Sialic Acid Engineered Prodrug Nanoparticles for Codelivery of Bortezomib and Selenium in Tumor Bearing Mice.

Most cancer patients rarely benefit from monodrug therapy because of both cancer complexity and tumor environment. One of the main reasons for this failure is insufficient accumulation of the optimal dose at the tumorous site. Our investigation implies a promising strategy to engineer prodrug nanoparticles (NPs) of bortezomib (BTZ) and selenium (Se) using sialic acid (SAL) as a ligand to improve breast cancer therapy. BTZ was conjugated with SAL and HPMA (N-2-hydroxypropyl methacrylamide) to prepare a prodrug conjugate; BTZ-SAL-HPMA (BSAL-HP) and then fabricated into prodrug NPs with Se (Se_BSAL-HP prodrug NPs). The self-assembly of prodrug NPs functionalized with Se showed size (204.13 ± 0.02 nm) and zeta potential (-31.0 ± 0.11 mV) in dynamic light scattering (DLS) experiments and spherical shape in TEM and SEM analysis. Good stability and low pH drug release profile were characterized by Se_BSAL-HP prodrug NPs. The tumor-selective boronate-ester-based prodrug NPs of BTZ in combination with Se endowed a synergistic effect against cancer cells. Compared to prodrug conjugate, Se_BSAL-HP prodrug NPs exhibited higher cell cytotoxicity and enhanced cellular internalization with significant changes in mitochondria membrane potential (MMP). Elevated apoptosis was observed in the (G2/M) phase of the cell cycle for Se_BSAL-HP prodrug NPs (2.7-fold) higher than BTZ. In vivo studies were performed on Sprague-Dawley rats and resulted in positive trends. The increased therapeutic activity of Se_BSAL-HP prodrug NPs inhibited primary tumor growth and showed 43.05 fold decrease in tumor volume than the control in 4T1 tumor bearing mice. The surprising and remarkable outcomes for Se_BSAL-HP prodrug NPs were probably due to the ROS triggering effect of boronate ester and selenium given together.

Lipid-Based Nanocarriers in the Treatment of Glioblastoma Multiforme (GBM): Challenges and Opportunities.

Glioblastoma multiforme (also known as glioblastoma; GBM) is one of the most malignant types of brain tumors that occurs in the CNS. Treatment strategies for glioblastoma are majorly comprised of surgical resection, radiotherapy, and chemotherapy along with combination therapy. Treatment of GBM is itself a tedious task but the involved barriers in GBM are one of the main impediments to move one step closer to the treatment of GBM. Basically, two of the barriers are of utmost importance in this regard, namely blood brain barrier (BBB) and blood brain tumor barrier (BBTB). This review will address different challenges and barriers in the treatment of GBM along with their etiology. The role and recent progress of lipid-based nanocarriers like liposomes, solid lipid nanocarriers (SLNs), nanostructured lipid carriers (NLCs), lipoplexes, and lipid hybrid carriers in the effective management of GBM will be discussed in detail.

Exploration of hemocompatibility and intratumoral accumulation of paclitaxel after loco-regional administration of thermoresponsive hydrogel composed of poloxamer and xanthan gum: An application to dose-dense chemotherapy.

Although paclitaxel is a front-line chemotherapeutic agent for the treatment of metastatic breast cancer, its intravenous therapy produces deleterious adverse effects. In an attempt to address the issue, the present study aimed to develop a paclitaxel loaded thermosensitive/thermoresponsive hydrogel (PTXNp-TGel) for loco-regional administration to breast tumors to provide dose-dense chemotherapy. Poloxamer and xanthan gum were used to prepare TGel by the cold method. In vitro and in vivo performance of PTXNp-TGel was compared with TGel, pure drug loaded TGel (PTX-TGel) and marketed formulation, Taxol®. The formulated PTXNp-TGel showed acceptable gelation temperature and time (37 °C and 57 s), lower viscosity at room temperature and higher viscosity at body temperature to support sol-gel transition with increasing temperature, and sustained drug release up to 21 days. Additionally, PTXNp-TGel showed negligible hemolytic toxicity as compared to PTX-TGel and Taxol®. Intratumoral administration of PTXNp-TGel produced significantly higher antitumor activity as indicated by lowest relative tumor volume (1.50) and relative antitumor proliferation rate (27.71 %) in comparison with PTX-TGel, Taxol®, and PTXNp (p < 0.05). Finally, insignificant body weight loss during the experimental period, lack of hematotoxicity, nephrotoxicity, and hepatotoxicity imply improved therapeutic performance of the locally administrated dose-dense therapy of PTXNp-TGel as compared to Taxol®.

N-2-Hydroxypropylmethacrylamide-Polycaprolactone Polymeric Micelles in Co-delivery of Proteasome Inhibitor and Polyphenol: Exploration of Synergism or Antagonism.

Breast cancer leads to the highest mortality among women resulting in a major clinical burden. Multidrug therapy is more efficient in such patients compared to monodrug therapy. Simultaneous combinatorial or co-delivery garnered significant interest in the past years. Caffeic acid (CFA) (a natural polyphenol) has received growing attention because of its anticarcinogenic and antioxidant potential. Bortezomib (BTZ) is a proteasome inhibitor and may be explored for treating breast cancer. Despite its high anticancer activity, the low water solubility and chemical instability restrict its efficacy against solid tumors. In the present study, we designed and investigated a HP-PCL (N-2-hydroxypropylmethacrylamide-polycaprolactone) polymeric micellar (PMCs) system for the simultaneous delivery of BTZ and CFA in the treatment of breast cancer. The designed BTZ+CFA-HP-PCL PMCs were fabricated, optimized, and characterized for size, zeta potential, surface morphology, and in vitro drug release. Developed nanosized (174.6 ± 0.24 nm) PMCs showed enhanced cellular internalization and cell cytotoxicity in both MCF-7 and MDA-MB-231 cells. ROS (reactive oxygen species) levels were highest in BTZ-HP-PCL PMCs, while CFA-HP-PCL PMCs significantly (p < 0.001) scavenged the ROS generated in 2',7'-dichlorofluorescein diacetate (DCFH-DA) assay. The mitochondrial membrane potential (MMP) assay revealed intense and significant green fluorescence in both types of cancer cells when treated with BTZ-HP-PCL PMCs (p < 0.001) indicating apoptosis or cell death. The pharmacokinetic studies revealed that BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs exhibited the highest bioavailability, enhanced plasma half-life, decreased volume of distribution, and lower clearance rate than the pure combination of drugs. In the organ biodistribution studies, the combination of BTZ+CFA showed higher distribution in the spleen and the heart. Overall findings of in vitro studies surprisingly resulted in better therapeutic efficiency of BTZ-HP-PCL PMCs than BTZ+CFA-HP-PCL PMCs. However, the in vivo tumor growth inhibition study performed in tumor-induced mice concluded that the tumor growth was inhibited by both BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs (p < 0.0001) more efficiently than pure BTZ and the combination (BTZ+CFA), which may be due to the conversion of boronate ester into boronic acid. Henceforth, the combination of BTZ and CFA provides further indications to be explored in the future to support the hypothesis that BTZ may work with polyphenol (CFA) in the acidic environment of the tumor.

Theranostic Applications of Nanomaterials in the Field of Cardiovascular Diseases.

A large percentage of people are being exposed to mortality due to cardiovascular diseases. Convention approaches have not provided satisfactory outcomes in the management of these diseases. To overcome the limitations of conventional approaches, nanomaterials like nanoparticles, nanotubes, micelles, lipid-based nanocarriers, dendrimers, and carbon-based nanoformulations represent the new aspect of diagnosis and treatment of cardiovascular diseases. The unique inherent properties of the nanomaterials are the major reasons for their rapidly growing demand in the field of medicine. Profound knowledge in the field of nanotechnology and biomedicine is needed for the notable translation of nanomaterials into theranostic cardiovascular applications. In this review, the authors have summarized different nanomaterials which are being extensively used to diagnose and treat the diseases, such as coronary heart disease, myocardial infarction, atherosclerosis, stroke and thrombosis.

Bifunctional Microwave-Assisted Molybdenum-Complex Carbon Sponge Production for Supercapacitor and Water-Splitting Applications.

The synthesis of dual-function molybdenum (Mo)-complex carbonous sponges is reported for elucidating their utilization as positive and negative electrodes in electrochemical devices and their applicability to the active oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) in electrocatalytic devices. Molybdenum (Mo)-coordinated polyvinyl alcohol gel is converted into a porous Mo-complex nitrogen-rich carbonous sponge (MNCS) via microwave and low-temperature-annealing processes as a positive electrode. This MNCS was further thermally treated at a higher temperature to prepare a more carbonized Mo-complex N-doped carbon sponge (cMNCS) as a negative electrode. Both sponges were lightweight and porous and exhibited excellent specific capacitances of 562 F g-1 as a positive MNCS electrode and 937 F g-1 as a negative cMNCS electrode. The asymmetric supercapacitor assembled using them reveals a power density of 887.5 W kg-1 at an energy density of 36 Wh kg-1, in addition to a retention rate of >95% after 5000 cycles. We furthermore demonstrate the electrocatalytic capabilities of these materials with overpotentials of -170 and -220 mV for the HER and 1.70 and 1.53 V for the OER at a current density of 10 mA cm-2 using a water-splitting electrocatalyzer.

Development and optimization of paclitaxel loaded Eudragit/PLGA nanoparticles by simplex lattice mixture design: Exploration of improved hemocompatibility and in vivo kinetics.

Anemia is the most common hematological abnormality of chemotherapy, which is responsible for poor clinical outcomes. To overcome this complication, the present study was aimed for developing a Eudragit/polylactic-co-glycolic acid (PLGA) based nanoparticulate system for a model drug paclitaxel (PTX). The study was planned using a simplex lattice mixture design. PTX nanoparticles (PTXNp) were evaluated in vitro for physicochemical properties, hemolytic effects and cytotoxic effects. Further, the nanoparticles were subjected to in vivo screening using rats for hemocompatibility, pharmacokinetic profile, and biodistribution to the vital organs. The PTXNps were 65.77-214.73 nm in size, showed more than 60% sustained drug release in 360 h and caused less than 8% hemolysis. The parameters like red blood cell count, activated partial thromboplastin time (aPTT), prothrombin time (PT) and C3 complement were similar to the negative control. Cytotoxicity results suggested that all the PTXNp demonstrated drug concentration-dependent cytotoxicity. The in vivo pharmacokinetic study concluded that PTXNp formulations had significantly higher blood AUC (93.194.55-163,071.15 h*ng/mL), longer half-lives (5.80-6.35 h) and extended mean residence times (6.05-8.54 h) in comparison to PTX solution (p < 0.05). Overall, the study provides a nanoparticulate drug delivery system to deliver PTX safely and effectively along with reducing the associated hematological adverse effects.

PEGylated Dendrimer Mediated Delivery of Bortezomib: Drug Conjugation versus Encapsulation.

Poor aqueous solubility of anticancer drug bortezomib (BTZ) still remains a major challenge in the development of a successful formulation. The dendrimeric platform can provide a better opportunity to deliver BTZ with improved solubility. BTZ encapsulated in PEGylated PAMAM dendrimers (BTZ-PEG-PAMAM) was characterized and evaluated comparatively with encapsulated and conjugated dendritic formulations. The particle size of BTZ-PEG-PAMAM was 188.6 ± 4.17 nm, with entrapment efficiency of 78.61 ± 2.91% and drug loading of 39.30 ± 1.98%. The aqueous solubility of BTZ in PAMAM-PEG conjugate was enhanced by 68.11 folds in comparison to pure drug. In vitro drug release profile was found to be sustained up to 72 h. A comparative colorimetric MTT assay against A549 and MCF-7 cancer cells resulted in maximum efficacy from BTZ-PEG-PAMAM with IC50 value 333.14 ± 15.42 and 152.60 ± 24.56 nM, respectively. Significantly higher cellular internalization was observed in FITC tagged BTZ-PEG-PAMAM. In vivo pharmacokinetic study performed on Sprague Dawley rats resulted in 8.63 folds increase in bioavailability for BTZ-PEG-PAMAM than pure drug. Pharmacokinetic parameters of BTZ-PEG-PAMAM were better and improved over BTZ and other dendritic formulations. In conclusion, the prepared formulation of BTZ-PEG-PAMAM has given significant outcome and this strategy may be further explored for better delivery of BTZ in future.

Biotinylated HPMA centered polymeric nanoparticles for Bortezomib delivery.

Bortezomib (BTZ) is a proteasome inhibitor as approved by US FDA for the treatment of multiple myeloma. It exhibits significant anti-cancer properties, against solid tumors; but lacks aqueous solubility, chemical stability which hinders its successful formulation development. The present study is an attempt to deliver BTZ using N-(2-hydroxypropyl) methacrylamide (HPMA) based copolymeric conjugates and biotinylated PNPs in an effective manner. Study describes a systematic synthetic pathway to synthesize functional polymeric conjugates such as HPMA-Biotin (HP-BT) HPMA-Polylactic acid (HPLA) and HPMA-PLA-Biotin (HPLA-BT) followed by exhaustive characterization both spectroscopically and microscopically. Our strategy yielded polymeric nanoparticles (PNPs) of narrow size range of 199.7 ± 1.32 nm. Release studies were performed at pH 7.4 and 5.6. PNPs were 2-folds less hemolytic (p < 0.0001) than pure drug. BTZ loaded PNPs of HPLA-BT demonstrated significant anti-cancer activity against MCF-7 cells. IC50 value of these PNPs was 56.06 ± 0.12 nM, which was approximately two folds less than BTZ (p < 0.0001). Cellular uptake study confirmed that higher uptake of formulations might be an outcome of biotin surface tethering characteristics that enhanced selectivity and targeting of formulations efficiently. In vivo pharmacokinetics evidenced increased bioavailability (AUC0 t-∞) of DL-HPLA-BT PNPs (drug loaded) than BTZ with an improved half-life. Overall the developed PNPs led to the improved and effective BTZ delivery.

Sb2S3 Nanoparticles Anchored or Encapsulated by the Sulfur-Doped Carbon Sheet for High-Performance Supercapacitors.

The specific capacitance and energy density of antimony trisulfide (Sb2S3)@carbon supercapacitors (SCs) have been limited and are in need of significant improvement. In this work, Sb2S3 nanoparticles were selectively encapsulated or anchored in a sulfur-doped carbon (S-carbon) sheet depending on the use of microwave-assisted synthesis. The microwave-triggered Sb2S3 nanoparticle growth resulted in core-shell hierarchical spherical particles of uniform diameter assembled with Sb2S3 as the core and an encapsulated S-carbon layer as the shell (Sb2S3-M@S-C). Without the microwave mediation, the other nanostructure was found to comprise fine Sb2S3 nanoparticles widely anchored in the S-carbon sheet (Sb2S3-P@S-C). Structural and morphological analyses confirmed the presence of encapsulated and anchored Sb2S3 nanoparticles in the carbon. These two materials exhibited higher specific capacitance values of 1179 (0 to +1.0 V) and 1380 F·g-1 (-0.8 to 0 V) at a current density of 1 A·g-1, respectively, than those previously reported for Sb2S3 nanomaterials in considerable SCs. Furthermore, both materials exhibited outstanding reversible capacitance and cycle stability when used as SC electrodes while retaining over 98% of the capacitance after 10 000 cycles, which indicates their long-term stability. Furthermore, a hybrid Sb2S3-M@S-C/Sb2S3-P@S-C device was designed, which delivers a remarkable energy density of 49 W·h·kg-1 at a power density of 2.5 kW·kg-1 with long-term cycle stability (94% over 10 000 cycles) and is comparable to SCs in the recent literature. Finally, a light-emitting diode (LED) panel comprising 32 LEDs was powered using three pencil-type hybrid SCs in series.

Asymmetric faradaic assembly of Bi2O3 and MnO2 for a high-performance hybrid electrochemical energy storage device.

In the current study, we have explored the coupling of Bi2O3 negative electrode and MnO2 positive electrode materials as an asymmetric faradaic assembly for a high-performance hybrid electrochemical energy storage device (HEESD). Aiming at a low-cost device, both the electrodes have been synthesized by a simple, scalable, and cost-effective chemical synthesis method. After their requisite structure-morphological confirmation and correlation, these electrodes were separately examined for their electrochemical performance in a three-electrode configuration. The results obtained confirm that Bi2O3 and MnO2 exhibit 910 C g-1 and 424 C g-1 specific capacity, respectively, at 2 A g-1 current density. Notably, the performance of both electrodes has been analyzed using Dunn's method to highlight the distinct nature of their faradaic properties. Afterwards, the asymmetric faradaic assembly of both electrodes, when assembled as a HEESD (MnO2//Bi2O3), delivered 411 C g-1 specific capacity at 1 A g-1 current density due to the inclusive contribution from the capacitive as well as the non-capacitive faradaic quotient. Consequently, the assembly offers an excellent energy density of 79 W h kg-1 at a power density of 702 W kg-1, with a magnificent retention of energy density up to 21.1 W h kg-1 at 14 339 W kg-1 power density. Moreover, it demonstrates long-term cycling stability at 10 A g-1, retaining 85.2% of its initial energy density after 5000 cycles, which is significant in comparison with the previously reported literature. Additionally, to check the performance of the device in real time, two HEESDs were connected in series to power a light-emitting diode. The results obtained provide significant insight into hybrid coupling, where two different faradaic electrodes can be combined in a synergistic combination for a high-performance HEESD.