HER2 siRNA Facilitated Gene Silencing Coupled with Doxorubicin Delivery: A Dual Responsive Nanoplatform Abrogates Breast Cancer.

The present study investigated the concurrent delivery of antineoplastic drug, doxorubicin, and HER2 siRNA through a targeted theranostic metallic gold nanoparticle designed using polysaccharide, PSP001. The as-synthesized HsiRNA@PGD NPs were characterized in terms of structural, functional, physicochemical, and biological properties. HsiRNA@PGD NPs exposed adequate hydrodynamic size, considerable ζ potential, and excellent drug/siRNA loading and encapsulation efficiency. Meticulous exploration of the biocompatible dual-targeted nanoconjugate exhibited an appealing biocompatibility and pH-sensitive cargo release kinetics, indicating its safety for use in clinics. HsiRNA@PGD NPs deciphered competent cancer cell internalization, enhanced cytotoxicity mediated via the induction of apoptosis, and excellent downregulation of the overexpressing target HER2 gene. Further in vivo explorations in the SKBR3 xenograft breast tumor model revealed the appealing tumor reduction properties, selective accumulation in the tumor site followed by significant suppression of the HER2 gene which contributed to the exclusive abrogation of breast tumor mass by the HsiRNA@PGD NPs. Compared to free drugs or the monotherapy constructs, the dual delivery approach produced a synergistic suppression of breast tumors both in vitro and in vivo. Hence the drawings from these findings implicate that the as-synthesized HsiRNA@PGD NPs could offer a promising platform for chemo-RNAi combinational breast cancer therapy.

Electrospun polysaccharide scaffolds: wound healing and stem cell differentiation.

Irrespective of the labyrinth of fastidiously woven artificial scaffolds, the lack of biocompatibility hampers effective clinical translation, which is the definitive purpose of any biomedical system or device. Hence, the current exploration deals with the fabrication of scaffolds with enhanced bioactivities for wound healing. The methodology used for the fabrication of the scaffolds was electrospinning of the polysaccharide, which is isolated from tamarind seed kernel using the electrospinning process. To improve the antimicrobial activity of the scaffolds, in-house synthesized silver nanoparticles were added to the scaffolds. Wound healing and antimicrobial efficiency of the scaffolds were established in murine models. An insight into the wound healing mechanism was also analyzed using differentiation screening of stem cells grown on scaffolds. The results showed that newly synthesized scaffolds presented excellent wound healing ability along with antimicrobial activity. Furthermore, detailed toxicological evaluations through the histopathology and collagen staining wound sections, the probability of any off-target effects were also ruled out. Differentiation screening showed that adipogenesis was more prominent in cells attached to the scaffolds and markers of adipogenesis were strongly expressed in fluorescent microscopy. Thus we hope that the scaffolds mediate stem cell differentiation in wounds and promote a progressive healing response. Results thus obtained were encouraging and further studies need to embark on to establish the combined role in all aspects studied here.

A biocompatible glycol-capped nano-delivery system with stimuli-responsive drug release kinetics abrogates cancer cell survival.

An eco-friendly polysaccharide (PSP001) isolated from the fruit rind of Punica granatum is a biodegradable polymer with immunostimulatory and anticancer properties. PSP001 was employed for the stimuli-responsive targeted delivery of antineoplastic agent doxorubicin (Dox) by the fabrication of Dox-holding PSP nanoparticles (DPN). The galactose moieties of PSP001 were occupied as an effective tumor-targeted motif against the over-expressed asialoglycoprotein and galectin receptors of cancers. DPN followed a pH-sensitive cargo release kinetics, competent cancer cell internalization profile, and appealing biocompatibility towards peripheral red blood cells. The selective execution of caspase-mediated programmed cell death by the DPN on cancer cells was confirmed with multiple apoptosis studies. Extensive toxicity profiling on BALB/c mice rules out any palpable signs of abnormality with DPN administration while bare Dox produced vital signs of toxicity. Studies on syngraft solid tumor-bearing mice uncovered the tumor homing nature of DPN with the subsequent release of the entrapped drug which further translated in the direction of a significant reduction in the tumor payload and enhanced survival benefits, thus offering a robust approach towards endurable cancer management.

Emergence of Gold-Mesoporous Silica Hybrid Nanotheranostics: Dox-Encoded, Folate Targeted Chemotherapy with Modulation of SERS Fingerprinting for Apoptosis Toward Tumor Eradication.

Strategically fabricated theranostic nanocarrier delivery system is an unmet need in personalized medicine. Herein, this study reports a versatile folate receptor (FR) targeted nanoenvelope delivery system (TNEDS) fabricated with gold core silica shell followed by chitosan-folic acid conjugate surface functionalization by for precise loading of doxorubicin (Dox), resembled as Au@SiO2 -Dox-CS-FA. TNEDS possesses up to 90% Dox loading efficiency and internalized through endocytosis pathway leading to pH and redox-sensitive release kinetics. The superior FR-targeted cytotoxicity is evaluated by the nanocarrier in comparison with US Food and Drug Administration (FDA)-approved liposomal Dox conjugate, Lipodox. Moreover, TNEDS exhibits theranostic features through caspase-mediated apoptosis and envisages high surface plasmon resonance enabling the nanoconstruct as a promising surface enhanced Raman scattering (SERS) nanotag. Minuscule changes in the biochemical components inside cells exerted by the TNEDS along with the Dox release are evaluated explicitly in a time-dependent fashion using bimodal SERS/fluorescence nanoprobe. Finally, TNEDS displays superior antitumor response in FR-positive ascites as well as solid tumor syngraft mouse models. Therefore, this futuristic TNEDS is expected to be a potential alternative as a clinically relevant theranostic nanomedicine to effectively combat neoplasia.

Indole-coumarin-thiadiazole hybrids: An appraisal of their MCF-7 cell growth inhibition, apoptotic, antimetastatic and computational Bcl-2 binding potential.

Cancer therapeutic potential of thiadiazole hybrids incorporating pharmacologically active indole and coumarin moieties have not been explored much. In the current investigation, three new thiadiazole hybrids with spacers of varying lengths linking indole and thiadiazole units were synthesized and their structures were well-established using various spectroscopic techniques. 3-(1-(5-(3-(1H-indol-3-yl)propyl)-1,3,4-thiadiazol-2-ylimino)ethyl)-6-bromo-2H-chromen-2-one (IPTBC) exhibited dose-dependent cytotoxicity in breast adenocarcinoma (MCF-7) cells. The circumvention of apoptosis is a prominent hallmark of cancer and hence triggering apoptosis in specific cancer cells is one of the convenient and widely used approaches for the development of anticancer chemotherapeutics. The induction of apoptosis upon treatment with IPTBC was confirmed by multiple apoptosis assays like Acridine orange-ethidium bromide, Hoechst staining, TUNEL staining, and colorimetric quantification using APOPercentage™ Apoptosis assay. The apoptosis initialisation through the active involvement of caspases was confirmed by caspase profiling tests. The wound healing assay displayed an intense impairment in the motility of MCF-7 cells suggesting the anti-metastatic potential of IPTBC. The ability of IPTBC to inhibit the antiapoptotic Bcl-2 protein by acting as a small molecule BH3 mimetic was explored through docking simulation studies. Although auxiliary investigations are warranted with this promising thiadiazole hybrid IPTBC, the perspective anticancer potential through programmed cell death, anti-metastatic and probable Bcl-2 inhibitory action will enable its further exploration in oncology.

Galactoxyloglucan-doxorubicin nanoparticles exerts superior cytotoxic effects on cancer cells-A mechanistic and in silico approach.

Galactoxyloglucan (PST001), isolated from seed kernel of Tamarindus indica is a non-toxic immunostimlatory agent with selective cytotoxicity on cancer cells. Toxicity associated with the chemotherapeutic drug doxorubicin (Dox) is the major barrier in its clinical application. Stable, spherically shaped PST-Dox nanoparticles with an average size of 10nm were prepared via ionic gelation of Dox with PST001 which displayed a pH dependent cumulative Dox release kinetics. PST-Dox nanoparticles demonstrated cancer-specific enhanced cytotoxic effects than PST001 and Dox in cancer cells by enhanced cellular uptake of Dox through the induction of apoptosis, sparing normal cells and RBCs. Elucidation of molecular mechanism by whole genome microarray revealed down-regulation of tyrosine kinase oncogenic pathways as PST-Dox mode of action. An in silico model of PST-Dox was developed and computed the activity against topoisomerase IIß, human Abl kinase and protein tyrosine kinases. Computational studies further affirmed the findings of genomic and proteomic investigations with an increased interaction energy between PST-Dox complexes with target system than with Dox and PST001 alone. The important findings and profoundly restrained methodologies highlighted in the current study will accelerate the therapeutic potential of this nanoparticle formulation for substantial clinical studies and testing in several cancers. To conclude, PST-Dox nanoparticles represent a superior drug delivery nanosystem for the effective treatment of cancer even though detailed investigations are warranted.