency of most therapeutic substances is a major challenge for effective treatment of ischemic stroke. Inspired by the prominent merit of nanoscale particles in brain targeting and blood-brain barrier (BBB) penetration, various functional nanoparticles have been designed as promising drug delivery platforms that are expected to improve the therapeutic effect of ischemic stroke. Based on the complex pathological mechanisms of ischemic stroke, this review outline and summarize the rationally designed nanoparticles-mediated emerging approaches for effective treatment of ischemic stroke, including recanalization therapy, neuroprotection therapy, and combination therapy. On this bases, the potentials and challenges of nanoparticles in the treatment of ischemic stroke are revealed, and new thoughts and perspectives are proposed for the design of feasible nanoparticles for effective treatment of ischemic stroke.

Pulmonary surfactants affinity Pluronic-hybridized liposomes enhance the treatment of drug-resistant lung cancer.

For a long time, the incidence and mortality of lung cancer have ranked first among all kinds of cancers, of which the major type is non-small cell lung cancer (NSCLC). Until now, chemotherapy and radiotherapy are still the first choice for patients with advanced or metastatic NSCLC. However, the emergence of multi-drug resistance (MDR) always leads to the failure of chemotherapy and increases cancer-related mortality. In this study, we prepared a Pluronic-hybridized paclitaxel-loaded liposome (PPL), which was used in combination with ambroxol (Ax) to not only resensitize drug-resistant tumor cells, but also increase the preparation retention in the lung. On the one hand, Ax induced the production of pulmonary surfactants (PS) and responsively improved the accumulation of pulmonary surfactants affinity liposomes whose skeleton was exogenous pulmonary surfactant phospholipids DPPC, because of the specific affinity of phospholipids related to pulmonary surfactant proteins. On the other hand, drug-resistant tumor cells were resensitized due to the inhibition of autophagy by Ax and the reduced expression of the drug-resistant protein P-glycoprotein (P-gp) by Pluronic P105. Therefore, we concluded that the combination of PPL and Ax achieved excellent killing tumor effects through multi-path and multi-strategy, having great application prospects in the future.

Optimized Loading of Idarubicin in CalliSpheres® Drug-Eluting Beads and Characterization of Release Profiles and Morphological Properties.

This study aimed to investigate the idarubicin loading method, compatible stability with contrast agent, release profiles, and morphological properties of 50-150, 100-300, and 300-500 µm CalliSpheres®. The amounts of idarubicin added, loading medium, loading condition, and drug concentration were investigated as factors influencing drug loading efficiency. The drug loading rate was negatively correlated with the amount drug added and diameter of CalliSpheres® and positively correlated with the drug concentration. Compared to loading in purified water and incubation at room temperature, 5% glucose, heating, and ultrasound could accelerate drug loading. The idarubicin loading efficiency was above 95% after 10 min for all three CalliSpheres® with the optimized method of adding 20 mg of idarubicin at a concentration of 2 mg/mL and incubating at room temperature. The drug leak rate was under 1% within 8 h after mixing with iopamidol. Drug release tests indicated the sustained-release performance of CalliSpheres®, and the time to reach 75% of the release plateau level was 8, 26, and 51 min for 50-150, 100-300, and 300-500 µm CalliSpheres®, respectively. After idarubicin loading, the diameters increased by 12%, 36%, and 38% for 50-150, 100-300, and 300-500 µm CalliSpheres®, respectively, and the surface of CalliSpheres® was observed to become smoother than that before drug loading. All three CalliSpheres® presented satisfactory loading efficiency with the optimized method, as well as proper compatible stability and sustained release performance. Among them, 100-300 µm CalliSpheres® are recommended.

TPGS assists the percutaneous administration of curcumin and glycyrrhetinic acid coloaded functionalized ethosomes for the synergistic treatment of psoriasis.

Combined therapy with anti-inflammatory drugs is preferred for the topical treatment of psoriasis, but the codelivery of drugs is restricted due to the lack of a suitable delivery system. Ethosomes with excellenttransdermal propertiesare perfect as carriers for hyperplastic skin. Therefore, glycyrrhetinic acid-D-α-tocopherol acid polyethylene glycol succinate (GA-TPGS) was synthesized, which prevented the inflammation and lipid peroxidation damage, thus effectively stabilizing the psoriasis. Then GA-TPGS was surface-modified on the curcumin (Cur) loaded ethosomes to construct curcumin-loaded GA-TPGS-modified multifunctional ethosomes (Cur@GA-TPGS-ES), exerting synergistic treatment for psoriasis. Using an interleukin-6-induced cell model, we found that Cur@GA-TPGS-ES displayed desirable suppression of inflammation response and oxidative stress damage. Compared with the ethanol solution, the percutaneous penetration rates of Cur and GA in Cur@GA-TPGS-ES were superior. In vivo microdialysis revealed similar results, suggesting an increase of transcutaneous absorption in Cur@GA-TPGS-ES. Fluorescence staining revealed that the cellular uptake and skin distribution were distinctly enhanced with the delivery by Cur@GA-TPGS-ES. After topical administration to imiquimod-induced psoriatic mice, the Cur@GA-TPGS-ES group showed powerful treatment from inflammatory infiltration inhibition of Cur, glucocorticoid-like effects of GA and anti-lipid peroxidation of TPGS. Overall, GA-TPGS mediated ethosomes possess more advantageous transdermal properties and synergistic antipsoriatic efficacy.

Preferential Targeting Cerebral Ischemic Lesions with Cancer Cell-Inspired Nanovehicle for Ischemic Stroke Treatment.

The poor drug delivery to cerebral ischemic regions is a key challenge of ischemic stroke treatment. Inspired by the intriguing blood-brain barrier (BBB)-penetrating ability of 4T1 cancer cells upon their brain metastasis, we herein designed a promising biomimetic nanoplatform by camouflaging a succinobucol-loaded pH-sensitive polymeric nanovehicle with a 4T1 cell membrane (MPP/SCB), aiming to promote the preferential targeting of cerebral ischemic lesions to attenuate the ischemia/reperfusion injury. In transient middle cerebral artery occlusion (tMCAO) rat models, MPP/SCB could be preferentially delivered to the ischemic hemisphere with a 4.79-fold higher than that in the normal hemisphere. Moreover, MPP/SCB produced notable enhancement of microvascular reperfusion in the ischemic hemisphere, resulting in a 69.9% reduction of infarct volume and showing remarkable neuroprotective effects of tMCAO rats, which was superior to the counterpart uncamouflaged nanovehicles (PP/SCB). Therefore, this design provides a promising nanoplatform to target the cerebral ischemic lesions for ischemic stroke therapy.

Oxygen-Delivering Polyfluorocarbon Nanovehicles Improve Tumor Oxygenation and Potentiate Photodynamic-Mediated Antitumor Immunity.

Hypoxia is a critical cause of tumor immunosuppression, and it significantly limits the efficacy of many anticancer modalities. Herein, we report an amphiphilic F11-derivative-based oxygen-delivering polyfluorocarbon nanovehicle loading photodynamic DiIC18(5) and reactive oxygen species (ROS)-sensitive prodrug of chemo-immunomodulatory gemcitabine (PF11DG), aimed at relieving tumor hypoxia and boosting antitumor immunity for cancer therapy. We optimized F11-based polyfluorocarbon nanovehicles with a 10-fold enhancement of tumor oxygenation. PF11DG exhibited intriguing capabilities, such as oxygen-dissolving, ROS production, and responsive drug release. In tumors, PF11DG exhibited flexible intratumoral permeation and boosted robust antitumor immune responses upon laser irradiation. Notably, the treatment of PF11DG plus laser irradiation (PF11DG+L) significantly retarded the tumor growth with an 82.96% inhibition in the 4T1 breast cancer model and a 93.6% inhibition in the PANC02 pancreatic cancer model with better therapeutic benefits than non-oxygen-delivering nanovehicles. Therefore, this study presents an encouraging polyfluorocarbon nanovehicle with deep tumor-penetrating and hypoxia-relieving capacity to boost antitumor immunity for cancer treatment.

Biomimetic Drug Delivery Systems Oriented by Biological Function in Tumor Targeting.

The emergence of nanoscale drug delivery systems provides new opportunities for targeting the delivery of chemotherapeutic drugs and has achieved excellent results. In recent years, with the rise in the concept of intelligent drug delivery systems, the design and preparation of carriers have become more and more complicated, which is not conducive to clinical transformation. Researchers are gradually focused on biomimetic nanoscale drug delivery systems, trying to combine the physicochemical properties of nanoscale carriers with the natural biological functions of endogenous substances, so as to boost tumor targeting delivery. In this article, we first classify and introduce biomimetic nanoscale drug delivery systems, and then emphasize their unique biological functions. The biomimetic nanoscale drug delivery systems have the advantages of simple preparation, powerful functions, and low immunogenicity, having a good application prospect.

Tumor-Activated Size-Enlargeable Bioinspired Lipoproteins Access Cancer Cells in Tumor to Elicit Anti-Tumor Immune Responses.

The limited lymphocytes infiltration and immunosuppression in tumor are the major challenges of cancer immunotherapy. The use of immunogenic cell death (ICD)-inducing agents has potential to potentiate antitumor immune responses, but is tremendously hampered by the poor delivery efficiency. Herein, a tumor-activated size-enlargeable bioinspired lipoprotein of oxaliplatin (TA-OBL) is designed to access cancer cells and boost the ICD-induced antitumor immunity for synergizing immune-checkpoint blockades (ICBs)-mediated immunotherapy. TA-OBL is constructed by integrating a legumain-sensitive melittin conjugate for improving intratumoral permeation and cancer cell accessibility, a pH-sensitive phospholipid for triggering size-enlargement and drug release in intracellular acidic environments, a nitroreductase-sensitive hydrophobic oxaliplatin prodrug (N-OXP) for eliciting antitumor immunity into the bioinspired nano-sized lipoprotein system. TA-OBL treatment produced robust antitumor immune responses and its combination with ICBs demonstrates strong therapeutic benefits with delayed tumor growth and extended survival rate, making it a promising delivery nanoplatform to elicit antitumor immunity for cancer immunotherapy.

Compatible Stability and Aerosol Characteristics of Atrovent® (Ipratropium Bromide) Mixed with Salbutamol Sulfate, Terbutaline Sulfate, Budesonide, and Acetylcysteine.

(1) Background: It is common practice in the treatment of respiratory diseases to mix different inhalation solutions for simultaneous inhalation. At present, a small number of studies have been published that evaluate the physicochemical compatibility and aerosol characteristics of different inhalation medications. However, none of them studied Atrovent®. Our work aims to address the lack of studies on Atrovent®. (2) Methods: Portions of admixtures were withdrawn at certain time intervals after mixing and were tested by pH determination, osmolarity measurement, and high-performance liquid chromatography (HPLC) assay of each active ingredient as measures of physicochemical compatibility. The geometrical and aerosol particle size distribution, active drug delivery rate, and total active drug delivered were measured to characterize aerosol behaviors. (3) Results: During the testing time, no significant variation was found in the pH value, the osmotic pressure, or the active components of admixtures. With the increase in nebulization volume after mixing, fine particle dose (FPD) and total active drug delivered showed statistically significant improvements, while the active drug delivery rate decreased compared to the single-drug preparations. (4) Conclusions: These results endorse the physicochemical compatibility of Atrovent® over 1 h when mixed with other inhalation medications. Considering aerosol characteristics, simultaneous inhalation is more efficient.

Pulmonary-Affinity Paclitaxel Polymer Micelles in Response to Biological Functions of Ambroxol Enhance Therapeutic Effect on Lung Cancer.

PURPOSE: Cancer chemotherapy effect has been largely limited by cell autophagy and little drug accumulation at the action sites. Herein, we designed an intelligent strategy involving paclitaxel (PTX) polymer micelles in response to biological functions of ambroxol (Ax). The amphiphilic polymers polyethyleneglycol-polylactic acid (PEG-PLA) and Pluronic P105 were selected as nanocarriers to encapsulate PTX to form into lung affinity PEG-PLA/P105/PTX micelles. Ax which can up-regulate the secretion of pulmonary surfactant (PS) and inhibit autophagy was hired to change the microenvironment of the lung, thereby promoting the lung accumulation and increasing cell-killing sensitivity of the micelles. METHODS: The physical and chemical properties of the micelles were characterized including size, morphology, critical micellar concentration (CMC) and in vitro drug release behavior. The therapeutic effects of the combination regimen were characterized both in vitro and in vivo including study on Ax in promoting the secretion of pulmonary surfactant, in vitro cytotoxicity, cellular uptake, Western blotting, in vivo biodistribution, in vivo pharmacokinetics and in vivo antitumor efficacy. RESULTS: The PEG-PLA/P105/PTX micelles showed a particle size of 16.7 ± 0.5 nm, a nearly round shape, small CMC and sustained drug release property. Moreover, the in vitro results indicated that Ax could increase PS and LC3 protein secretion and enhance the cytotoxicity of PEG-PLA/P105/PTX micelles toward A549 cells. The in vivo results indicated that the combination therapeutic regimen could promote the micelles to distribute in lung and enhance the therapeutic effect on lung cancer. CONCLUSION: This multifunctional approach of modulating the tumor microenvironment to enhance drug transportation and cell-killing sensitivity in the action sites might offer a new avenue for effective lung cancer treatment.