Essential oils and their nanoformulations for breast cancer therapy.

Breast Cancer (BC) is the most prevalent type of cancer in the world. Current treatments include surgery, radiation, and chemotherapy but often are associated with high toxicity to normal tissues, chemoresistance, and relapse. Thus, developing novel therapies which could combat these limitations is essential for effective treatment. In this context, phytochemicals are increasingly getting popular due to their safety profile, ability to efficiently target tumors, and circumvent limitations of existing treatments. Essential Oils (EOs) are mixtures of various phytochemicals which have shown potential anticancer activity in preclinical BC models. However, their clinical translation is limited by factors such as high volatility, low stability, and poor solubility. Nanotechnology has facilitated their encapsulation in a variety of nanostructures and proven to overcome these limitations. In this review, we have efficiently summarized the current knowledge on the anticancer effect of EOs and constituents in both in in vitro and in in vivo BC models. Further, we also provide a descriptive account on the potential of nanotechnology in enhancing the anti-BC activity of EOs and their constituents. The papers discussed in this review were selected using the keywords "antiproliferative Essential Oils in breast cancer," "anticancer activity of Essential Oil in breast cancer," and "cytotoxicity of Essential Oils in breast cancer" performed in PubMed and ScienceDirect databases.

Phytochemical-Based Nanomedicine for Targeting Tumor Microenvironment and Inhibiting Cancer Chemoresistance: Recent Advances and Pharmacological Insights.

Cancer remains the leading cause of death and rapidly evolving disease worldwide. The understanding of disease pathophysiology has improved through advanced research investigation, and several therapeutic strategies are being used for better cancer treatment. However, the increase in cancer relapse and metastatic-related deaths indicate that available therapies and clinically approved chemotherapy drugs are not sufficient to combat cancer. Further, the constant crosstalk between tumor cells and the tumor microenvironment (TME) is crucial for the development, progression, metastasis, and therapeutic response to tumors. In this regard, phytochemicals with multimodal targeting abilities can be used as an alternative to current cancer therapy by inhibiting cancer survival pathways or modulating TME. However, due to their poor pharmacokinetics and low bioavailability, the success of phytochemicals in clinical trials is limited. Therefore, developing phytochemical-based nanomedicine or phytonanomedicine can improve the pharmacokinetic profile of these phytochemicals. Herein, the molecular characteristics and pharmacological insights of the proposed phytonanomedicine in cancer therapy targeting tumor tissue and altering the characteristics of cancer stem cells, chemoresistance, TME, and cancer immunity are well discussed. Further, we have highlighted the clinical perspective and challenges of phytonanomedicine in filling the gap in potential cancer therapeutics using various nanoplatforms. Overall, we have discussed how clinical success and pharmacological insights could make it more beneficial to boost the concept of nanomedicine in the academic and pharmaceutical fields to counter cancer metastases and drug resistance.

In silico ranking of phenolics for therapeutic effectiveness on cancer stem cells.

BACKGROUND: Cancer stem cells (CSCs) have features such as the ability to self-renew, differentiate into defined progenies and initiate the tumor growth. Treatments of cancer include drugs, chemotherapy and radiotherapy or a combination. However, treatment of cancer by various therapeutic strategies often fail. One possible reason is that the nature of CSCs, which has stem-like properties, make it more dynamic and complex and may cause the therapeutic resistance. Another limitation is the side effects associated with the treatment of chemotherapy or radiotherapy. To explore better or alternative treatment options the current study aims to investigate the natural drug-like molecules that can be used as CSC-targeted therapy. Among various natural products, anticancer potential of phenolics is well established. We collected the 21 phytochemicals from phenolic group and their interacting CSC genes from the publicly available databases. Then a bipartite graph is constructed from the collected CSC genes along with their interacting phytochemicals from phenolic group as other. The bipartite graph is then transformed into weighted bipartite graph by considering the interaction strength between the phenolics and the CSC genes. The CSC genes are also weighted by two scores, namely, DSI (Disease Specificity Index) and DPI (Disease Pleiotropy Index). For each gene, its DSI score reflects the specific relationship with the disease and DPI score reflects the association with multiple diseases. Finally, a ranking technique is developed based on PageRank (PR) algorithm for ranking the phenolics. RESULTS: We collected 21 phytochemicals from phenolic group and 1118 CSC genes. The top ranked phenolics were evaluated by their molecular and pharmacokinetics properties and disease association networks. We selected top five ranked phenolics (Resveratrol, Curcumin, Quercetin, Epigallocatechin Gallate, and Genistein) for further examination of their oral bioavailability through molecular properties, drug likeness through pharmacokinetic properties, and associated network with CSC genes. CONCLUSION: Our PR ranking based approach is useful to rank the phenolics that are associated with CSC genes. Our results suggested some phenolics are potential molecules for CSC-related cancer treatment.

Phytonanomedicine as a therapeutic regulator of the tumor microenvironment for inhibiting cancer metastasis.

TWEETABLE ABSTRACT "The development of phytonanomedicine-based approach seems to be a very promising candidate for modulating protumorigenic tumor microenvironment to suppress cancer metastasis."

Nanotheranostics: A Cutting-Edge Technology for Cancer Management.

Cancer is the second-leading cause of death in the 21st century, where early detection and appropriate therapeutic interventions are two components essential for effective cancer management. Despite the availability of several conventional diagnostics and therapeutic agents, cancer mortality rates are rising due to an increase in the frequency of recurrence and metastasis in cancer patients. Therefore, tremendous efforts have been expended to address this significant clinical issue and improve therapeutic efficacy. In this regard, nanotheranostic is a multipotential single platform for both cancer diagnosis and treatment through enhanced aqueous solubility and bioavailability of the encapsulated agent, stimulus responsiveness, tumor-specific targeting ability, precise tumor imaging, and real-time drug delivery. Nonetheless, the translational success of nanotheranostic platforms is still in its infancy and requires more extensive research in the context of tumor heterogeneity, safety profile, and regulatory issues, which pose one of the largest technological limitations. The present review summarizes different nanotheranostic platforms and nanotheranostic candidates in clinical trials (AGuIX® , NBTXR3, Ferumoxtran, MM-398, EndoTAG-1, etc.), along with disadvantages and challenges to improving cancer diagnosis and treatment. Overall, the concept, platform, and technical knowledge of nanotheranostics are really helpful to academic and pharmaceutical researchers.

Piperlongumine based nanomedicine impairs glycolytic metabolism in triple negative breast cancer stem cells through modulation of GAPDH & FBP1.

BACKGROUND: Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and exhibits high rate of chemoresistance, metastasis, and relapse. This can be attributed to the failure of conventional therapeutics to target a sub-population of slow cycling or quiescent cells called as cancer stem cells (CSCs). Therefore, elimination of CSCs is essential for effective TNBC treatment. PURPOSE: Research suggests that breast CSCs exhibit elevated glycolytic metabolism which directly contributes in maintenance of stemness, self-renewability and chemoresistance as well as in tumor progression. Therefore, this study aimed to target rewired metabolism which can serve as Achilles heel for CSCs population and have far reaching effect in TNBC treatment. METHODS: We used two preclinical models, zebrafish and nude mice to evaluate the fate of nanoparticles as well as the therapeutic efficacy of both piperlongumine (PL) and its nanomedicine (PL-NPs). RESULTS: In this context, we explored a phytochemical piperlongumine (PL) which has potent anti-cancer properties but poor pharmacokinetics impedes its clinical translation. So, we developed PLGA based nanomedicine for PL (PL-NPs), and demonstrated that it overcomes the pharmacokinetic limitations of PL, along with imparting advantages of selective tumor targeting through Enhanced Permeability and Retention (EPR) effect in zebrafish xenograft model. Further, we demonstrated that PL-NPs efficiently inhibit glycolysis in CSCs through inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by modulating glutathione S-transferase pi 1 (GSTP1) and upregulation of fructose-1,6-bisphosphatase 1 (FBP1), a rate-limiting enzyme in gluconeogenesis. We also illustrated that inhibition of glycolysis results in overall tumor regression in two preclinical models. CONCLUSION: This study discusses novel mechanism of action by which PL acts on CSCSs. Taken together our study provides insight into development of PL based nanomedicine which could be exploited in clinics to achieve complete eradication of TNBC by targeting CSCs.

Reversal of cisplatin resistance in oral squamous cell carcinoma by piperlongumine loaded smart nanoparticles through inhibition of Hippo-YAP signaling pathway.

Cisplatin alone or in combination with 5FU and docetaxel is the preferred chemotherapy regimen for advanced-stage OSCC patients. However, its use has been linked to recurrence and metastasis due to the development of drug resistance. Therefore, sensitization of cancer cells to conventional chemotherapeutics can be an effective strategy to overcome drug resistance. Piperlongumine (PL), an alkaloid, have shown anticancer properties and sensitizes numerous neoplasms, but its effect on OSCC has not been explored. However, low aqueous solubility and poor pharmacokinetics limit its clinical application. Therefore, to improve its therapeutic efficacy, we developed piperlongumine-loaded PLGA-based smart nanoparticles (smart PL-NPs) that can rapidly release PL in an acidic environment of cancer cells and provide optimum drug concentrations to overcome chemoresistance. Our results revealed that smart PL-NPs has high cellular uptake in acidic environment, facilitating the intracellular delivery of PL and sensitizing cancer cells to cisplatin, resulting in synergistic anticancer activity in vitro by increasing DNA damage, apoptosis, and inhibiting drug efflux. Further, we have mechanistically explored the Hippo-YAP signaling pathway, which is the critical mediator of chemoresistance, and investigated the chemosensitizing effect of PL in OSCC. We observed that PL alone and in combination with cisplatin significantly inhibits the activation of YAP and its downstream target genes and proteins. In addition, the combination of cisplatin with smart PL-NPs significantly inhibited tumor growth in two preclinical models (patient-derived cell based nude mice and zebrafish xenograft). Taken together, our findings suggest that smart PL-NPs with cisplatin will be a novel formulation to reverse cisplatin resistance in patients with advanced OSCC.

Flavonoids for the Treatment of Breast Cancer, Present Status and Future Prospective.

Breast Cancer is one of the most notorious cancer affecting women globally. Current therapies available for breast cancer treatment have certain limited efficacy; develop drug resistance and severe adverse effects. Thus, identifying novel therapies for treatment will reduce the devastating effect on cancer survivors. The exhilarating and fastgrowing studies on flavonoids have evidenced that it has the potential to inflect various antitumor activity and modulate various signal transduction pathways in carcinogenesis. Flavonoids also have been found to regulate cellular metabolism and oxidative stress, cell cycle progression, angiogenesis and metastasis, ultimately preventing the progression of the diseases. As per the reports, a flavonoid-rich diet appears to be the most potent and promising approach to abate the risk of cancer. Thus, now a day, these are the prime target for drug discovery research. Based on existing findings, it can be concluded that beyond the currently employed chemotherapeutics, natural products (like flavonoids) exhibit pleiotropic, multi-target activities and are budding as possible complementary chemopreventive molecules against breast cancer with fewer side effects than conventional therapy. In this review, we comprehensively highlight an outline of the multiple pleiotropic pharmacological effects of various major classes of flavonoids on breast cancer with their specific mechanisms underlying its anticancer effect.

In-vitro anticancer evaluation of newly designed and characterized tri/tetra-substituted imidazole congeners- maternal embryonic leucine zipper kinase inhibitors: Molecular docking and MD simulation approaches.

Our cascading attempt to develop new potent molecules now involves designing a series of imidazole derivatives and synthesizing two sets of 2,4,5- tri-substituted (4a-4d) and 1,2,4,5-tetra-substituted (6a-6d) imidazole by the principle of Debus-Radziszewski multicomponent synthesis reaction. The structures of the obtained compounds were confirmed by 1H/13C NMR, FT-IR, elemental analysis, purity and the retention time was analyzed by HPLC. Based upon the binding affinity in the molecular docking studies, we have synthesized different imidazole derivatives from which compound 6c have been found to show more anti-proliferative activity by inducing apoptosis at a higher rate than the other compounds corroborating the in-silico prediction. The structure and crystallinity of compound 4d have been confirmed by single XRD analysis. The synthesized molecules were screened for their in vitro anti-cancer properties in triple negative breast cancer cell line (MDA-MB-231), pancreatic cancer cell lines (MIA PaCa-2) and oral squamous cell carcinoma cell line (H357) and results indicated that all the compounds inhibited the cell proliferation in a concentration-dependent manner at different time points. The compounds 4b and 6d were found to be effective against the S. aureus bacterial strain whereas only compound 4d fairly inhibited the fungal strain of T. rubrum with a MIC 12.5 µg/mL. Molecular docking study reveals good interaction of the synthesized compounds with known target MELK involved in oncogenesis having high binding profiles. The lead compound 6c was further analyzed by the detailed molecular dynamics study to establish the stability of the ligand-enzyme complex.

Nimbolide-based nanomedicine inhibits breast cancer stem-like cells by epigenetic reprogramming of DNMTs-SFRP1-Wnt/ß-catenin signaling axis.

Triple-negative breast cancer (TNBC) harbors a high percentage of breast cancer stem-like cells (BCSCs) that significantly contribute to poor prognosis, metastasis, and relapse of the disease. Thus, targeting BCSCs could be a promising approach to combat TNBC. In this context, we investigated nimbolide (Nim), a limonoid triterpenoid that has potent anticancer properties, but poor pharmacokinetics and low bioavailability limit its therapeutic application. So, to enhance the therapeutic potential of Nim, Nim-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Nim NPs) were formulated and the anticancer stem cell (CSC) effects evaluated in vitro and in vivo. In vitro studies suggested that Nim NPs significantly inhibited several inherent characteristics of BCSCs, such as stemness, self-renewability, chemoresistance, epithelial-to-mesenchymal transition (EMT), and migration in comparison to native Nim. Next, the mechanism behind the anti-CSC effect of Nim was explored. Mechanistically, we found that Nim epigenetically restores tumor suppressor gene secreted frizzled-related protein 1 (SFRP1) expression by downregulating DNA methyltransferases (DNMTs), leading to Wnt/ß-catenin signaling inhibition. Further, in vivo results demonstrated that Nim NPs showed enhanced anti-tumor and anti-metastatic effects compared to native Nim in two preclinical models without any systemic toxicity. Overall, these findings provide proof of concept that Nim-based phytonanomedicine can inhibit BCSCs by epigenetic reprogramming of the DNMTs-SFRP1-Wnt/ß-catenin signaling axis.

A novel in vitro three-dimensional retinoblastoma model for evaluating chemotherapeutic drugs.

PURPOSE: Novel strategies are being applied for creating better in vitro models that simulate in vivo conditions for testing the efficacy of anticancer drugs. In the present study we developed surface-engineered, large and porous, biodegradable, polymeric microparticles as a scaffold for three dimensional (3-D) growth of a Y79 retinoblastoma (RB) cell line. We evaluated the effect of three anticancer drugs in naïve and nanoparticle-loaded forms on a 3-D versus a two-dimensional (2-D) model. We also studied the influence of microparticles on extracellular matrix (ECM) synthesis and whole genome miRNA-gene expression profiling to identify 3D-responsive genes that are implicated in oncogenesis in RB cells. METHODS: Poly(D,L)-lactide-co-glycolide (PLGA) microparticles were prepared by the solvent evaporation method. RB cell line Y79 was grown alone or with PLGA-gelatin microparticles. Antiproliferative activity, drug diffusion, and cellular uptake were studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a yellow tetrazole (MTT) assay, fluorescent microscope, and flow cytometry. Extra cellular matrix (ECM) synthesis was observed by collagenase assay and whole genome miRNA-microarray profiling by using an Agilent chip. RESULTS: With optimized composition of microparticles and cell culture conditions, an eightfold increase from the seeding density was achieved in 5 days of culture. The antiproliferative effect of the drugs in the 3-D model was significantly lower than in the 2-D suspension, which was evident from the 4.5 to 21.8 fold differences in their IC(50) values. Using doxorubicin, the flow cytometry data demonstrated a 4.4 fold lower drug accumulation in the cells grown in the 3-D model at 4 h. The collagen content of the cells grown in the 3-D model was 2.3 fold greater than that of the cells grown in the 2-D model, suggesting greater synthesis of the extracellular matrix in the 3-D model as the extracellular matrix acted as a barrier to drug diffusion. The microarray and miRNA analysis showed changes in several genes and miRNA expression in cells grown in the 3-D model, which could also influence the environment and drug effects. CONCLUSIONS: Our 3-D retinoblastoma model could be used in developing effective drugs based on a better understanding of the role of chemical, biologic, and physical parameters in the process of drug diffusion through the tumor mass, drug retention, and therapeutic outcome.

Piperlongumine loaded PLGA nanoparticles inhibit cancer stem-like cells through modulation of STAT3 in mammosphere model of triple negative breast cancer.

TNBC exhibits higher rate of chemoresistance, metastasis, and relapse among all subtypes of breast cancer. This malignant statein TNBC is due to self-renewing sub-population of cells called cancer stem cells (CSCs). They are major caveats in TNBC treatment and need to be obliterated. In this regard, we explored piperlongumine (PL) that has remarkable anti-cancerous property but poor pharmacokinetics limits its application. So, to enhance its biological activity we developed PLGA based nanoformulation for PL (PL-NPs) and examined anti-CSCs effects of PL and PL-NPs in mammospheres. Results indicated that PL-NPs have higher cellular uptake than PL in mammospheres. Further, we demonstrated that PL-NPs remarkably inhibit various characteristics of CSCs like expression of ALDH, self-renewability, chemoresistance, and EMT in mammopsheres. We next investigated the possible mechanism underlying these multi-modal effects, and found that inhibition of STAT3 might be the driving force. In order to confirm this, we used colivelin a potent synthetic peptide activator of STAT3 in combination with treatments and found that anti-CSCs effects of PL and PL-NPs were reversed. Taken together, our data indicates that PL-NPs show enhanced inhibition of CSCs through downregulation of STAT3 and provides insight into development of PL based nanomedicine for targeting CSCs in TNBC.

Application of Therapeutic Nanoplatforms as a Potential Candidate for the Treatment of CNS Disorders: Challenges and Possibilities.

Drug delivery to central nervous system (CNS) diseases is one of the most challenging tasks. The innate blood-brain barrier (BBB) and the blood-cerebrospinal fluid (BCSF) barrier create an obstacle to effective systemic drug delivery to the CNS, by limiting the access of drugs to the brain. Nanotechnology-based drug delivery platform offers a potential therapeutic approach for the treatment of neurological disorders. Several studies have shown that nanomaterials have great potential to be used for the treatment of CNS diseases. The nanocarriers have simplified the targeted delivery of therapeutics into the brain by surpassing the BBB and actively inhibiting the disease progression of CNS disorders. The review is an overview of the recent developments in nanotechnology-based drug delivery approaches for major CNS diseases like Alzheimer's disease, Parkinson's disease, ischemic stroke, and Glioblastoma. This review discusses the disease biology of major CNS disorders describing various nanotechnology-based approaches to overcome the challenges associated with CNS drug delivery, focussing on nanocarriers in preclinical and clinical studies for the same. The review also sheds light on the challenges during clinical translation of nanomedicine from bench to bedside. Conventional therapeutic agents used for the treatment of CNS disorders are inadequate due to their inability to cross BBB or BCSF, higher efflux from BBB, related toxicity, and poor pharmacokinetics. The amalgamation of nanotechnology with conventional therapeutic agents can greatly ameliorate the pharmacokinetic problems and at the same time assist in efficient delivery to the CNS.

Nimbolide-encapsulated PLGA nanoparticles induces Mesenchymal-to-Epithelial Transition by dual inhibition of AKT and mTOR in pancreatic cancer stem cells.

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis and remains highly aggressive despite current advancements in therapies. Chemoresistance and high metastatic nature of PDAC is attributed to a small subset of stem-like cells within the tumor known as Cancer Stem Cells (CSCs). Here, we developed a strategy for targeting pancreatic CSCs through forceful induction of mesenchymal-to-epithelial transition driven by encapsulating a phytochemical Nimbolide in nanoparticles. Binding of Nimbolide with the key regulator proteins of CSCs were studied through molecular docking and molecular dynamic simulation studies, which revealed that it binds to AKT and mTOR with high affinity. Further, in vitro studies revealed that Nim NPs are capable of inducing forceful mesenchymal-to-epithelial transition of pancreatospheres that leads to loss of multidrug resistance and self-renewal properties of pancreatospheres. Our study gives a proof of concept that encapsulation of Nim in PLGA nanoparticles increases its therapeutic effect on pancreatospheres. Further, binding of Nim to AKT and mTOR negatively regulates their activity that ultimately leads to mesenchymal-to-epithelial transition of pancreatic CSCs.

Curcumin Encapsulated into Biocompatible Co-Polymer PLGA Nanoparticle Enhanced Anti-Gastric Cancer and Anti-Helicobacter Pylori Effect.

BACKGROUND: The current disadvantages (high cost, toxicity, resistance) of chemotherapy for gastric cancer opted people for alternative therapy from natural source. Curcumin (natural product) possess multiple biological activities but low bio-availability limits their uses as therapeutic. The Nano-formulation of curcumin increased the bioavailability and productivity of anti-cancer and anti-bacterial properties. The present study was initiated to determine the anti-cancer and anti-bacterial effect of Nano curcumin against gastric cancer and H. pylori. METHODS: Curcumin loaded PLGA nanoparticles (CUR-NPs) was prepared by single emulsion solvent evaporation method. The MIC were determined using agar dilution method to find the anti-H. Pylori activity of Nano curcumin. The cytotoxicity of Nano curcumin was evaluated by MTT assay and the apoptotic effect (cell cycle arrest and morphology change) was shown by PI staining and microscopy. RESULTS: The MIC of nanocurcumin and curcumin for all four H. pylori strains were 8 µg/ml and 16 µg/ml respectively. The inhibition rate of gastric cancer cells after treatment with curcumin was increased from 6% to 67% for 24h, from 8% to 75% for 48h, from 10% to 83% for 72h. In case of nanocurcumin, the inhibition rate increased from 7% to 69% for 24h, 11% to 87% for 48h and 16% to 97% for 72h. The IC50 of curcumin and Nano-curcumin were 24.20 µM and 18.78 µM respectively for 72 h. The population of cells in sub-G0 population increased from 4.1% in the control group to 24.5% and 57.8% when treated with curcumin and nanocurcumin respectively. After 72h of treatment with nanocurcumin, the apoptotic cells population increased as compared to native curcumin treated cells. CONCLUSION: The Nano curcumin might be used as a potential therapeutics against gastric cancer and H. Pylori. There is need of further in vivo study in order to validate CUR-NPs activity.

Identification of Candidate Immune System MicroRNAs Differentially Found in Colostrum and Milk Exosomes.

BACKGROUND: The fetus grows in a sterile womb environment. After birth, the newborn immune system has two immediate hurdles to clear. First immediate suppression of the womb compatible immune system and turn on the immune system of the newborn that can counter the antigenic world. The underlying mechanism of immune fluctuation by milk microRNAs (miRNAs) can be crucial for the treatment of critical or premature newborn. METHODS: We collected fourteen samples of each colostrum and mature milk from lactating mothers, four samples of each were used for microarray analysis, and the other ten were used for miRNA expression profiling by real-time PCR. RESULTS: From the microarray, 154 differentially expressed miRNAs were identified, whereas 49 miRNAs were revealed as immune-related miRNAs based on a literature study. Among the 49 miRNAs, 33 were already shown as strongly validated immune-related miRNAs (validated by qPCR, Western Blot, and Luciferase assay) and were considered for further analysis. Twenty-two miRNA expressions were analysed by real-time PCR as their Ct values were within considerable limits. Twelve numbers of miRNAs were significantly downregulated in mature milk compared to colostrum, which were again subjected to bioinformatics analysis to predict the biological mechanisms behind the differentially expressed miRNAs. CONCLUSION: This study shed light on the human milk exosome miRNA expression dynamics during lactation and their possible role in the gradual skewing of the newborns' immune system. The information is crucial for the development and onset of sepsis in premature newborns in the NICU.

Reprogramming Cancer Stem-like Cells with Nanoforskolin Enhances the Efficacy of Paclitaxel in Targeting Breast Cancer.

Cancer stem-like cells (CSCs) have emerged as an important target for breast cancer therapy owing to their self-renewability, proliferation, and elevated chemoresistance properties. Here, we present a strategy of eliminating CSCs by differentiation therapy where "forced differentiation" reprograms CSCs so that they lose their intrinsic properties and become susceptible for conventional chemotherapeutic drugs. In this study, we report that a conventional chemotherapeutic paclitaxel enhances the stemness of CSCs, while a phytochemical forskolin being essentially nontoxic to CSCs possesses the intrinsic ability to reprogram them. To achieve simultaneous targeting of CSCs and bulk tumor cells, we used a co-delivery system where liquid crystal nanoparticles (LCN) were co-encapsulated with both paclitaxel and forskolin. LCN showed higher uptake, retention, and penetration potential in CSCs overcoming their high drug efflux property. Moreover, LCN improved the pharmacokinetic parameters of forskolin, which otherwise had very low retention and bioavailability. Forskolin-loaded LCN forced CSCs to exit from their mesenchymal state, which reduced their stemness and chemosensitized them while inhibiting E-cadherin-mediated survival and tumor-initiating potential as well as reversing paclitaxel-induced stemness. We further showed that upon administration of paclitaxel and forskolin co-loaded LCN to an orthotropic xenograft mouse model, the nanomedicine showed enhanced passive tumor targeting capability with very potent antitumor activity that eradicated small solid tumor in a single dose and showed no sign of tumor relapse or systemic toxicity over a long period. Overall, these findings give a proof of concept that co-delivery of forskolin and paclitaxel in a single nanoformulation can achieve overall tumor targeting where forskolin can efficiently reprogram/differentiate CSCs and paclitaxel can induce cytotoxicity in both differentiated CSCs and bulk tumor cells simultaneously. Hence, this study can provide a nanoformulation that can offer an efficient strategy for cancer therapy.

Phytonanomedicine: a novel avenue to treat recurrent cancer by targeting cancer stem cells.

Research suggests that tumor relapse and metastasis is caused by minor population of tumor-initiating cells called cancer stem cells (CSCs), which exhibit self-renewability, quiescence, antiapoptosis, and drug resistance. Conventional chemotherapeutics target rapidly proliferating cells but fail to exert cytotoxic effects on CSCs, thus enriching them and driving metastasis and relapse. Hence, targeting CSCs is essential for developing novel therapies for effective cancer treatment. Pertaining to this, several phytochemicals have been identified that exhibit anti-CSC activity. However, poor pharmacokinetics prevents their clinical translation. Hence, developing phytonanomedicine can help to improve the pharmacokinetic profile of these biologically active molecules. In this review, we summarize the current state of the art of phytonanomedicine in the context of CSCs and their clinical status in cancer treatment.

Magnetic nanoparticles for amalgamation of magnetic hyperthermia and chemotherapy: An approach towards enhanced attenuation of tumor.

Targeted cancer therapy facilitates localizing the action of chemotherapeutic drugs at the tumor site enhancing the therapeutic efficacy and reducing the side effects to the healthy cells. The homing property of mesenchymal stem cells (MSCs), towards the tumor tissues makes them a potential cell-based delivery system for targeted cancer therapy. Along with chemotherapy, hyperthermia has gained interest as a treatment modality of cancer due to the higher sensitivity of the cancer cells towards heat and also due to its action on tumor cells to enhance sensitization towards chemotherapy or radiotherapy. In the current study, we have shown the multifaceted application of magnetic nanoparticles (MNPs) as a drug delivery vehicle to deliver anti-cancer drug paclitaxel and also as an inducer for magnetic hyperthermia under alternating magnetic field. The combined approach of paclitaxel loaded MNPs and hyperthermia demonstrated enhanced therapeutic efficacy as compared to any single therapy. Further, we have employed MSCs as carrier for these drugs loaded MNPs to achieve targeted and uniform distribution of the MNPs at the tumor site. We have evaluated the efficacy of the system in in vitro and in vivo prostate tumor model. The in vivo tumor study shows uniform distribution of drug loaded MNPs with use of mesenchymal stem cells as a delivery vehicle and combination of hyperthermia and MNP mediated drug delivery results in better tumor remission.

Recent trends of nanomedicinal approaches in clinics.

Nanotechnology has become the indispensable cutting edge science providing solutions to many problems associated with human being. The application of nanotechnology associated to human health "nanomedicine" has revolutionized the drug delivery system by providing improved pharmacological and therapeutic properties of drugs. These advantageous effects of drug loaded nanocarrier systems are embraced by the pharmaceutical industries for the development of different effective nanocarriers. Currently, several drug loaded nanoformulations are approved by the Food and Drug Administration (FDA), and some of them are undergoing clinical trials for the human use. In this review, we have discussed the progress achieved so far for various drug loaded nanoformulations along with few emerging nanoformulations that are about to enter into clinical trials.