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The evolving dynamics of drug resistance due to tumor heterogeneity often creates impediments to traditional therapies making it a challenging issue for cancer cure. Breast cancer often faces challenges of current therapeutic interventions owing to its multiple complexities and high drug resistivity， for example against drugs like trastuzumab and tamoxifen. Drug resistance in the majority of breast cancer is often aided by the overtly expressed P-glycoprotein (P-gp) that guides in the rapid drug efflux of chemotherapy drugs. Despite continuous endeavors and ground-breaking achievements in the pursuit of finding better cancer therapeutic avenues, drug resistance is still a menace to hold back. Among newer therapeutic approaches, the application of phytonutrients such as alkaloids to suppress P-gp activity in drug-resistant cancers has found an exciting niche in the arena of alternative cancer therapies. In this work, we would like to present a black pepper alkaloid derivative known as BioPerine-loaded chitosan (CS)-polyethylene glycol (PEG) coated polylactic acid (PLA) hybrid polymeric nanoparticle to improve the bioavailability of BioPerine and its therapeutic efficacy in suppressing P-gp expression in MDA-MB 453 breast cancer cell line. Our findings revealed that the CS-PEG-BioPerine-PLA nanoparticles demonstrated a smooth spherical morphology with an average size of 316 nm, with improved aqueous solubility, and provided sustained BioPerine release. The nanoparticles also enhanced in vitro cytotoxicity and downregulation of P-gp expression in MDA-MB 453 cells compared to the commercial inhibitor verapamil hydrochloride, thus promising a piece of exciting evidence for the development of BioPerine based nano-drug delivery system in combination with traditional therapies as a crucial approach to tackling multi-drug resistance in cancers., Graphical abstract Image, graphical abstract

Fluorographene (FG) ultra-thin films are directly grown on flexible and non-flexible insulating silicate substrates and are characterized in terms of their structural and electronic properties. FG ...

Cholesterol-rich arterial plaques characterize atherosclerosis, a significant cause of heart disease. Nutraceuticals have received attention over the years, demonstrating potential benefits towards treating and preventing cardiovascular diseases (CVD), including atherosclerosis. Curcumin, a potent polyphenol present in Curcuma longa, has shown remarkable anti-atherosclerotic activity via anti-inflammatory and anti-oxidative properties. The bioavailability and low water solubility of curcumin limit its clinical translational purposes. These issues can be circumvented effectively by nano-drug delivery systems that can target atherosclerotic plaque sites. In this work, we chose to use curcumin and a natural bioenhancer called Bioperine (derived from Piper nigrum) inside a polymeric nano-drug delivery system for targeting atherosclerotic plaque sites. We selected two different ratios of curcumin:Bioperine to study its comparative effect on the inhibition of oxidized low-density lipoprotein (Ox-LDL)-induced foam cell formation. Our studies demonstrated that Cur-Bio PLGA NPs (both ratios) maintained the cell viability in THP-1 monocyte-derived macrophages above 80% at all periods. The 1:0.2:10 ratio of Cur-Bio PLGA NPs at a concentration of 250 μg/mL illustrated an enhanced reduction in the relative cholesterol content in the THP-1-derived foam cells compared to the 1:1:10 ratio. Confocal microscopy analysis also revealed a reduction in macrophage-mediated foam cell formation when administered with both the ratios of Cur-Bio PLGA NPs. Relative fold change in the mRNA expression of the genes involved in the inflammatory pathways in the atherosclerotic process downregulated NF-κB, CCL2/MCP-1, CD-36, and STAT-3 activity while upregulating the SCAR-B1 expression when treated with the Cur-Bio PLGA NPs. This study thus highlights the importance of natural-based compounds towards the therapeutic intervention against atherosclerotic activity when administered as preventive medicine.

Magnetic analogue of an isolated free electric charge, i.e., a magnet with a single north or south pole, is a long sought-after particle which remains elusive so far. In magnetically frustrated pyrochlore solids, a classical analogue of monopole was observed as a result of excitation of spin ice vertices. Direct visualization of such excitations were proposed and later confirmed in analogous artificial spin ice (ASI) systems of square as well as Kagome geometries. However, such magnetically charged vertices are randomly created as they are thermally driven and are always associated with corresponding equal and opposite emergent charges, often termed as monopole–antimonopole pairs, connected by observable strings. Here, we demonstrate a controlled stabilisation of a robust isolated emergent monopole-like magnetically charged vertices in individual square ASI systems by application of an external magnetic field. The excitation conserves the magnetic charge without the involvement of a corresponding excitation of opposite charge. Well supported by Monte Carlo simulations our experimental results enable, in absence of a true elemental magnetic monopole, creation of electron vortices and studying electrodynamics in presence of a monopole-like field in a solid state environment.

Substrates that can be utilized to assist in expression of the inherent characteristics of cells under in vitro conditions are necessary to mimic the in vivo scenario to the maximum extent possible. We demonstrate the application of functionalized carbon nanowalls (CNW) in facilitating human endothelial cell attachment and proliferation. The CNW films were grown on silicon substrates by surface-wave microwave plasma-enhanced chemical vapor deposition (SWMWPECVD) technique. These CNW were then functionalized using nitrogen (N

Malignant brain tumors remain a major cause of concern and mortality as successful treatment is hindered due to the poor transport and low penetration of chemotherapeutics across the blood-brain barrier (BBB). In this study, a nano formulation composed of chlorotoxin (CTX)-conjugated morusin loaded PLGA nanoparticles (PLGA-MOR-CTX) was devised against Glioblastoma Multiforme (GBM) and its anti-proliferative effects were evaluated in vitro. The synthesized nanoparticles were loaded with morusin, a naturally derived chemotherapeutic drug, and surface conjugated with CTX, a peptide derived from scorpion venom, highly specific for chloride channels (CIC-3) expressed in glioma tumor cells, as well as for matrix metalloproteinase (MMP-2), which is up regulated in the tumor microenvironment. Subsequently, the anti-cancer potential of the NPs was assessed in U87 and GI-1 (human glioblastoma) cells. Antiproliferative, cell apoptosis, and other cell-based assays demonstrated that the PLGA-MOR-CTX NPs resulted in enhanced inhibitory effects on U87 and GI-1 glioma cells. Prominent cytotoxicity parameters such as ROS generation, enhanced caspase activity, cytoskeletal destabilization, and inhibition of MMP-activity were observed in glioblastoma cells upon PLGA-MOR-CTX NP treatment. The cytocompatibility observed with normal human neuronal cells (HCN-1A) and the enhanced lethal effects in glioblastoma cells highlight the potential of PLGA-MOR-CTX nanoparticles as promising therapeutic nanocarriers towards GBM.

Atherosclerosis is Caesar’s sword, which poses a huge risk to the present generation. Understanding the atherosclerotic disease cycle would allow ensuring improved diagnosis, better care, and treatment. Unfortunately, a highly effective and safe way of treating atherosclerosis in the medical community remains a continuous challenge. Conventional treatments have shown considerable success, but have some adverse effects on the human body. Natural derived medications or nutraceuticals have gained immense popularity in the treatment of atherosclerosis due to their decreased side effects and toxicity-related issues. In hindsight, the contribution of nutraceuticals in imparting enhanced clinical efficacy against atherosclerosis warrants more experimental evidence. On the other hand, nanotechnology and drug delivery systems (DDS) have revolutionized the way therapeutics are performed and researchers have been constantly exploring the positive effects that DDS brings to the field of therapeutic techniques. It could be as exciting as ever to apply nano-mediated delivery of nutraceuticals as an additional strategy to target the atherosclerotic sites boasting high therapeutic efficiency of the nutraceuticals and fewer side effects.

Star-shaped polylactide (SSPLA) nanoparticles (NPs) with dipyridamole (DIP) core conjugated with 5-fluorouracil (5FU) and 4-piperidinopiperidine (4PIP) were designed and synthesized to achieve apoptosis by synergistic dose-dependent delivery than using free drugs. In our current investigation, DIP was employed as the initiator in ring-opening polymerization reaction to make SSPLADIP. We then described the synthesis of tailor-made, self-assembled, carboxyl group-substituted fluorescent SSPLADIP conjugated with a secondary amine group of 5FU anticancer drug to form a dual prodrug complex (SSPLADIP5FU). To compare the efficacy of this combination, another anticancer drug 4PIP was also covalently conjugated with a hydroxyl-end terminal by nucleophilic substitution on SSPLADIP to form SSPLADIP4PIP. 4PIP inhibits the topoisomerase enzyme in DNA replication. Synthesized star-shaped drug constructs were characterized by atomic force microscopy, scanning electron microscopy, NMR, fluorescence spectroscopy, gel permeation chromatography, and MALDI-TOF. This is the first report on these drug combinations (DIP-5FU and DIP-4PIP) fabricated on the polylactic acid biopolymer to form NPs of size

The anti-apoptotic defense mechanism of cancer cells poses a major hurdle which makes chemotherapy less effective. Combinatorial delivery of drugs and siRNAs targeting anti-apoptotic proteins is a vital means for improving therapeutic effects. The present study aims at designing a suitable carrier which can effectively co-deliver doxorubicin and plk1 siRNA to tumor cells. Low molecular weight poly(styrene-alt-maleic anhydride) was chemically modified via a click reaction to obtain a cationic amphiphilic polymer for the co-delivery of therapeutic agents. Short glycol chains were utilized as linker molecules for grafting which in turn imparted a stealth nature and minimized plasma protein adsorption to the polymeric surface. Isonicotinic acid was grafted to the polymer due to its ability to penetrate the endolysosomal membrane and arginine–lysine conjugates were embedded for complexing siRNA. The polymer was able to self-assemble in to smooth, spherical micellar structures with a CMC of ∼3 μg mL−1. The particle size of the micelles was ∼14–30 nm as depicted using TEM and FESEM. Atomic force microscopic analysis showed an average height of ∼12 nm for the polymeric micelles. An optimum doxorubicin loading of ∼9% w/w was achieved with the micelles using a dialysis method. Effective complexation of siRNA occurred above a polymer/siRNA weight ratio of 10 without any significant change in the particle size. Doxorubicin and fluorescent labeled siRNA loaded micelles exhibited excellent co-localization within the cytoplasm of MCF-7 cells. The synergistic effect of the active agents in inhibiting tumor cell proliferation was depicted using an MTT assay and visualized using calcein/propidium iodide staining of the treated cells. Co-administration of doxorubicin and plk1 siRNA in EAT tumor bearing Swiss albino mice using the cationic micelles significantly enhanced the antitumor efficacy.

Glioblastoma multiforme (GBM), one of the most lethal Brain tumors, characterized by its high invasive nature and increased mortality rates forms a major bottleneck in transport of therapeutics across the Blood Brain Barrier (BBB). Matrix metalloproteinases (MMPs) are classified as enzymes, which are found to be up regulated in the Glioma tumor microenvironment and thus can be considered as a target for inhibition for curbing GBM. Many chemotherapeutics and techniques have been employed for inhibiting MMPs till now but all of them failed miserably and were withdrawn in clinical trials due to their inability in restricting the tumor growth or increasing the overall survival rates. Thus, the quest for finding the suitable MMP inhibitor is still on and there is a critical need for identification of novel compounds which can alter the BBB permeability, restrain tumor growth and prevent tumor recurrence. Currently, naturally derived substances are gaining widespread attention as tumor inhibitors and many studies have been reported by far highlighting their importance in restricting MMP expression thus serving as chemotherapeutics for cancer due to their minimal toxicity. These substances may serve as probable candidates for inhibiting MMP expression in GBM. However, targeting and delivering the inhibitor to its target site is an issue that needs to be overcome in order to attain maximum specificity and sustained release. The birth of nanotechnology served as a boon in delivering drugs to the most complicated areas thus paving way for Nano drug delivery. An efficient Nano carrier with ability to cross the BBB and competently kill the Glioma cells forms the prerequisite for GBM chemotherapy. Vesicular drug delivery systems are one such class of carriers, which have the capacity to release the drug at a predetermined rate at the target site thus minimizing any undesirable side effects. Exploiting vesicular systems as promising Nano drug carriers to formulate naturally derived substances, that can bypass the BBB and act as an inhibitor against MMPs in GBM is the main theme of this review.

Cellulosic materials have been of tremendous importance to mankind since its discovery due to its superior properties and its abundance in nature. Recently, an increase in demand for alternate green materials has rekindled the interest for cellulosic materials. Here, bacterial cellulose has been functionalized with sulfate groups through acetosulfation to gain solubility in aqueous media, which provides access to several applications. The cell viability, antioxidant, and hemocompatibility assays have verified the biocompatible and antioxidant characteristics of bacterial cellulose sulfate (BCS) in both in vitro and ex vivo conditions. Further, novel BCS/polyvinyl alcohol nanofibers were fabricated by simple electrospinning route to engineer ultrafine nanoscale fibers. The biological evaluation of BCS/polyvinyl alcohol nanofiber scaffolds was done using L929 mouse fibroblast cells, which confirmed that these nanofibers are excellent matrices for cell adhesion and proliferation.

Materials with efficient potential in imaging as well as therapy are gaining particular attention in current medical research. Photodynamic therapy (PDT) has been recently recognized as a promising treatment option for solid tumors. Still, most of the nanomaterial-based PDT modules either employ an additional photosensitizer or require high power laser sources. Also, they suffer from a lack of responsiveness in the near-infrared (NIR) region. Nanomaterials that could realize PDT independently (without any photosensitizer), at safe laser dose and in the deep tissue penetrative NIR region would definitely be better solid tumor treatment options. Methods: Herein, Cu- and Bi-based bimetal chalcogenide (Cu3BiS3), with absorption in the NIR region was developed. High-performance PDT of cancer and high-contrast x-ray imaging of tumor were performed in vivo. Biocompatibility of the NCs was also assessed in vivo. Results: The highlight of the results was the realization of ultra-low dose NIR laser-mediated PDT, which has not been achieved before, leading to complete tumor regression. This could be a breakthrough in providing a pain- and scar-less treatment option, especially for solid tumors and malignant/benign subcutaneous masses. Though the NCs are active in the photo-thermal therapy (PTT) regime as well, focus is given to the exciting aspect of extremely low power-induced PDT observed here. Conclusion: Their extended in vivo biodistribution with commendable hemo- and histo-compatibilities, along with imaging and multi-therapeutic capabilities, project these Cu3BiS3 NCs as promising, prospective theranostic candidates.

Bioinert gold nanoparticles of various shapes and functionalities are widely accepted as contrast agents (CAs) for several modalities of imaging, viz., electron microscopy, computerized tomography (CT), X-ray and photoacoustic (PA) imaging. However, testing of novel compact-imaging probes for ocular diagnostic imaging is always challenging. Here, ultra-fast microwave oven synthesized gold nanocages (AuNcgs) were successfully demonstrated for high-contrast PA ocular imaging for the first time. Methods are described for the synthesis, characterization and application of quickly synthesized AuNcgs in diagnostic ocular imaging. PA and ultrasound (US) images were acquired using a commercial US imaging scanner integrated with a tunable nanosecond pulsed laser. This integrated hybrid-modality system is a combined PA and US platform for imaging which enabled acquiring of complementary structural and optical absorption-based information simultaneously. Initial experiments were conducted using tubings filled with solutions of different concentrations of quickly synthesized AuNcgs. Biological PA and US imagings were demonstrated using enucleated porcine eye samples. Based on the acquired results, it is envisaged that AuNcgs can be employed as a high strength PA CA to potentially diagnose ocular disease like uveal melanoma in the near future. MOE (Min. of Education, S’pore) Accepted version

A miniaturized prototype sensor based on TiO2 nanotubes/porous silicon (PS) heterojunction is developed for selective ethanol sensing in sub-ppm range. Titanium (Ti) of thickness ∼ 200 nm was deposited on PS using RF sputtering technique. Both silicon and Ti were sequentially anodized to form PS and nanotubes respectively. Electrical contacts for testing of resistive sensors were fabricated using lift off process. The sensor was packaged onto a 12-pin header and tested in presence of different VOCs with concentration ranging from 0.5 to 100 ppm. The selective ethanol sensing at around 150 °C stems from the formation of TiO2 nanotubes/PS heterojunction. The sensitivity of such a sensor, improved manifold in comparison to the response of pure PS and pure TiO2 based sensors. The formation of heterojunction, selective response to ethanol, sub-ppm level sensing at comparatively low operating temperature is discussed. The study unfolds the collective properties of TiO2/PS heterojunction and demonstrates the potential of wafer scale integrated repeatable ethanol sensor tested at sub-ppm level.

Design of safe and efficient vehicles for the combinatorial delivery of drugs and genetic agents is an emerging requisite for achieving enhanced therapeutic effect in cancer. Even though several nanoplatforms have been explored for the co-delivery of drugs and genetic materials the translation of these systems to clinical phase is still a challenge, mainly due to tedious synthesis procedures, lack of serum stability, inefficient scalability etc. Here in, we report development of reduction and pH sensitive polymeric graft of low molecular weight poly (styrene -alt -maleic anhydride) and evaluation of its efficacy in co-delivering drug and siRNA. The polymer was modified with suitable components, which could help in overcoming various systemic and cellular barriers for successful co-delivery of drugs and nucleic acids to cancer cells, using simple chemical reactions. The polymeric derivative could easily self assemble in water to form smooth, spherical micellar structures, indicating their scalability. Doxorubicin and PLK-1 siRNA were selected as model drug and nucleic acid, respectively. Doxorubicin could be loaded in the self assembling micelles with an optimum loading content of ∼8.6% w/w and efficient siRNA complexation was achieved with polymer/siRNA weight ratios >40. The polyplexes were stabilized in physiological saline by coating with bovine serum albumin (BSA). Stable drug loaded nanoplexes, for clinical administration, could be easily formulated by gently dispersing them in physiological saline containing appropriate amount of albumin. Drug release from the nanoplexes was significantly enhanced at low pH (5) and in the presence of 10 mM glutathione (GSH) showing their dual stimuli sensitive nature. In vitro cell proliferation assay and in vivo tumor regression study have shown synergistic effect of the drug loaded nanoplexes in inhibiting cancer cell proliferation. Facile synthesis steps, scalability and ease of formulation depict excellent clinical translation potential of the proposed nanosystem.

Gold nanocages (AuNcgs) are well-studied, hollow, metallic nanostructures that have fascinated researchers in the fields of nanotechnology, materials science, photoelectronics, biotechnology, and medical science for the last decade. However, the time-consuming synthesis of AuNcgs has limited their widespread use in materials science and nano-biotechnology. A novel, ultra-fast, simple, and highly convenient method for the production of AuNcgs using microwave heating is demonstrated herein. This quick method of AuNcg synthesis requires mild laboratory conditions for large-scale production of AuNcgs. The microwave heating technique offers the advantage of precise mechanical control over the temperature and heating power, even for the shortest reaction period (i.e., seconds). Microwave-synthesized AuNcgs were compared with conventionally synthesized AuNcgs. Structural maneuver studies employing the conventionally produced AuNcgs revealed the formation of screw dislocations and a shift in the lattice plane. Detailed characterization of the microwave-generated AuNcgs was performed using high resolution transmission electron microscopy (HRTEM), scanning electron microscopy (SEM), X-ray powder diffraction (XRD), and spectroscopic techniques.

Hedgehog (Hh) and Notch signaling are embryonic signaling pathways involved in cell patterning, cell fate, and differentiation during the developmental stages. Dysregulation in these pathways is implicated as an early sign of the tumorigenic process, among many other contributing factors. The discovery of tumor-initiating cells or cancer stem cells (CSCs) in cancer supports the role of these two signaling pathways in the maintenance of CSC self-renewal capacity, ultimately leading to recurrence and chemoresistance. Due to their involvement and the association in progression of several cancers, the two signaling pathways are attractive therapeutic targets to eliminate CSCs. This chapter focuses on the role of Hh and Notch signaling in cancer for the maintenance of CSCs and also the current therapeutic approaches that are being developed to eliminate CSCs.

Plant genetic engineering is at the epicenter of environmental sustainability endeavors, synthesis of natural products of commercial and pharmaceutical value, while also addressing the ever-expanding food and energy requirements of an ever-growing global population impacting the global climate in more ways than one. Though the importance of this field has been emphasized, still progress remains at a slow pace, partly owing to the drawbacks of conventional plant biotransformation approaches such as limited host range, below par transformation efficiencies, cellular toxicity, in addition to foreign DNA integration into the host genome. These drawbacks are additionally supported by the presence of plant cell wall which has been a limiting checkpoint for essential exogenous biomolecules entry. Nanotechnology, with its well-established impact on the materials, electronics, energy, and medical sectors, has found a new role in plant genetic engineering. Nanomaterials with their unique physicochemical properties have attracted immense interest from plant scientists and are the solution to the conventional limitations faced in plant biotransformation. A wide array of nanoparticles have been already studied for carrying and delivering sensitive cargo (DNA, RNA, proteins) to specific cells without any damage to the cargo or the host. This chapter deals with such nanomaterials, their success, challenges and future scope in agriculture.

Heat Shock Protein 90 (Hsp90) has been extensively explored as a potential drug target for cancer therapies. 17- N-allylamino- 17-demethoxygeldanamycin (17AAG) was the first Hsp90 inhibitor to enter clinical trials for cancer therapy. However, native drug is being shown to have considerable anticancer efficacy against pancreatic cancer when used in combination therapy regime. Further, magnetic hyperthermia has shown to have promising effects against pancreatic cancer in combination with known cyto-toxic drugs under both target and non-targeted scenarios. Hence, in order to enhance the efficacy of 17AAG against pancreatic cancer, we developed poly (lactic-co-glycolic acid) (PLGA) coated, 17AAG and Fe3O4 loaded magnetic nanoparticle formulations by varying the relative concentration of polymer. We found that polymer concentration affects the magnetic strength and physicochemical properties of formulation. We were also able to see that our aqueous dispensable formulations were able to provide anti-pancreatic cancer activity for MIA PaCa-2 cell line in dose and time dependent manner in comparison to mice fibroblast cell lines (L929). Moreover, the in-vitro magnetic hyperthermia against MIA PaCa-2 provided proof principle that our 2-in-1 particles may work against cancer cell lines effectively. Refereed/Peer-reviewed

Suboptimal chemotherapy of anticancer drugs may be attributed to a variety of cellular mechanisms, which synergize to dodge the drug responses. Nearly 2 decades of heat-shock protein 90 (Hsp90)-targeted drug discovery has shown that the mono-therapy with Hsp90 inhibitors seems to be relatively ineffective compared with combination treatment due to several cellular dodging mechanisms. In this article, we have tried to analyze and review the Hsp90 and mammalian target of rapamycin (m-TOR)-mediated drug resistance mechanisms. By using this information we have discussed about the rationale behind use of drug combinations that includes both or any one of these inhibitors for cancer therapy. Currently, biodegradable nano vector (NV)-loaded novel drug delivery systems have shown to resolve the problems of poor bioavailability. NVs of drugs such as paclitaxel, doxorubicin, daunorubicin, and others have been successfully introduced for medicinal use. Hence, looking at the success of NVs, in this article we have also discussed the progress made in the delivery of biodegradable NV-loaded Hsp90 and m-TOR-targeted inhibitors in multiple drug combinations. We have also discussed the possible ways by which the market success of biodegradable NVs can positively impact the clinical trials of anti-Hsp90 and m-TOR combination strategy. Refereed/Peer-reviewed

Current conventional mono and combination therapeutic strategies often fail to target breast cancer tissue effectively due to tumor heterogeneity comprising cancer stem cells (CSCs) and bulk tumor cells. This is further associated with drug toxicity and resistivity in the long run. A nanomedicine platform incorporating combination anti-cancer treatment might overcome these challenges and generate synergistic anti-cancer effects and also reduce drug toxicity. GANT61 and curcumin were co-delivered via polymeric nanoparticles (NPs) for the first time to elicit enhanced anti-tumor activity against heterogeneous breast cancer cell line MCF-7. We adopted the single-emulsion-solvent evaporation method for the preparation of the therapeutic NPs. The GANT61-curcumin PLGA NPs were characterized for their size, shape and chemical properties, and anti-cancer cell studies were undertaken for the plausible explanation of our hypothesis. The synthesized GANT61-curcumin PLGA NPs had a spherical, smooth surface morphology, and an average size of 347.4 d. nm. The NPs induced cytotoxic effects in breast cancer cells at a mid-minimal dosage followed by cell death via autophagy and apoptosis, reduction in their target protein expression along with compromising the self-renewal property of CSCs as revealed by their in vitro cell studies. The dual-drug NPs thus provide a novel perspective on aiding existing anti-cancer nanomedicine therapies to target a heterogeneous tumor mass effectively.

Despite aggressive surgical resections and combinatorial chemoradiations, certain highly malignant populations of tumor cells resurrect and metastasize. Mixed-grade cancer cells fail to respond to standard-of-care therapies by developing intrinsic chemoresistance and subsequently result in tumor relapse. Macroautophagy is a membrane trafficking process that underlies drug resistance and tumorigenesis in most breast cancers. Manipulating cellular homeostasis by a combinatorial nanotherapeutic model, one can evaluate the crosstalk between type I and type II cell death and decipher the fate of cancer therapy. Here, we present a multi-strategic approach in cancer targeting to mitigate the autophagic flux with subcellular toxicity via lysosome permeation, accompanied by mitochondrial perturbation and apoptosis. In this way, a nanoformulation is developed with a unique blend of a lysosomotropic agent, an immunomodulating sulfated-polysaccharide, an adjuvant chemotherapeutic agent, and a monoclonal antibody as a broad-spectrum complex for combinatorial nanotherapy of all breast cancers. To the best of our knowledge, this manuscript illustrates for the first time the applications of advanced microscopic techniques such as electron tomography, three-dimensional rendering and segmentation of subcellular interactions, and fate of the multifunctional therapeutic gold nanocages specifically targeted toward breast cancer cells.

Morusin, a water-insoluble prenylated flavonoid is known for its numerous medicinal properties. It manifests its anticancer potential by suppression of genes involved in tumor progression. However, poor solubility of the drug results in low bioavailability and rapid degradation thus hindering its clinical utilization. In order to overcome this, we have synthesized a niosome system composed of non-ionic surfactant span 60 and cholesterol using a thin-layer evaporation technique to improve the aqueous-phase solubility of the drug. Highly cytocompatible niosomes of 479 nm average size with smooth and uniform spherical morphology were synthesized in a facile manner. Unlike free morusin, nanomorusin was found to be freely dispersible in aqueous media. Having an extremely high drug entrapment efficiency (97%), controlled and sustained release of morusin resulting in enhanced therapeutic efficacy was observed in cancer cell lines of 4 different lineages. The results demonstrate that the morusin-niosome system is a promising strategy for enhanced anti-cancer activity against multiple cancer types and could be an indispensable tool for future targeted chemotherapeutic strategies.