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%.

Drug-loaded polymer-coated silver nanoparticles for lung cancer theranostics.

Lung cancer is the leading cause of death in cancer across the globe. To minimize these deaths, the replacement of traditional chemotherapy with novel strategies is significant. We have developed a nanotheranostic approach using silver nanoparticles for imaging and treatment. Silver nanoparticles (AgNPs) are fabricated by chemical reduction method. The formulation of AgNPs was confirmed by different characterization techniques like stability test, UV-Visible spectroscopy, Confocal Raman Spectroscopy, and Energy-Dispersive X-ray analysis. Further, AgNPs are coated with poly lactic-co-glycolic acid (PLGA) and then loaded with paclitaxel (Pac). Then the drug-loaded PLGA-coated AgNPs were characterized for size and zeta potential measurement by zetasizer, surface morphology study by atomic force microscopy, Fourier transform infrared spectroscopy, and release kinetics study. The imaging and anticancer properties of these nanoformulations are investigated using lung cancer cell lines. The results proved that the particles are in the nanometer range with smooth surface morphology. Moreover, the drug-loaded NPs showed a sustained release of the drug for a longer period of time. Further the formulations showed imaging property with greater anticancer efficacy. Thus, the results suggest the effective use of these nanoformulation in both lung cancer imaging and treatment using a simple and efficient approach.

A convenient protonated strategy for constructing nanodrugs from hydrophobic drug-inhibitor conjugates to reverse tumor multidrug resistance.

Combination therapy has proven effective in counteracting tumor multidrug resistance (MDR). However, the pharmacokinetic differences among various drugs and inherent water insolubility for most small molecule agents greatly hinder their synergistic effects, which makes the delivery of drugs for combination therapy in vivo a key problem. Herein, we propose a protonated strategy to transform a water-insoluble small molecule drug-inhibitor conjugate into an amphiphilic one, which then self-assembles into nanoparticles for co-delivery in vivo to overcome tumor MDR. Specifically, paclitaxel (PTX) is first coupled with a third-generation P-glycoprotein (P-gp) inhibitor zosuquidar (Zos) through a glutathione (GSH)-responsive disulfide bond to produce a hydrophobic drug-inhibitor conjugate (PTX-ss-Zos). Subsequently treated with hydrochloric acid ethanol solution (HCl/EtOH), PTX-ss-Zos is transformed into the amphiphilic protonated precursor and then forms nanoparticles (PTX-ss-Zos@HCl NPs) in water by molecular self-assembly. PTX-ss-Zos@HCl NPs can be administered intravenously and accumulated specifically at tumor sites. Once internalized by cancer cells, PTX-ss-Zos@HCl NPs can be degraded under the overexpressed GSH to release PTX and Zos simultaneously, which synergistically reverse tumor MDR and inhibit tumor growth. This offers a promising strategy to develop small molecule self-assembled nanoagents to reverse tumor MDR in combination therapy.

Polymeric liposomes targeting dual transporters for highly efficient oral delivery of paclitaxel.

A novel delivery system comprising N-succinic anhydride (N-SAA) and D-fructose co-conjugated chitosan (NSCF)-modified polymeric liposomes (NSCF-PLip) were designed to enhance oral delivery of paclitaxel (PTX) by targeting monocarboxylate transporters (MCT) and glucose transporters (GLUT). The synthesized NSCF was characterised by FT-IR and 1H NMR spectra. The prepared 30.78 % (degree of substitution of N-SAA) NSCF-PTX-PLip were approximately 150 nm in size, with a regular spherical shape, the zeta potential of -25.4 ± 5.13 mv, drug loading of 2.35 % ± 0.05 %, and pH-sensitive and slow-release characteristics. Compared with PTX-Lip, 30.78 % NSCF-PTX-PLip significantly enhanced Caco-2 cellular uptake via co-mediation of MCT and GLUT, showing relatively specific binding of propionic acid and MCT. Notably, the NSCF modification of PTX-Lip had no appreciable influence on their original cellular uptake pathway. The fructose modification of 30.78 % NSC-PTX-PLip significantly increased the concentration after tmax, indicating their continuous and efficient absorption. Compared with PTX-Lip, the 30.78 % NSCF-PTX-PLip resulted in a 2.09-fold extension of MRT, and a 6.06-fold increase of oral bioavailability. It significantly increased tumour drug distribution and tumour growth inhibition rate. These findings confirm that 30.78 % NSCF-PLip offer a potential oral delivery platform for PTX and targeting the dual transporters of MCT and GLUT is an effective strategy for enhancing the intestinal absorption of drugs.

Lipid-coated nanocrystals of paclitaxel as dry powder for inhalation: Characterization, in-vitro performance, and pharmacokinetic assessment.

BACKGROUND: Nanocrystals can be produced as a dry powder for inhalation (DPIs) to deliver high doses of drug to the lungs, owing to their high payload and stability to the shear stress of aerosolization force. Furthermore, lipid-coated nanocrystals can be formulated to improve the drug accumulation and retention in lung. OBJECTIVE: The present work involved the fabrication of paclitaxel nanocrystals using hydrophilic marine biopolymer fucoidan as a stabilizer. Thereafter, fabricated nanocrystals (FPNC) were surface-modified with phospholipid to give lipid-coated nanocrystals (Lipo-NCs). METHODS: The nanocrystals were fabricated by antisolvent crystallization followed by the probe sonication. The lipid coating was achieved by thin film hydration followed ultrasonic dispersion technique. Prepared nanocrystals were lyophilized to obtain a dry powder of FPNC and Lipo-NCs, used later for physicochemical, microscopic, and spectroscopic characterization to confirm the successful formation of desired nanocrystals. In-vitro and in-vivo investigations were also conducted to determine the role of nanocrystal powder in pulmonary drug delivery. RESULTS: Lipo-NCs exhibited slower drug release, excellent flow properties, good aerosolization performance, higher drug distribution, and prolonged retention in the lungs compared to FPNC and pure PTX. CONCLUSION: Lipid-coated nanocrystals can be a novel formulation for the maximum localization of drugs in the lungs, thereby enhancing therapeutic effects and avoiding systemic side effects in lung cancer therapy.

Light emitting diode (LED) irradiation of liposomes enhances drug encapsulation and delivery for improved cancer eradication.

Liposomes are widely used as drug delivery nanoplatforms because of their versatility and biocompatibility; however, their ability to load certain drugs may be suboptimal. In this study, we generated liposomes using a combination of DSPE and DSPE-PEG-2 k lipids and loaded them with doxorubicin (DOX) and paclitaxel (PTX), to investigate the effects of light emitting diode (LED) irradiation on liposome structure and drug loading efficiency. Scanning and transmission electron microscopy revealed that the surface of liposomes irradiated with blue or near-infrared LEDs (LsLipo) was rougher and more irregular than that of non-LED-irradiated liposomes (NsLipo). Nuclear magnetic resonance analysis showed that the hydrogen peak originating from the lipid head groups was lower in LsLipo than in NsLipo preparations, indicating that LED irradiation changed the chemical and physical properties of the liposome. Structural changes, such as reduced rigidity, induced by LED irradiation, increased the loading efficiency of DOX and PTX. In vitro and in vivo experiments showed that LsLipo were more effective at inhibiting the growth of cancer cells than NsLipo. Our findings suggest that LED irradiation enhances the drug delivery efficacy of liposomes and offer new possibilities for improving drug delivery systems.

Development of Aerosol Dry Powder Chemotherapeutic-Loaded Microparticles for the Treatment of Lung Cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide, resulting in the highest mortality rates among both men and women with respect to all other types of cancer. Difficulties in treating lung cancer arise from late-stage diagnoses and tumor heterogeneity and current treatment involves a combination of chemotherapeutics, surgery, and radiation. Chemotherapeutics administered systemically can lead to undesirable side effects and severe off-site toxicity. For example, chronic administration of the chemotherapeutic doxorubicin (DOX) leads to cardiotoxicity, thereby limiting its long-term use. Systemic administration of the highly lipophilic molecule paclitaxel (PTX) is hindered by its water solubility, necessitating the use of solubilizing agents, which can induce side effects. Thus, in this investigation, formulations consisting of spray-dried microparticles (MP) containing DOX and PTX were produced to be administered as dry powder aerosols directly to the lungs. Acetalated dextran (Ac-Dex) was used as the polymer in these formulations, as it is a biocompatible and biodegradable polymer that exhibits pH-responsive degradation. Solid-state characterization revealed that DOX and PTX remained in solubility favoring amorphous states in the MP formulations and that both drugs remained thermally stable throughout the spray drying process. In vitro release studies demonstrated the pH sensitivity of the formulations due to the use of Ac-Dex, as well as the release of both therapeutics over the course of at least 48 h. In vitro aerosol dispersion studies demonstrated that both formulations exhibited suitable aerosol dispersion properties for deep lung delivery.

Novel ligand decorated theranostic zein nanoparticles coloaded with paclitaxel and carbon quantum dots: formulation and optimization.

Aim: The present research focused on development and optimization of ligand decorated theranostic nanocarrier encapsulating paclitaxel and carbon quantum dots (CQDs). Methods: CQDs were prepared by microwave-assisted pyrolysis and were characterized for particle size and fluorescence behavior. Ligand decorated zein nanoparticles, coloaded with paclitaxel and CQDs, were formulated using a one-step nanoprecipitation method and optimized for various process parameters. Results: Particle size for coated and uncoated nanoparticles was 90.16 ± 1.65 and 179.26 ± 3.61 nm, respectively, and entrapment efficiency was >80%. The circular dichroism spectroscopy showed zein retained its secondary structure and release study showed biphasic release behavior. Conclusion: The prepared theranostic nanocarrier showed optimal fluorescence and desired release behavior without altering the secondary structure of zein.

AIE luminogen labeled polymeric micelles for biological imaging and chemotherapy.

In this study, an amphiphilic polymer FA-CS-DBA-CHO with aggregation-induced emission (AIE) feature was prepared by introducing 4-(diphenylamino)benzaldehyde derivative (DBA-CHO), imine bond and folic acid (FA) to the molecular structure of chitosan (CS). The amphiphilicity drove the polymer to self-assemble into micelles, and paclitaxel (PTX) could be solubilized in the hydrophobic core. Due to the excellent AIE effect, FA-CS-DBA-CHO exhibited strong cellular imaging capability. The pH-sensitive imine bond in the polymer allowed for accurate drug release in acidic environment. Both in vitro and in vivo studies demonstrated that the PTX-loaded FA-CS-DBA-CHO micelles could significantly inhibit the growth of tumor cells but without any notable toxicity. This micellar system was excellent carrier for bioimaging and chemotherapeutic drug delivery.

Folate receptor-mediated delivery system based on chitosan coated polymeric nanoparticles for combination therapy of breast cancer.

Combination therapy using two or more drugs with different mechanisms of action is an effective strategy for treating cancer. This is because of the synergistic effect of complementary drugs that enhances their effectiveness. However, this approach has some limitations, such as non-specific distribution of the drugs in the tumor and the occurrence of dose-dependent toxicity to healthy tissues. To overcome these issues, we have developed a folate receptor-mediated co-delivery system that improves the access of chemotherapy drugs to the tumor site. We prepared a nanoplatform by encapsulating paclitaxel (PTX) and curcumin (CUR) in poly(caprolactone)-poly(ethylene glycol)-poly(caprolactone) (PCL-PEG-PCL) co-polymer using a double emulsion method and coating nanoparticles with pH-responsive chitosan-folic acid (CS-FA) conjugate. The nanocarrier's physicochemical properties were studied, confirming successful preparation with appropriate size and morphology. PTX and CUR could be released synchronously in a controlled and acid-facilitated manner. The dual drug-loaded nanocarrier exhibited excellent anti-tumor efficiency in MDA-MB-231 cells in vitro. The active targeting effect of FA concluded from the high inhibitory effect of dual drug-loaded nanocarrier on MDA-MB-231 cells, which have overexpressed folate receptors on their surface, compared to Human umbilical vein endothelial cells (HUVEC). Overall, the nanoengineered folate receptor-mediated co-delivery system provides great potential for safe and effective cancer therapy.

Electrospun polydioxanone/fucoidan blend nanofibers loaded with anti-cancer precipitate from Jaspis diastra and paclitaxel: Physico-chemical characterization and in-vitro screening.

Nanofibers for drug delivery systems have gained much attention during the past years. This paper describes for the first time the loading of a bioactive precipitate (JAD) from the marine sponge Jaspis diastra in PDX and fucoidan-PDX. JAD was characterized by LC-MS/MS and the major component was jaspamide (1) with a purity of 62.66 %. The cytotoxicity of JAD was compared with paclitaxel (PTX). JAD and PTX displayed IC50 values of 1.10 ± 0.7 µg/mL and 0.21 ± 0.12 µg/mL on skin fibroblasts L929 cells whilst their IC50 values on uveal MP41 cancer cells, were 2.10 ± 0.55 µg/mL and 1.38 ± 0.68 µg/mL, respectively. JAD was found to be less cytotoxic to healthy fibroblasts compared to PTX. JAD and PTX loaded scaffolds showed sustained release over 96 h in physiological medium which is likely to reduce the secondary cytotoxic effect induced by JAD and PTX alone. The physico-chemical properties of the loaded and unloaded scaffolds together with their degradation and action on tumor microenvironment by using L929 and MP41 cells were investigated. JAD and PTX at a concentration of 0.5 % (drug/polymer, w/w) in the electrospun mats prevented growth and proliferation of L929 and MP41 cells. Co-culture of L929 and MP41 showed that the JAD and PTX loaded mats inhibited the growth of both cells and caused cell death.

Paclitaxel and its semi-synthetic derivatives: comprehensive insights into chemical structure, mechanisms of action, and anticancer properties.

Cancer is a disease that can cause abnormal cell growth and can spread throughout the body. It is among the most significant causes of death worldwide, resulting in approx. 10 million deaths annually. Many synthetic anticancer drugs are available, but they often come with side effects and can interact negatively with other medications. Additionally, many chemotherapy drugs used for cancer treatment can develop resistance and harm normal cells, leading to dose-limiting side effects. As a result, finding effective cancer treatments and developing new drugs remains a significant challenge. However, plants are a potent source of natural products with the potential for cancer treatment. These biologically active compounds may be the basis for enhanced or less toxic derivatives. Herbal medicines/phytomedicines, or plant-based drugs, are becoming more popular in treating complicated diseases like cancer due to their effectiveness and are a particularly attractive option due to their affordability, availability, and lack of serious side effects. They have broad applicability and therapeutic efficacy, which has spurred scientific research into their potential as anticancer agents. This review focuses on Paclitaxel (PTX), a plant-based drug derived from Taxus sp., and its ability to treat specific tumors. PTX and its derivatives are effective against various cancer cell lines. Researchers can use this detailed information to develop effective and affordable treatments for cancer.

Engineering of surface-modified CuBTC-MXene nanocarrier for adsorption and co-loading of curcumin/paclitaxel from aqueous solutions for synergistic multi-therapy of cancer.

Two-dimensional (2D) nanomaterials can improve drug delivery by reducing toxicity, increasing bioavailability and boosting efficacy. In this study, the simultaneous use of transition metal carbides and nitrides (MXenes) along with copper (II) benzene-1, 3, 5-tricarboxylate metal-organic framework (Cu - BTC/MOF) as attractive nanocarriers are investigated for loading and delivering curcumin (CUR) and paclitaxel (PTX) drugs to cancer cells. The efficiency of surface termination (bare and oxygen) in the adsorption of PTX and CUR drugs and the co-loading of these two drugs are evaluated. Our results show that the strongest interaction energy belongs to the adsorption of drug CUR on the MXNNO-Cu-BTC adsorbent, while the interaction of PTX drug with the MXNO- Cu-BTC in the MXNO-Cu-BTC/PTX&CUR system is the lowest due to the particular structure of the drug and the adsorbent. Our results show that at the beginning simulation, the interaction energy between the PTX drug and water in PTX/MXN system is -4645.48 kJ/mol, which reduces to -3848.71 kJ/mol after the system reaches equilibrium. Therefore, the inspected adsorbents have a good performance in adsorbing CUR and PTX drugs. The obtained results from this investigation provide valuable information about experimental studies by medical scientists in the future.Communicated by Ramaswamy H. Sarma.

A novel electrospun nanofiber system with PEGylated paclitaxel nanocrystals enhancing the transmucus permeability and in situ retention for an efficient cervicovaginal cancer therapy.

Overcoming the vaginal barrier to achieve sufficient drug penetration and retention is a huge obstacle for drug delivery in chemotherapeutics for cervical cancer. In this study, we investigate the feasibility of a novel composite nanocrystal/nanofiber system for improving the transmucus penetration and, thus, enhancing retention and drug delivery to the lesion of a cervicovaginal tumor. Herein, paclitaxel (PTX) was sequentially formulated in the form of nanocrystals, coated with polydopamine (PDA), and modified with PEG. The nanocrystals (NCs@PDA-PEG) were creatively fabricated to create a composite nanofibrous membrane (NCs@PDA-PEG NFs) by using an electrospinning technique. The morphology, size distribution, drug loading, encapsulation efficiency, X-ray powder diffraction (XRD), Fourier transform infrared (FTIR) spectra, in vitro release, in vivo vaginal retention, apoptosis index, anti-tumor efficacy in a murine cervicovaginal tumor model, and local irritation were characterized. The NCs@PDA-PEG were formulated in a cube-like shape with an average size of 385.6 ± 35.47 nm; they were dispersed in electrospun nanofibers, and the drug loading was 7.94 %. The XRD curves indicated that the phase state of PTX changed after the creation of the nanocrystals. The FTIR spectra showed that the drug and the excipients were compatible with each other. In vitro delivery showed that the dissolution of PTX in the electrospun nanofibers was significantly faster than that when using bulk PTX. Compared with the PTX NC NFs, the NC@PDA-PEG NFs exhibited prolonged vaginal residence, superior transmucus penetration, minimal mucosal irritation, and significant tumor inhibition efficacy after the intravaginal administration of the NFs in tumor-bearing mice. In conclusion, by acting as novel pharmaceutical repositories, NCs@PDA-PEG NFs can be promising candidates for non-invasive local treatment, leading to efficient tumor inhibition in cervicovaginal cancer.

Bovine serum albumin and folic acid-modified aurum nanoparticles loaded with paclitaxel and curcumin enhance radiotherapy sensitization for esophageal cancer.

BACKGROUND: Nanocarrier systems have been used in the study of esophageal cancer (EC) and other diseases, with significant advantages in improving the non-targeted and nonspecific toxicity of traditional formulations. Some chemotherapeutic drugs and high atomic number nanomaterials have sensitization effects on ionizing radiation and can be used as chemoradiation sensitizers. METHODS: Aurum (Au) nanoparticles were modified by bovine serum albumin (BSA) and folic acid (FA), and were core-loaded with paclitaxel (PTX) and curcumin (CUR). The basic characteristics of FA-BSA-Au@PTX/CUR nanomedicines were evaluated by transmission electron microscopy, Fourier transform infrared spectroscopy, and Malvern Zetasizer. The encapsulation and release of drugs were monitored by ultraviolet-visible spectrophotometry (UV-Vis). The biological toxicity and radiotherapy sensitization effect of FA-BSA-Au@PTX/CUR were observed by cell viability, colony formation, cell apoptosis, cell cycle distribution, and γ-H2AX analysis experiments. RESULTS: The prepared nanomedicines showed good stability and spherical morphology. The results of cell uptake and cell viability detection revealed that FA-BSA-Au@PTX/CUR could specifically target EC cell KYSE150 and exert a certain inhibitory effect on proliferation, with no obvious toxicity on healthy cells Het-1A. In addition, the results of the colony formation experiment, cell apoptosis detection, cell cycle distribution, and γ-H2AX analysis showed that compared with X-rays alone, FA-BSA-Au@PTX/CUR combined with X-rays exhibited relatively stronger radiotherapy sensitization and anti-tumor activity. CONCLUSIONS: FA-BSA-Au@PTX/CUR could target EC cancer cells and act as a safe and effective radiotherapy sensitizer to improve the radiotherapy efficacy of EC.

Enhancing Targeted Therapy in Hepatocellular Carcinoma through a pH-Responsive Delivery System: Folic Acid-Modified Polydopamine-Paclitaxel-Loaded Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) Nanoparticles.

Currently, there is an inherent contradiction between the multifunctionality and excellent biocompatibility of anticancer drug nanocarriers, which limits their application. Therefore, to overcome this limitation, we aimed to develop a biocompatible drug delivery system for the treatment of hepatocellular carcinoma (HCC). In this study, we employed poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) as the fundamental framework of the nanocarrier and utilized the emulsion solvent evaporation method to fabricate nanoparticles loaded with paclitaxel (PTX), known as PTX-PHBV NPs. To enhance the tumor-targeting capability, a dopamine self-polymerization strategy was employed to form a pH-sensitive coating on the surface of the nanoparticles. Then, folic acid (FA)-targeting HCC was conjugated to the nanoparticles with a polydopamine (PDA) coating by using the Michael addition reaction, resulting in the formation of HCC-targeted nanoparticles (PTX-PHBV@PDA-FA NPs). The PTX-PHBV@PDA-FA NPs were characterized and analyzed by using dynamic light scattering, scanning electron microscopy, fourier-transform infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. Encouragingly, PTX-PHBV@PDA-FA NPs exhibited remarkable anticancer efficacy in an HCC xenograft mouse model. Furthermore, compared to raw PTX, PTX-PHBV@PDA-FA NPs showed less toxicity in vivo. In conclusion, these results demonstrate the potential of PTX-PHBV@PDA-FA NPs for HCC treatment and biocompatibility.

Suicide gene delivery by morphology-adaptable enantiomeric peptide assemblies for combined ovarian cancer therapy.

Suicide gene therapy is a promising therapeutic model for ovarian cancer (OC), while suffering from poor gene delivery and limited therapeutic efficacy. To address this concern, here we reported the GSH-responsive morphology-transformable enantiomeric peptide assemblies as delivering vehicles for suicide genes and co-delivery of paclitaxel (PTX). Connecting a lipid-like amphiphile and a hydrophilic arginine segment through disulfide bonds led to the enantiomeric peptides. The enantiomeric peptide assemblies are able to simultaneously uptake plasmid DNA (pDNA) and PTX based on electrostatic and hydrophobic interactions. The resulting co-assemblies underwent GSH-responsive disulfide cleavage and thereby promoting their assembly from nanoparticles to nanofibers, leading to the co-release of pDNA and PTX. Cellular and animal studies confirmed the co-delivery of pDNA and PTX into OC cells and the cell apoptosis by the enantiomeric peptides. In addition, in vitro and in vivo experiments supported the advanced uptake and cytotoxicity for L-type peptide vehicles by OC cells, and their great potential for OC-imaging, growth-inhibition and apoptosis-induction compared to D-counterpart. Our results demonstrate that the GSH-responsive morphology-transformable chiral peptide assemblies accurately and simultaneously release suicide genes and chemodrugs at tumor sites, thus providing a new strategy for the development of delivering vehicles for suicide gene and establishment of new therapeutic models for ovarian cancer. STATEMENT OF SIGNIFICANCE: Appropriate delivery carriers are essential for the clinical translation of cancer gene therapy, including the emerging suicide gene therapy. By combining the advantages of morphological transformable vehicles with the chirality peptides towards their bioactivity, we developed the GSH-responsive morphology-transformable enantiomeric peptide assemblies as delivering vehicles for suicide genes and co-delivery of paclitaxel. The GSH-responsive assembly of the enantiomeric peptides allows for precise release of plasmid DNA and paclitaxel in cancer cells, and promotes the formation of nanofibrils that facilitate gene entering nuclei for transfection. The enantiomeric peptide-based vehicles show the chirality-dependent capability for inducing cell apoptosis and inhibiting tumor growth. Our findings demonstrate a new strategy for developing therapeutic models for ovarian cancer.

In Silico Investigation on the Molecular Behavior and Structural Stability of the Rosette Nanotubes as the Drug Vehicles for Paclitaxel, an Anti-Cancer Drug.

Most anticancer drugs affect healthy cells in addition to cancer cells, causing severe side effects. Targeted delivery by nano-based drug delivery systems (NDDS) can reduce these severe side effects while maintaining therapeutic efficacy. This work introduced rosette nanotube (RNT) as a potential drug vehicle for paclitaxel (PTX) due to its self-assembling property, biocompatibility, amphiphilicity, and low toxicity. Molecular dynamics (MD) simulations aided with molecular mechanics Poisson Boltzmann surface area (MMPBSA) analysis are used here to investigate the molecular behavior and the loading energetics of each type of RNT (K1, xK1, and iEt-xK1) with PTX. Analysis showed that the most probable configuration of PTX is on either end of each RNT. The binding free energies (-117.74 to -69.29 kJ/mol) when PTX is closer to one end were stronger than when it is in the inner channel (-53.51 to -40.88 kJ/mol). The latter alludes to the encapsulation of the PTX by each RNT. Thus, loading is possible by encapsulation during the self-assembly process given the favorable estimated binding free energies. Based on the results, RNT has potential as a drug vehicle for PTX, which warrants further investigation.

Total Synthesis of Taxol Enabled by Intermolecular Radical Coupling and Pd-Catalyzed Cyclization.

Taxol (1) is a clinically used antineoplastic diterpenoid. The tetracyclic ring system comprises a 6/8/6-membered carbocycle (ABC-ring) and a fused oxetane ring (D-ring) embedded with a bridgehead double bond and decorated with multiple oxygen functionalities. Here, we report a convergent total synthesis of this exceedingly complex natural product. The C-ring fragment was designed to possess a bromocyclohexenone and an extra tetrahydrofuran ring to control the reactivity and selectivity, as well as to minimize functional group manipulations en route to 1. The α-alkoxyacyl telluride of the A-ring served as a radical precursor, and intermolecular radical coupling with the C-ring realized the installation of the C2- and C3-stereocenters and reductive removal of the bromide. After the C8-quaternary stereocenter was constructed by exploiting the three-dimensional shape of the intermediate, the C11-vinyl triflate of A-ring and the C8-methyl ketone of C-ring were utilized for Pd(0)-catalyzed cyclization of the central eight-membered B-ring with the bridgehead olefin. Adjustment of the oxidation level and attachment of the oxetane D-ring completed the total synthesis of 1 (28 steps, as the longest linear sequence). The fragment design principle and implementation of the powerful radical coupling reaction described in the present synthesis provide valuable information for planning and executing syntheses of diverse densely oxygenated terpenoids.

Thermo- and pH-responsive targeted lipid-coated mesoporous nano silica platform for dual delivery of paclitaxel and gemcitabine to overcome HER2-positive breast cancer.

In the current study, a new monoclonal antibody conjugated dual stimuli lipid-coated mesoporous silica nanoparticles (L-MSNs) platform was developed and investigated for specific co-delivery of the paclitaxel (PTX) and gemcitabine (Gem) to cancer cells and preventing their side effects during the treatment process. First, MSNs were synthesized and then coated with as-prepared pH-, and thermo-sensitive niosomes to produce L-MSNs. For this aim, Dipalmitoylphosphatidylcholine (DPPC) was used to create thermo-sensitivity, and 1, 2-Distearoyl-sn-glycerol-3-phosphoethanolamine -Citraconic Anhydride-Polyethylene Glycol (DSPE-CA-PEG) polymers were prepared and incorporated to the lipid layer for creation of pH-sensitivity. In the next step, trastuzumab as a monoclonal antibody (mAb) was conjugated to the maleimide groups of the 1, 2-Distearoyl-sn-glycerol-3-phosphoethanolamine DSPE-polyethylene glycol (PEG)-maleimide agents in the lipid bilayer via a disulfide bond. Dynamic light scattering (DLS) and zeta potential measurements, Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Brunauer-Emmett-Teller (BET), and scanning electron microscopy (SEM) analyses were utilized to characterize the synthesized particles before and after surface modification. The encapsulation efficiency (EE%) and loading efficiency (LE%) of the particles were also evaluated. Additionally, the drug release study and MTT assay were done to evaluate the bioactivity potential of the fabricated platforms. The results of DLS and zeta potential measurements revealed an average size of 200 nm and a neutral zeta potential of about -1 mV for mAb-L-MSNs. Also, the FTIR spectra confirmed the formation of mAb-L-MSNs. Moreover, SEM analysis showed spherical-shaped MSNs with amorphous structure confirmed by XRD analysis, and BET test revealed âˆ¼ 820 m2/g specific surface area and pore about 5 nm in size. The values of EE% and LE% of PTX were 90.3 % and 26.7 %, while these values for GEM were 89.5 % and 38.8 % in the co-loaded form, respectively. The thermo-pH-sensitivity examination showed approximately 500 nm of size increase after the change of pH and temperature from 7.4 and 37˚C to 5 and 42˚C. The release profile showed a pH-, and thermo-dependence manner, which led to about 89 % and 95 % of PTX and GEM released from the co-loaded platform at a pH of 5 and 42 °C while these values were 31.1 % and 32.2 % at pH of 7.4 and 37˚C, respectively. MTT assay data presented that when the mAb-L-co-loaded-MSNs platform containing 250 µg/mL drug was used, about 92 % of cells died in human epidermal receptors (HER2)-positive breast cancer cells (SKBR3), while just about 4 % of HER2-negative normal cells were killed. However, the growth inhibition rate of SKBR3 cells was caused by empty-mAb-L-MSNs, pure PTX and GEM combination were 9 % and 87 %, respectively. Moreover, the half inhibitory concentration (IC50) of the pure PTX, pure GEM, and mAb-coloaded-L-MSNs were 33, 17.6, and 6.5 µg/mL. The synergic effect of co-encapsulation of PTX and GEM in addition to trastuzumab conjugated L-MSNs was confirmed by a combinational index (CI) of 0.34. Therefore, this strategy leads to specific targeted drug delivery to cancer cells using a key-lock interaction between the trastuzumab and HER-2 receptors on the cancer cell membrane which stimuli the endocytosis of the particles to the cells followed by the destruction of the lipid layer in the acidic pH and the temperature of the lysosome, leading to enhanced release of PTX and GEM (pH of 5 and 42˚C). So, this platform can be considered a suitable carrier for cancer treatment.