Investigation of morphology and structure of drug-loaded PLA-b-PEO-b-PLA polymeric micelle: A dissipative particle dynamics simulations study.

The dissipative particle dynamics (DPD) simulation was used to study the morphologies and structures of the paclitaxel-loaded PLA-b-PEO-b-PLA polymeric micelle. We focused on the influences of PLA block length, PLA-b-PEO-b-PLA copolymer concentration, paclitaxel drug content on morphologies and structures of the micelle. Our simulations show that: (i) with the PLA block length increase, the self-assemble structure of PLA-b-PEO-b-PLA copolymers with paclitaxel vary between onion-like structure (core-middle layer-shell) to spherical core-shell structure. The PEO shell thins and the size of the PLA core increases. The onionlike structures are comprised of the PEO hydrophilic core, the PLA hydrophobic middle layer, and the PEO hydrophilic shell, the distribution of the paclitaxel drug predominantly occurs within the hydrophobic intermediate layer; (ii) The system forms a spherical core-shell structure when a small amount of the drug is added, and within a certain range, the size of the spherical structure increases as the drug amount increases. When the drug contents (volume fraction) cdrug = 10%, it can be observed that the PLA4-b-PEO19-b-PLA4 spherical structures connect to form rod-shaped structures. With the length of PLA block NPLA = 8, as the paclitaxel drug concentrations cdrug = 4%, PEO has been insufficient to completely encapsulate the PLA and paclitaxel drug beads. To enhance drug loading capacity while maintaining stability of the system in aqueous solution, the optimal composition for loading paclitaxel is PLA4-b-PEO19-b-PLA4; the drug content is not higher than 4%; (iii) The paclitaxel-loaded PLA4-b-PEO19-b-PLA4 micelle undergo the transition from onionlike (core-middle layer-shell) to spherical (core-shell) to rod-shaped and lamellar structure as the PLA4-b-PEO19-b-PLA4 copolymer concentration increases from ccp = 10% to 40%.

Exploring the synergistic behavior of paclitaxel and vorinostat upon co-loading in albumin nanoparticles for breast cancer management.

Breast cancer is challenging to treat accompanied with poor clinical outcomes. Paclitaxel (PTX) is a first-line chemotherapeutic agent, but possesses limitations due to side effects, high dose, non-specific tissue distribution, and drug resistance. An epigenetic modulator, vorinostat (VOR) is known to enhance PTX efficacy and therefore to resolve the issues of conventional PTX formulations, we designed PTX- and VOR-bound albumin nanoparticles (PTX-VOR-BSA-NPs) using antisolvent precipitation technique where albumin is used as a carrier and a targeting agent. The PTX-VOR-BSA-NPs were of 140 nm size, polydispersity index around 0.18, and about 78% and 68% of entrapment efficiency for PTX and VOR, respectively. A bi-pattern release of both PTX and VOR was observed from PTX-VOR-BSA-NPs with a burst release for 2 h succeeded by sustained release until 24 h. A significantly lower %cell viability was observed in MCF-7 cell lines, while efficient cellular drug uptake was found in MDA-MB-231 cells. Furthermore, a greater apoptotic index was found compared to free PTX and VOR because of the synergistic activity of these drugs. The PTX-VOR-BSA-NPs also showcased superior pharmacokinetic profile and noteworthy reduction in the tumor volume compared to Intaxel in 4T1 cell line-induced breast tumor model. Further, the NPs showed similar levels of toxicity biomarkers as that of control. Overall, the developed PTX-VOR-BSA-NPs were found to have less toxicity and more effectiveness compared to the marketed formulation, thus affirming the generation of a potent as well as and safe product.

Evaluation of microstructure, dissolution rate, and oral bioavailability of paclitaxel poloxamer 188 solid dispersion.

Poor solubility is a major challenge for enhancing the oral bioavailability and clinical application of many drugs, including the broad-spectrum chemotherapy drug paclitaxel (PTX). A practical approach to improving the solubility of insoluble drugs is through the use of solid dispersion (SD). This study aimed to investigate the potential of the triblock copolymer, poloxamer 188 (P188), as a carrier for preparing solid dispersion of paclitaxel using spray drying technology. We systematically studied its microstructure, dissolution behavior in vitro, and pharmacokinetics. Our findings demonstrate that PTX exists in an amorphous state in copolymer composed of polyoxyethylene-polyoxypropylene-polyoxyethylene (PEO-PPO-PEO) P188, with stronger miscibility with hydrophobic PPO segments. All three in vitro dissolution models revealed that the release rate of drugs in SD was significantly higher compared to that of physical mixtures (PM) as well as raw drugs. Furthermore, our pharmacokinetic results showed that the area under the curve(AUC) of PTX in SD was 6 times higher than that of active pharmaceutical ingredient(API), 4.5 times higher than PM, and the highest blood drug concentration (Cmax) reached 357.51 ± 125.54 (ng/mL), approximately 20 times higher than API. Overall, our findings demonstrate that the dissolution rate of amorphous PTX in SD significantly improves, effectively enhancing the oral bioavailability of PTX.

Delivery of paclitaxel by carboxymethyl chitosan-functionalized dendritic fibrous nano-silica: Fabrication, characterization, controlled release performance and pharmacokinetics.

In this study, carboxymethyl chitosan (CMCS) with excellent biocompatibility was used as the "gatekeeper" to design and fabricate a pH-responsive drug delivery system (CMCS-DFNS) as paclitaxel carriers. Characterization results showed that CMCS-DFNS was successfully prepared and the nanocarriers displayed excellent drug loading efficiency of 19.8 %, and the results of the adsorption mechanism revealed that the adsorption of PTX was consistent with the Freundlich isotherm and pseudo-second-order kinetic model. Furthermore, the pH-responsive controlled release behavior at different pH (pH = 7.4, 6.5, and 5.0) was evaluated, and the results demonstrated that the cumulative release at pH 5.0 was 58.8 %, which was 2.7 times higher than that at pH 7.4, suggesting that the carrier exhibited a good pH sensitivity. The results of in vitro cellular experiments further indicated that CMCS-DFNS significantly improved the drug uptake efficiency in breast cancer MCF-7 cells. Importantly, the results of in vivo and cellular pharmacokinetic revealed that CMCS-DFNS can improve the circulation time and enhance the relative bioavailability of paclitaxel. Therefore, the fabricated pH-responsive drug delivery system has potential applications in the delivery of anti-tumor drugs, and provides a new delivery pathway for other compounds with low bioavailability.

Physiologically-based pharmacokinetic model to predict doxorubicin and paclitaxel exposure in infants through breast milk.

Limited information is available concerning infant exposure and safety when breastfed by mothers receiving chemotherapy. Whereas defining distribution to breast milk is important to infer drug exposure, infant pharmacokinetics also determine to what extent the infant will be exposed to potential toxic effects. We aimed to assess the impact of chemotherapy containing breast milk on infants by predicting systemic and local (intestinal) exposure of paclitaxel and doxorubicin in infants through breast milk using a physiologically-based pharmacokinetic (PBPK) approach. Whole-body PBPK models of i.v. paclitaxel and doxorubicin were extended from the literature, with an oral absorption component to enable predictions in infants receiving paclitaxel or doxorubicin-containing breast milk. For safety considerations, worst-case scenarios were explored. Finally, paclitaxel and doxorubicin exposures in plasma and intestinal tissue of infants following feeding of breast milk from paclitaxel- or doxorubicin-treated mothers were simulated and breast milk discarding strategies were evaluated. The upper 95th percentile of the predicted peak concentrations in peripheral venous blood were 3.48 and 0.74 nM (0.4%-1.7% and 0.1%-1.8% of on-treatment) for paclitaxel and doxorubicin, respectively. Intestinal exposure reached peak concentrations of 1.0 and 140 µM for paclitaxel and doxorubicin, respectively. Discarding breast milk for the first 3 days after maternal chemotherapy administration reduced systemic and tissue exposures even further, to over 90% and 80% for paclitaxel and doxorubicin, respectively. PBPK simulations of chemotherapy exposure in infants after breastfeeding with chemotherapy containing breast milk suggest that particularly local gastrointestinal adverse events should be monitored, whereas systemic adverse events are not expected.

Polysorbate 80-coated albumin nanoparticles to deliver paclitaxel into the brain to treat glioma.

Aim: To develop stable paclitaxel (PTX)-loaded bovine serum albumin (BSA) nanoparticles (BSA-NPs-PTX) as drug-delivery vehicles for delivering paclitaxel into the brain to treat glioma. Methods: This study used PTX-loaded BSA NPs coated with polysorbate 80 (Ps 80) to enhance PTX concentration in the brain. Results: The low IC50 indicated that the fabricated BSA-NPs-PTX and BSA-NPs-PTX-Ps 80 showed significantly enhanced cytotoxicity. The pharmacokinetic and biodistribution analysis of BSA-NPs-PTX and BSA-NPs-PTX 80 showed comparable pharmacokinetic profiles but were significantly different compared with free PTX. Conclusion: BSA-NPs-PTX-Ps 80 exhibited higher plasma concentration-time curves, as compared with BSA-NPs-PTX and PTX. BSA-NPs-PTX and BSA-NPs-PTX-Ps 80 showed significantly improved PTX distribution in the frontal cortex, posterior brain and cerebellum.

Semi-physiological Enriched Population Pharmacokinetic Modelling to Predict the Effects of Pregnancy on the Pharmacokinetics of Cytotoxic Drugs.

BACKGROUND AND OBJECTIVE: As a result of changes in physiology during pregnancy, the pharmacokinetics (PK) of drugs can be altered. It is unclear whether under- or overexposure occurs in pregnant cancer patients and thus also whether adjustments in dosing regimens are required. Given the severity of the malignant disease and the potentially high impact on both the mother and child, there is a high unmet medical need for adequate and tolerable treatment of this patient population. We aimed to develop and evaluate a semi-physiological enriched model that incorporates physiological changes during pregnancy into available population PK models developed from non-pregnant patient data. METHODS: Gestational changes in plasma protein levels, renal function, hepatic function, plasma volume, extracellular water and total body water were implemented in existing empirical PK models for docetaxel, paclitaxel, epirubicin and doxorubicin. These models were used to predict PK profiles for pregnant patients, which were compared with observed data obtained from pregnant patients. RESULTS: The observed PK profiles were well described by the model. For docetaxel, paclitaxel and doxorubicin, an overprediction of the lower concentrations was observed, most likely as a result of a lack of data on the gestational changes in metabolizing enzymes. For paclitaxel, epirubicin and doxorubicin, the semi-physiological enriched model performed better in predicting PK in pregnant patients compared with a model that was not adjusted for pregnancy-induced changes. CONCLUSION: By incorporating gestational changes into existing population pharmacokinetic models, it is possible to adequately predict plasma concentrations of drugs in pregnant patients which may inform dose adjustments in this population.

Construction of Curcumin and Paclitaxel Co-Loaded Lipid Nano Platform and Evaluation of Its Anti-Hepatoma Activity in vitro and Pharmacokinetics in vivo.

Purpose: The present study aimed to construct a co-loading platform encapsulating curcumin and paclitaxel at ratios of 2:1-80:1 (w/w) designated "CU-PTX-LNP" and explored the synergistic effects of CU-PTX at different composite proportions on liver cancer cells using the combination index (CI) method. Methods: The CU lipid nanoplatform (CU-LNP) formulation was optimized via single-factor and orthogonal experiments. Various concentrations of PTX were added to the optimal formulation of CU-LNP to generate CU-PTX-LNP and the nanoplatform characterized via differential scanning calorimetry (DSC), transmission electron microscope (TEM), X-ray diffraction (XRD), zeta potential, polydispersity index (PDI), and size analyses. The cumulative release, stability, and cytotoxicity of CU-PTX-LNP in LO2, HepG2, and SMMC-7221 cells were assessed in vitro, followed by safety investigation and pharmacokinetic studies in vivo. The anti-tumor activity of CU-PTX-LNP was also evaluated using nude mice. Results: CU-PTX-LNP formulations containing CU:PTX at a range of proportions (2:1-80:1; w/w) appeared as uniformly dispersed nanosized spherical particles with high entrapment efficiency (EE> 90%), sustained release and long-lasting stability. Data from in vitro cytotoxicity assays showed a decrease in the IC50 value of PTX of CU-PTX-LNP (by 5.47-332.7 times in HepG2 and 4.29-143.21 times in SMMC-7221 cells) compared to free PTX. In vivo, CU-PTX-LNP displayed excellent biosafety, significant anti-tumor benefits and enhanced pharmacokinetic behavior with longer mean residence time (MRT(0-t); CU: 4.31-fold, PTX: 4.61-fold) and half-life (t1/2z; CU: 1.83-fold, PTX: 2.28-fold) relative to free drugs. Conclusion: The newly designed CU-PTX-LNP platform may serve as a viable technological support system for the successful production of CU-PTX composite preparations.

Plasma Stability and Plasma Metabolite Concentration-Time Profiles of Oligo(Lactic Acid)8-Paclitaxel Prodrug Loaded Polymeric Micelles.

Paclitaxel (PTX) is a frequently prescribed chemotherapy drug used to treat a wide variety of solid tumors. Oligo(lactic acid)8-PTX prodrug (o(LA)8-PTX) loaded poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) micelles have higher loading, slower release and higher antitumor efficacy in murine tumor models over PTX-loaded PEG-b-PLA micelles. The goal of this work is to study plasma stability of o(LA)8-PTX-loaded PEG-b-PLA micelles and its pharmacokinetics after IV injection in rats. In rat plasma, o(LA)8-PTX prodrug is metabolized into o(LA)1-PTX and PTX. In human plasma, o(LA)8-PTX is metabolized more slowly into o(LA)2-PTX, o(LA)1-PTX, and PTX. After IV injection of 10 mg/kg PTX-equiv of o(LA)8-PTX prodrug loaded PEG-b-PLA micelles in Sprague-Dawley rats, metabolite abundance in plasma follows the order: o(LA)1-PTX > o(LA)2-PTX > o(LA)4-PTX > o(LA)6-PTX. Bile metabolite profiles of the o(LA)8-PTX prodrug is similar to plasma metabolite profiles. In comparison to equivalent doses of Abraxane®, plasma PTX exposure is two orders of magnitude higher for Abraxane® than PTX from o(LA)8-PTX prodrug loaded PEG-b-PLA micelles, and plasma o(LA)1-PTX exposure is fivefold higher than PTX from Abraxane®, demonstrating heightened plasma metabolite exposure for enhanced antitumor efficacy.

Scanning Electron-Raman Cryomicroscopy for Characterization of Nanoparticle-Albumin Drug Products.

Nanomaterials have expanded the use of active pharmaceutical ingredients by improving efficacy, decreasing toxicity, and facilitating targeted delivery. To systematically achieve this goal, nanomaterial-containing drugs need to be manufactured with precision in attributes such as size, morphology, surface chemistry, and composition. Their physicochemical characterization is essential as their attributes govern pharmacokinetics yet can be challenging due to the nature of many nanomaterial-based formulations unless advanced sample fixation and in vitro characterization methods are utilized. Here, different cryogenic and other fixation strategies were assessed, and a novel physicochemical characterization method was developed using scanning electron Raman cryo-microscopy (SERCM). A complex nanoparticle albumin bound paclitaxel (nab-paclitaxel) formulation was chosen as a model drug. Plunge freezing (PF), high pressure freezing (HPF), freeze substitution (FS), and membrane filtration were compared for their influence on size and morphology measurements, and formulation-based variations were quantified. SERCM was introduced as a multiattribute physicochemical characterization platform, and the composition of nanoparticles was confirmed as albumin-paclitaxel complexes. By coupling image-based quantitative analysis with chemical analysis, SERCM has the potential to pave the way for the development of comprehensive tools for assessing injectable and ophthalmic nanomaterial-containing drugs in their native-like state.

Paclitaxel-loaded liposome-incorporated chitosan (core)/poly(ε-caprolactone)/chitosan (shell) nanofibers for the treatment of breast cancer.

Liposomes and nanofibers have been introduced as effective drug delivery systems of anticancer drugs. The performance of chitosan (core)/poly(ε-caprolactone) (PCL)/paclitaxel simple nanofibers, chitosan/paclitaxel (core)/PCL/chitosan (shell) nanofibers and paclitaxel-loaded liposome-incorporated chitosan (core)/PCL-chitosan (shell) nanofibers was investigated for the controlled release of paclitaxel and the treatment of breast cancer. The synthesized formulations were characterized using polydispersity index, dynamic light scattering, zeta potential, scanning electron microscopy, transmission electron microscopy, and Fourier transform infrared analysis. The sustained release of paclitaxel from liposome-loaded nanofibers was achieved within 30 days. The release data was best described using Korsmeyer-Peppas pharmacokinetic model. The cell viabilities of synthesized nanofibrous samples were higher than 98 % ± 1 % toward L929 normal cells after 168 h. The maximum cytotoxicity against MCF-7 breast cancer cells was 85 % ± 2.5 % using liposome-loaded core-shell nanofibers. The in vivo results indicated the reduction of tumor weight from 1.35 ± 0.15 g to 0.65 ± 0.05 g using liposome-loaded core-shell nanofibers and its increasing from 1.35 ± 0.15 g to 3.2 ± 0.2 g using pure core-shell nanofibers. The three-stage drug release behavior of paclitaxel-loaded liposome-incorporated core-shell nanofibers and the high in vivo tumor efficiency suggested the development of these formulations for cancer treatment in the future.

Exploring paclitaxel-loaded adenosine-conjugated PEGylated PLGA nanoparticles for targeting triple-negative breast cancer.

In present investigation, we developed paclitaxel (PTX)-loaded adenosine (ADN)-conjugated PLGA nanoparticles for combating triple-negative breast cancer (TNBC), where ADN acts as a substrate for adenosine receptors (AR) that are overexpressed in TNBC. Using synthesized PLGA-PEG-ADN, PTX-loaded nanoparticles (PTX ADN-PEG-PLGA NPs) were prepared via emulsion diffusion evaporation process that rendered particles of size 135 ± 12 nm, PDI of 0.119 ± 0.03, and entrapment-efficiency of 79.26 ± 2.52%. The NPs showed higher %cumulative release at pH 5.5 over 7.4 with Higuchi release kinetics. The PTX ADN-PEG-PLGA NPs showed ~ 4.87- and 5.22-fold decrease in %hemolysis in comparison to free PTX and Intaxel®, indicating their hemocompatible nature. The ADN modification assisted cytoplasmic internalization of particles via AR-mediated endocytosis that resulted in ~ 3.77- and 3.51-fold reduction in IC50 and showed apoptosis index of 0.93 and 1.18 in MDA-MB-231 and 4T1 cells respectively. The pharmacokinetic profile of ADN-PEG-PLGA NPs revealed higher AUC and t1/2 than Intaxel® and Nanoxel® pharmacodynamic activity showed ~ 18.90-fold lower %tumor burden than control. The kidney and liver function biomarkers showed insignificant change in the levels, when treated with PTX ADN-PEG-PLGA NPs and exhibited no histological alterations in the liver, spleen, and kidney. Overall, the optimized particles were found to be biocompatible with improved anti-TNBC activity.

Bioinspired Nanocomplexes Comprising Phenolic Acid Derivative and Human Serum Albumin for Cancer Therapy.

Inspired by the natural phenomenon of phenolic-protein interactions, we translate this "naturally evolved interaction" to a "phenolic acid derivative based albumin bound" technology, through the synthesis of phenolic acid derivatives comprising a therapeutic cargo linked to a phenolic motif. Phenolic acid derivatives can bind to albumin and form nanocomplexes after microfluidic mixing. This strategy has been successfully applied to different types of anticancer drugs, including taxanes, anthraquinones, etoposides, and terpenoids. Paclitaxel was selected as a model drug for an in-depth study. Three novel paclitaxel-phenolic acid conjugates have been synthesized. Molecular dynamics simulations provide insights into the self-assembled mechanisms of phenolic-protein nanocomplexes. The nanocomplexes show improved pharmacokinetics, elevated tolerability, decreased neurotoxicity, and enhanced anticancer efficacies in multiple murine xenograft models of breast cancer, in comparison with two clinically approved formulations, Taxol (polyoxyethylated castor oil-formulated paclitaxel) and Abraxane (nab-paclitaxel). Such a robust system provides a broadly applicable platform for the development of albumin-based nanomedicines and has great potential for clinical translation.

Dual-targeted enzyme-sensitive hyaluronic acid nanogels loading paclitaxel for the therapy of breast cancer.

In this study, a CD44 and biotin receptors dual-targeted enzyme-sensitive hyaluronic acid nanogel loading paclitaxel (PTX/Bio-NG) for targeting breast cancer was constructed. Spherical nanogels with a mean particle size of 149.1 ± 1.6 nm, higher entrapment efficiency (90.17 ± 0.52 %) and drug loading (15.28 ± 0.10 %) were obtained. PTX/Bio-NG quickly released drugs under the catalysis of hyaluronidase and/or lipase. Cell studies revealed that the uptake of Bio-NG by 4T1 cells was mediated by CD44 receptor and Bio-specific receptor. Compared with PTX-loaded biotin-free NG (PTX/NG), PTX/Bio-NG had higher cytotoxicity against breast cancer cells (4T1 cells). The rats pharmacokinetic profile indicated higher AUC0-t but lower clearance rates of PTX/NG (6.24 times and 15.96 %, respectively) and PTX/Bio-NG (6.66 times and 14.89 %, respectively) than control group (Taxol). In vivo studies showed that PTX/Bio-NG possessed excellent therapeutic efficacy in 4T1 tumor-bearing Balb/c mice, which suggest that PTX/Bio-NG could be an excellent candidate for the treatment of breast cancer.

Paclitaxel-Loaded TPGS2k/Gelatin-Grafted Cyclodextrin/Hyaluronic Acid-Grafted Cyclodextrin Nanoparticles for Oral Bioavailability and Targeting Enhancement.

The clinical applications of paclitaxel (PTX), a natural compound with broad-spectrum antitumor effects, have been markedly limited owing to its poor oral bioavailability and lack of targeting ability. Recently, several drug carriers, such as TPGS2k, gelatin (Gel), cyclodextrin (CD), and hyaluronic acid (HA), have been identified as promising enhancers of drug efficacy. Therefore, Gel-grafted CD (GEL-CD) and HA-grafted CD (HA-CD) were synthesized via grafting, and PTX-loaded TPGS2k/GEL-CD/HA-CD nanoparticles (TGHC-PTX-NPs) were successfully prepared using the ultrasonic crushing method. The mean particles size, polydispersity index, and Zeta potential of TGHC-PTX-NPs were 253.57 ± 2.64 nm, 0.13 ± 0.03, and 0.087 ± 0.005 mV, respectively. TGHC-PTX-NPs with an encapsulation efficiency of 61.77 ± 0.47% and a loading capacity of 6.86 ± 0.32% appeared round and uniformly dispersed based on transmission electron microscopy. In vitro release data revealed that TGHC-PTX-NPs had good sustained-release properties. Further, TGHC-PTX-NPs had increased the targeted uptake by HeLa cells as HA can specifically bind to the CD44 receptor at the cell surface, and its intestinal absorption is related to caveolin-mediated endocytosis. The pharmacokinetic results indicated that TGHC-PTX-NPs significantly enhanced the absorption of PTX in vivo compared to the PTX suspension, with a relative bioavailability of 227.21%. Such findings indicate the potential of TGHC-PTX-NPs for numerous clinical applications.

Validated HPLC-UV Method for Simultaneous Estimation of Paclitaxel and Doxorubicin Employing Ion Pair Chromatography: Application in Formulation Development and Pharmacokinetic Studies.

Though paclitaxel (PTX) and doxorubicin (DOX) are amongst the most widely used and investigated drug pair for combination chemotherapy but surprisingly, not a single validated HPLC-UV method is available to analyze PTX and DOX simultaneously. So, herein a HPLC-UV method is developed and validated for the same, filling an indispensable gap in the literature. As these two moieties have characteristically different polarities, resolving them under the common chromatographic conditions is a challenging task. Herein, the principle of ion pair chromatography is utilized to resolve these two moieties on a C18 column employing an isocratic mobile phase comprised of acetonitrile and octane sulfonic acid buffer (67 : 37) and detected simultaneously at 231 nm using a UV detector only. The retention time is 4.4 and 7.2 min for PTX and DOX, respectively, with a total analysis time of less than 10 minutes, suitable for the formulation development and research, while LOQ is less than 0.066 µg/ml for both the drugs, suitable for the therapeutic drug monitoring at preclinical and clinical research setup. To substantiate the applicability of the developed method, a nanoformulation coloaded with PTX and DOX was designed and analyzed using the developed protocol. The method is also applied successfully to study the plasma kinetic profile of both the moieties simultaneously in Balb/c mice. Further, the method is validated as per the ICH guidelines fulfilling the unmet need of a validated analytical tool to simultaneously estimate PTX and DOX. Moreover, the results suggest that the principal of common ion chromatography demonstrated here can also be applied further for the simultaneous chromatographic separation of other polar and nonpolar moieties too. Consequently, the reported method surely will advance the toolset required for the precision-based combination chemotherapy.

Improved Core Viscosity Achieved by PDLLA10kCo-Incorporation Promoted Drug Loading and Stability of mPEG2k-b-PDLLA2.4k Micelles.

PURPOSE: This study aims to investigate the effect of poly(D, L-lactic acid)10K (PDLLA10K) incorporation on the drug loading and stability of poly(ethylene glycol)2K-block-poly(D, L-lactide)2.4K (mPEG2k-b-PDLLA2.4k) micelles. In addition, a suitable lyophilization protector was screened for this micelle to obtain favorable lyophilized products. METHODS: The incorporation ratios of PDLLA10k were screened based on the particle size and drug loading. The dynamic stability, core viscosity, drug release, stability in albumin, and in vivo pharmacokinetic characteristics of PDLLA10k incorporated micelles were compared with the original micelles. In addition, the particle size variation was used as an indicator to screen the most suitable lyophilization protectant for the micelles. DSC, FTIR, XRD were used to illustrate the mechanism of the lyophilized protectants. RESULTS: After the incorporation of 5 wt% PDLLA10K, the maximum loading of mPEG2k-b-PDLLA2.4k micelles for TM-2 was increased from 26 wt% to 32 wt%, and the in vivo half-life was increased by 2.25-fold. Various stability of micelles was improved. Also, the micelles with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) as lyophilization protectants had minimal variation in particle size. CONCLUSIONS: PDLLA10k incorporation can be employed as a strategy to increase the stability of mPEG2k-b-PDLLA2.4k micelles, which can be attributed to the viscosity building effect. HP-ß-CD can be used as an effective lyophilization protectant since mPEG and HP-ß-CD form the pseudopolyrotaxanesque inclusion complexes.

Limited Impact of Murine Placental MDR1 on Fetal Exposure of Certain Drugs Explained by Bypass Transfer Between Adjacent Syncytiotrophoblast Layers.

PURPOSE: Multidrug resistance protein 1 (MDR1) is located at the interface between two syncytiotrophoblast layers in rodent placenta, and may influence fetal drug distribution. Here, we quantitatively compare the functional impact per single MDR1 molecule of MDR1 at the placental barrier and blood-brain barrier in mice. METHODS: MDR1A and MDR1B proteins were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Paclitaxel or digoxin was continuously administered to pregnant Mdr1a-/-/Mdr1b-/- or wild-type mice, and the drug concentrations in the maternal and fetal plasma and maternal brain were quantified by LC-MS/MS. RESULTS: MDR1A and MDR1B proteins are expressed in the membrane of mouse placental labyrinth, and total MDR1 at the placental barrier amounts to about 30% of that at the blood-brain barrier. The fetal-to-maternal plasma concentration ratio of digoxin was only marginally affected in Mdr1a-/-/Mdr1b-/- mice, while that of paclitaxel showed a several-fold increase. No such difference between the two drugs was found in the maternal brain distribution. The impact per single MDR1 molecule on the fetal distribution of digoxin was calculated to be much lower than that on the brain distribution, but this was not the case for paclitaxel. Our pharmacokinetic model indicates that the impact of placental MDR1 is inversely correlated to the ratio of permeability through gap junctions connecting the two syncytiotrophoblast layers to passive diffusion permeability. CONCLUSION: Our findings indicate that murine placental MDR1 has a minimal influence on the fetal concentration of certain substrates, such as digoxin, due to bypass transfer, probably via connexin26 gap junctions.

GSH-responsive poly-resveratrol based nanoparticles for effective drug delivery and reversing multidrug resistance.

Cancer poses a serious threat to human health and is the most common cause of human death. Polymer-based nanomedicines are presently used to enhance the treatment effectiveness and decrease the systemic toxicity of chemotherapeutic agents. However, the disadvantage of currently polymeric carriers is without therapy procedure. Herein, for the first time, glutathione (GSH)-responsive polymer (PRES) with anti-cancer effect was synthesized following the condensation-polymerization method using resveratrol (RES) and 3,3'-dithiodipropionic acid. PRES can not only suppress the tumor cells growth but can also self-assemble into nanoparticles (∼93 nm) for delivering antitumor drugs, such as paclitaxel (PTX@PRES NPs). The system could achieve high drug loading (∼7%) and overcome multidrug resistance (MDR). The results from the in vitro studies revealed that the NPs formed of PRES were stable in the systemic circulation, while could be efficiently degraded in tumor cells high GSH environment. Results from cytotoxicity tests confirmed that PTX@PRES NPs could effectively suppress the growth of cancer cells (A549) and drug-resistant cells (A549/PTX). The NPs could also be used to significantly increase the therapeutic efficacy of the drugs in A549/PTX tumor-bearing mice. In vivo investigations also demonstrated that the PRES-based NPs exhibited tumor inhibition effects. In summary, we report that the GSH-responsive polymer synthesized by us exhibited multiple interesting functions and could be used for effective drug delivery. The polymer exhibited good therapeutic effects and could be used to overcome MDR. Thus, the synthesized system can be used to develop a new strategy for treating cancer.

Phase I study of weekly nab-paclitaxel plus carboplatin and concurrent thoracic radiotherapy in elderly patients with unresectable locally advanced non-small cell lung cancer.

Few clinical studies have been designed for elderly patients with locally advanced non-small cell lung cancer (NSCLC). We conducted a phase I study to evaluate the tolerability of carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy in elderly patients with locally advanced NSCLC. The eligibility criteria were: unresectable stage III NSCLC, performance status 0 or 1, and age ≥ 75 years. Eligible patients received 6 weeks of weekly carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy with a total dose of 64 Gy in 32 fractions. Carboplatin was fixed to an area under the plasma concentration time curve (AUC) of 2 mg/mL/min, and the recommended dose of nab-paclitaxel was evaluated using a dose-escalation study (30 or 40 mg/m2). Tolerability at the recommended dose was evaluated in an expansion study. Nineteen patients were enrolled at four institutions, all of whom were eligible and assessable. The recommended nab-paclitaxel dose was set at 30 mg/m2 because two patients experienced dose-limiting toxicity at 40 mg/m2. The treatment completion rate of the 17 patients analyzed at the recommended dose was 100% (80% confidence interval (CI), 83.8-100%). The overall response rate was 76.5%, and the median progression free survival was 13.4 months (95% CI, 4.2-21.4 months). Common grade 3 and 4 toxicities included leukopenia (23.5%), neutropenia (17.6%), anemia (5.9%), and infection (5.9%). One treatment-related death due to pneumonitis was observed six months after the end of the study. In conclusion, carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy show good tolerability and exhibit promising efficacy in elderly patients with locally advanced NSCLC. This trial was registered with the Japan Registry of Clinical Trials on March 11, 2019 (trial no. jRCTs042180077).