Codelivery of anti-cancer agents via double-walled polymeric microparticles/injectable hydrogel: A promising approach for treatment of triple negative breast cancer.

Triple negative breast cancer (TNBC) is an aggressive sub-type of breast cancer that rarely responds to conventional chemotherapy. Therefore, novel agents or new routes need to be developed to improve treatment efficacy and diminish severe side-effects of anti-cancer agents in TNBC patients. This study explores a novel localized co-delivery platform with potential application against TNBC. Uniform core-shell microparticles encapsulating cisplatin (Cis-DDP) and paclitaxel (PTX) are fabricated using coaxial electrohydrodynamic atomization technique and subsequently are embedded into an injectable hydrogel. The hydrogel provides an additional diffusion barrier against Cis-DDP and confines premature release of drugs. In addition, the hydrogel can provide a versatile tool for retaining particles in the tumor resected cavity during the injection following debulking surgery and prevent surgical site infection due to its inherent antibacterial properties. The combination of Cis-DDP and PTX demonstrates a synergistic effect against MDA-MB-231 cell line assigned to three different mechanisms of action, including denaturation of DNA strands, stabilization of microtubules, and amplification of intracellular reactive oxygen species (ROS) and activation of caspase-3 pathways. The results show a significant accumulation of mitochondrial ROS insults in cells upon treatment that consequently causes programmed cells death. The performance of microparticles/hydrogel carrier is evaluated against three-dimensional MDA-MB-231 (breast cancer) 3D spheroids, where a superior efficacy and a greater reduction in spheroid growth are observed over 14 days, as compared with free-drug treatment. Overall, drug-loaded core-shell microparticles embedded into injectable hydrogel provides a promising strategy to treat aggressive cancers and a modular platform for a broad range of localized multidrug therapies customizable to the cancer type.

Effective co-delivery of nutlin-3a and p53 genes via core-shell microparticles for disruption of MDM2-p53 interaction and reactivation of p53 in hepatocellular carcinoma.

The tumor suppressor protein p53 is the most frequently inactivated, mutated, or deleted transcriptional factor in tumor cells. Recent studies have shown that the negative regulation of p53 by the murine double minute 2 (MDM2) protein in human cells interrupts the p53 apoptotic pathway and causes tumorigenesis. Therefore, the disruption of the MDM2-p53 complex by small molecules such as nutlin-3a and the administration of the active p53 protein can effectively restore the apoptotic activity of the p53 protein in tumor cells. This study aims to introduce a unique combined p53-based gene and chemotherapy approach using core-shell polymeric microparticles for the localized treatment of cancers. Core-shell microparticles were successfully fabricated in a single step using a modified electrohydrodynamic atomization (EHDA) technique, where the core and shell layers were loaded with nutlin-3a and ß-cyclodextrin-g-chitosan/p53 nanoparticles, respectively. The grafting of ß-cyclodextrin (ß-CD) onto chitosan chains demonstrated remarkable cellular uptake (∼5-fold) compared to pure chitosan at N/P = 6, attributed to a strong interaction and temporary disruption of the lipid bilayer in the cell membrane by the synthesized copolymer. The therapeutic efficiencies of single- and dual-agent loaded microparticle formulations were also evaluated and compared against free-drug treatment in terms of cell viability and intracellular expression of p53, caspase 3, and MDM2 proteins via an MTS assay, an enzyme-linked immunosorbent assay, and an immunostaining assay. The results revealed that the controlled and sustained release of both agents from the microparticles synergistically enhanced the anti-proliferative efficacy of the agents via the continuous overexpression of p53 and caspase 3 proteins over 5 days. However, MDM2 protein expression remained at the basal level over that period. The findings also indicated that nutlin-3a could impose excessive oxidative stress on cancer cells, where the overproduction of reactive oxygen species (ROS) with irreversible destructive effects on subcellular organelles such as the nucleus (DNA) and mitochondria could be considered as a secondary apoptotic pathway induced by nutlin-3a. Inspired by the observations, the proposed drug delivery system can serve as a unique and powerful drug and gene delivery system with a far-reaching application in human cancer therapy.

Double-Walled Microparticles-Embedded Self-Cross-Linked, Injectable, and Antibacterial Hydrogel for Controlled and Sustained Release of Chemotherapeutic Agents.

First-line cancer chemotherapy has been prescribed for patients suffered from cancers for many years. However, conventional chemotherapy provides a high parenteral dosage of anticancer drugs over a short period, which may cause serious toxicities and detrimental side effects in healthy tissues. This study aims to develop a new drug delivery system (DDS) composed of double-walled microparticles and an injectable hydrogel for localized dual-agent drug delivery to tumors. The uniform double-walled microparticles loaded with cisplatin (Cis-DDP) and paclitaxel (PTX) were fabricated via coaxial electrohydrodynamic atomization (CEHDA) technique and subsequently were embedded into injectable alginate-branched polyethylenimine. The findings show the uniqueness of CEHDA technique for simply swapping the place of drugs to achieve a parallel or a sequential release profile. This study also presents the simulation of CEHDA technique using computational fluid dynamics (CFD) that will help in the optimization of CEHDA's operating conditions prior to large-scale production of microparticles. The new synthetic hydrogel provides an additional diffusion barrier against Cis-DDP and confines premature release of drugs. In addition, the hydrogel can provide a versatile tool for retaining particles in the tumor resected cavity during the injection after debulking surgery and preventing surgical site infection due to its inherent antibacterial properties. Three-dimensional MDA-MB-231 (breast cancer) spheroid studies demonstrate a superior efficacy and a greater reduction in spheroid growth for drugs released from the proposed composite formulation over a prolonged period, as compared with free drug treatment. Overall, the new core-shell microparticles embedded into injectable hydrogel can serve as a flexible controlled release platform for modulating the release profiles of anticancer drugs and subsequently providing a superior anticancer response.

Synthesis of intracellular reduction-sensitive amphiphilic polyethyleneimine and poly(ε-caprolactone) graft copolymer for on-demand release of doxorubicin and p53 plasmid DNA.

UNLABELLED: This study aims to present a new intelligent polymeric nano-system used for combining chemotherapy with non-viral gene therapy against human cancers. An amphiphilic copolymer synthesized through the conjugation of low molecular weight polyethyleneimine (LMw-PEI) and poly(ε-caprolactone) (PCL) via a bio-cleavable disulfide linkage was successfully employed for the simultaneous delivery of drug and gene molecules into target cells. Compared to the conventional PCL copolymerization pathway, this paper represents a straightforward and efficient reaction pathway including the activation of PCL-diol hydroxyl end groups, cystamine attachment and LMw-PEI conjugation which are successfully performed at mild conditions as confirmed by FTIR and (1)H NMR. Thermal, morphological characteristics as well as biocompatibility of the copolymer were investigated. The copolymer showed great tendency to form positively charged nanoparticles (∼163.1nm, +35.3mV) with hydrophobic core and hydrophilic shell compartments implicating its potential for encapsulation of anti-cancer drug and plasmid DNA, respectively. The gel retardation assay confirmed that the nanoparticles could successfully inhibit the migration of pDNA at ∼5 nanoparticle/pDNAw/w. The in vitro cytotoxicity tests and LDH assay revealed that the cationic amphiphilic copolymer was essentially non-toxic in different carcinoma cell lines in contrast to branched PEI 25K. Moreover, the presence of redox sensitive disulfide linkages provided smart nanoparticles with on-demand release behavior in response to reducing agents such as cytoplasmic glutathione (GSH). Importantly, confocal microscopy images revealed that in contrast to free Dox, the nanoparticles were capable of faster internalizing into the cells and accumulating in the perinuclear region or even in the nucleus. Finally, the co-delivery of Dox and p53-pDNA using the copolymer displayed greater cytotoxic effect compared with the Dox-loaded nanoparticle counterpart as revealed by cell viability and Caspase 3 expression assay. These results suggest the copolymer as a promising candidate for the development of smart delivery systems. STATEMENT OF SIGNIFICANCE: We employed cystamine dihydrochloride as a disulfide linkage for the conjugation of PCL diol and low molecular weight PEI segments through a straightforward and efficient reaction pathway at mild conditions. The new copolymer was essentially non-toxic in different carcinoma cell lines and showed great tendency to form positively charged nanoparticles. Therefore, it can be utilized as a promising platform for simultaneous drug and gene delivery to aggressive cancers. The results of drug and gene co-delivery experiments confirmed the pivotal role of disulfide linkage on the controlled release of both drug and gene molecules in response to glutathione concentration gradient between extracellular and intracellular microenvironments. In addition, the co-delivery of doxorubicin and p53 plasmid DNA using the new copolymer displayed greater cytotoxic effect compared with single agent (i.e. Dox) loaded counterpart, which indicated the significance of rapid dissociation of therapeutic agents from the carrier for synergistic cytotoxic effects on cancer cells.

Unveiling TiNb2 O7 as an insertion anode for lithium ion capacitors with high energy and power density.

This is the first report of the utilization of TiNb2 O7 as an insertion-type anode in a lithium-ion hybrid electrochemical capacitor (Li-HEC) along with an activated carbon (AC) counter electrode derived from a coconut shell. A simple and scalable electrospinning technique is adopted to prepare one-dimensional TiNb2 O7 nanofibers that can be characterized by XRD with Rietveld refinement, SEM, and TEM. The lithium insertion properties of such electrospun TiNb2 O7 are evaluated in the half-cell configuration (Li/TiNb2 O7 ) and it is found that the reversible intercalation of lithium (≈3.45 mol) is feasible with good capacity retention characteristics. The Li-HEC is constructed with an optimized mass loading based on the electrochemical performance of both the TiNb2 O7 anode and AC counter electrode in nonaqueous media. The Li-HEC delivers very high energy and power densities of approximately 43 Wh kg(-1) and 3 kW kg(-1) , respectively. Furthermore, the AC/TiNb2 O7 Li-HEC delivers a good cyclability of 3000 cycles with about 84% of the initial value.