Piperlongumine and its derivatives against cancer: A recent update and future prospective.

Piperlongumine, or piplartine (PL), is a bioactive alkaloid isolated from Piper longum L. and a potent phytoconstituent in Indian Ayurveda and traditional Chinese medicine with a lot of therapeutic benefits. Apart from all of its biological activities, it demonstrates multimodal anticancer activity by targeting various cancer-associated pathways and being less toxic to normal cells. According to their structure-activity relationship (SAR), the trimethylphenyl ring (cinnamoyl core) and 5,6-dihydropyridin-2-(1H)-one (piperdine core) are responsible for the potent anticancer activity. However, it has poor intrinsic properties (low aqueous solubility, poor bioavailability, etc.). As a result, pharmaceutical researchers have been trying to optimise or modify the structure of PL to improve the drug-likeness profiles. The present review selected 26 eligible research articles on PL derivatives published between 2012 and 2023, followed by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) format. We have thoroughly summarised the anticancer potency, mode of action, SAR and drug chemistry of the proposed PL-derivatives against different cancer cells. Overall, SAR analyses with respect to anticancer potency and drug-ability revealed that substitution of methoxy to hydroxyl, attachment of ligustrazine and 4-hydroxycoumarin heterocyclic rings in place of phenyl rings, and attachment of heterocyclic rings like indole at the C7-C8 olefin position in native PL can help to improve anticancer activity, aqueous solubility, cell permeability, and bioavailability, making them potential leads. Hopefully, the large-scale collection and critical drug-chemistry analyses will be helpful to pharmaceutical and academic researchers in developing potential, less-toxic and cost-effective PL-derivatives that can be used against different cancers.

Coumaryl-sulfonamide moiety: Unraveling their synthetic strategy and specificity toward hCA IX/XII, facilitating anticancer drug development.

Currently, cancer is the most grieving threat to society. The cancer-related death rate has had an ascending trend, despite the implementation of numerous treatment strategies or the discovery of an array of potent molecules against several pathways of cancer growth. The need of the hour is to prevent the multidrug resistance toll, and the current efforts have been bestowed upon a versatile small molecule scaffold, coumarin (benz[α]pyrone), a natural compound possessing interesting affinity toward the cancer target human carbonic anhydrase (hCA), focusing on hCA I, II, IX, and XII. Along with coumarin, the age-old known antibacterial drug sulfonamide, when conjugated at positions 3, 7, and 8 of coumarin either with a linker group or as a single entity, has been reported to enhance the affinity of coumarin toward the overexpressed enzymes in tumor cell lines. The sulfonamides have been listed as obsolete drugs due to the severe side effects caused by them; however, their affinity toward the hCA-zinc-binding core has attracted the attention of researchers. Hence, in the process of drug development, coumarin and sulfonamides have remained the choice of last resort. To unveil the synthetic strategy of coumarin-sulfonamide conjugation, their rationale for inhibiting cancer cells/enzymes, and their affinity toward various types of carcinoma have been the sole goal of the researchers. This review specifically focuses on the mechanism of action and the structure-activity relationship through synthetic strategies and the binding affinity of coumaryl-sulfonamide conjugates with the anticancer targets possessing the highest enzyme affinity, since 2008.

Responsive Role of Nanomedicine in the Tumor Microenvironment and Cancer Drug Resistance.

Cancer remains a major worldwide health challenge. Current studies emphasize the tumor microenvironment that plays a vital role in tumor proliferation, invasion, metastasis, and drug resistance. The tumor microenvironment (TME) supports the cancer cell to evade conventional treatment such as surgery, radiotherapy, and chemotherapy. Moreover, the components of tumor microenvironments have a major contribution towards developing therapy resistance in solid tumors. Therefore, targeting the tumor microenvironment can be a novel approach for achieving advancement in cancer nanomedicine. The recent progress in understanding TME and developing TME-responsive nanoparticles offers a great advantage in treating cancer drug resistance. These nanoparticles are developed in response to TME stimuli such as low pH, redox, and hypoxia improve nanomedicine's pharmacokinetic and therapeutic efficacy. This review discusses the various components of the tumor microenvironment responsible for drug resistance and nanomedicine's role in overcoming it.

Cancer Nanotheranostics: A Nanomedicinal Approach for Cancer Therapy and Diagnosis.

The panorama of cancer treatment has taken a considerable leap over the last decade with the advancement in the upcoming novel therapies combined with modern diagnostics. Nanotheranostics is an emerging science that holds tremendous potential as a contrivance by integrating therapy and imaging in a single probe for cancer diagnosis and treatment thus offering the advantage like tumor-specific drug delivery and at the same time reduced side effects to normal tissues. The recent surge in nanomedicine research has also paved the way for multimodal theranostic nanoprobe towards personalized therapy through interaction with a specific biological system. This review presents an overview of the nano theranostics approach in cancer management and a series of different nanomaterials used in theranostics and the possible challenges with future directions.

Protective efficacy of crocetin and its nanoformulation against cyclosporine A-mediated toxicity in human embryonic kidney cells.

AIM: This study is aimed to formulate crocetin-loaded lipid Nanoparticles (NPs) and to evaluate its antioxidant properties in a cyclosporine A-mediated toxicity in Human Embryonic Kidney (HEK-293) cells in vitro. MAIN METHODS: Crocetin-loaded NPs were prepared followed by physicochemical characterization. In vitro protective efficacy of crocetin and crocetin loaded NPs was investigated in cyclosporine A-mediated toxicity in HEK-293 cells by assessing free radical scavenging, DNA Nicking, cytotoxicity, intracellular Reactive oxygen species (ROS) inhibition, Mitochondrial membrane potential (MMPs) loss and evaluating the activity and expression of antioxidant enzymes and non-enzyme level. Further, we have studied the mechanism of protective activity of crocetin either native or in NPs by studying the expression of phase II detoxifying proteins (HO-1) via Nrf2 mediated regulation. KEY FINDINGS: Our results showed that pretreatment with crocetin and crocetin-loaded NPs attenuated the cyclosporine A-mediated toxicity, ROS production and exhibited enhance free radical scavenging ability and cytoprotective activity. Further, the treatment prevented MMPs loss by directly scavenging the ROS and restored the antioxidant enzyme network with normalization of heme oxygenase-1 (HO-1) expression by inhibiting nuclear translocation of Nrf2. SIGNIFICANCE: Pretreatment of crocetin and crocetin-loaded NPs provided pronounce protective effect against cyclosporine A-mediated toxicity in HEK-293 cells by nullifying the ROS formation and restored antioxidant network through inhibition of Nrf2 translocation and followed by expression of HO-1. Such an approach may be anticipated to be beneficial for antioxidant therapy.

Curcumin and its topical formulations for wound healing applications.

Oxidative damage and inflammation have been identified, through clinical and preclinical studies, as the main causes of nonhealing chronic wounds. Reduction of persistent chronic inflammation by application of antioxidant and anti-inflammatory agents such as curcumin has been well studied. However, low aqueous solubility, poor tissue absorption, rapid metabolism and short plasma half-life have made curcumin unsuitable for systemic administration for better wound healing. Recently, various topical formulations of curcumin such as films, fibers, emulsion, hydrogels and different nanoformulations have been developed for targeted delivery of curcumin at wounded sites. In this review, we summarize and discuss different topical formulations of curcumin with emphasis on their wound-healing properties in animal models.

Delivery of Dual Drug Loaded Lipid Based Nanoparticles across the Blood-Brain Barrier Impart Enhanced Neuroprotection in a Rotenone Induced Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is the most widespread form of dementia where there is an age related degeneration of dopaminergic neurons in the substantia nigra region of the brain. Accumulation of α-synuclein (αS) protein aggregate, mitochondrial dysfunction, oxidative stress, and neuronal cell death are the pathological hallmarks of PD. In this context, amalgamation of curcumin and piperine having profound cognitive properties, and antioxidant activity seems beneficial. However, the blood-brain barrier (BBB) is the major impediment for delivery of neurotherapeutics to the brain. The present study involves formulation of curcumin and piperine coloaded glyceryl monooleate (GMO) nanoparticles coated with various surfactants with a view to enhance the bioavailability of curcumin and penetration of both drugs to the brain tissue crossing the BBB and to enhance the anti-parkinsonism effect of both drugs in a single platform. In vitro results demonstrated augmented inhibition of αS protein into oligomers and fibrils, reduced rotenone induced toxicity, oxidative stress, and apoptosis, and activation of autophagic pathway by dual drug loaded NPs compared to native counterpart. Further, in vivo studies revealed that our formulated dual drug loaded NPs were able to cross BBB, rescued the rotenone induced motor coordination impairment, and restrained dopaminergic neuronal degeneration in a PD mouse model.

Exploitation of redox discrepancy in leukemia cells by a reactive oxygen species nanoscavenger for inducing cytotoxicity in imatinib resistant cells.

Chronic myeloid leukemia (CML) has been the hub of exhilarating progress in cancer therapy with the advent of imatinib mesylate. However, therapeutic selectivity and drug resistance are two major issues in imatinib based leukemia therapy prompting development of strategies to surmount imatinib resistance for effective CML therapy. Growing evidences advocate that, cancer cells exhibit augmented intrinsic reactive oxygen species (ROS), due to oncogenic stimulation, amplified metabolic activity, and mitochondrial dysfunction. Since ROS activates multidrug resistant proteins in CML cells, we hypothesized that an herbal molecule having ROS scavenging property may therefore enhance imatinib induced cell death in drug resistant cells by counteracting ROS mediated drug resistance. In the present study, we document to explore an approach to simultaneously deliver two drugs (imatinib, an anticancer drug for CML therapy and curcumin a ROS scavenger) using poly (lactide-co-glycolide) (PLGA) nanoparticles for drug resistant CML cells. Such a combinational approach will help to enhance the therapeutic efficacy of imatinib by utilizing ROS scavenging properties of curcumin in imatinib resistant cell line thereby sensitizing them to chemotherapy by activating alternative modalities of cell death.

Brain Targeting of siRNA via Intranasal Pathway.

Brain diseases are the most serious health problems; represent a significant and worldwide public health problem. Small interfering RNAs (siRNAs) can initiate specific silencing of genes and are potential therapeutic agents for many genetically influenced diseases including brain disease. However, on systemic administration the blood-brain barrier (BBB) poses most significant obstacle for the therapeutic siRNAs delivery to the brain. Therefore, the development of successful approaches to enhance siRNA delivery to the brain is of immense interest in clinical and pharmaceutical research. At present, intranasal delivery approach serves as an effective mode of direct delivery of siRNAs to brain by bypassing BBB. In this review, we describe the principles of RNA interference (RNAi) machinery; challenges associated with siRNAs in therapeutics brain targeting and summarize the recent progress made in the use of vector based siRNA technology. Further, it is anticipated that intranasal delivery approach will have a very important role to play in the future for the translation of siRNAs therapeutics from bench to bedside for different brain diseases.

Magnetic Nanoparticles Labeled Mesenchymal Stem Cells: A Pragmatic Solution toward Targeted Cancer Theranostics.

Mesenchymal stem cells (MSCs) have gained much interest to be used as targeting vehicle in cancer therapy due to the intrinsic tumor-homing behavior associated with them. In this scenario, superparamagnetic nanoparticles are emerging as an ideal probe for noninvasive cell tracking for different stem cell applications. In the study, it is demonstrated that the formulated aqueous dispersible glyceryl monooleate coated magnetic nanoparticles (MNPs) can act as a better labeling and efficient tracking agent without affecting the inherent properties of MSCs. The MNPs-MSCs facilitate the stem cell tracking by magnetic resonance imaging at a very low cell number having high T2 relaxivity and potentiates the use of MNPs-MSCs as a prospective diagnostic tool. Most importantly, the homing of MNPs-MSCs toward inflammation site, subcutaneous prostate tumor (small as well as large tumor), and in orthotopic prostate tumor suggests the clinical relevance of the system. In addition, intraperitoneal delivery of MNPs-MSCs shows enhanced tumor accumulation and less sequestration in liver as revealed by in vivo imaging and histological studies. The results here demonstrate that MNPs-MSCs may prove as a better targeted delivery agent for early diagnosis of tumors even of smaller size.

Synergistic activity of combination therapy with PEGylated pemetrexed and gemcitabine for an effective cancer treatment.

Combination therapy in cancer is now opted as a potential therapeutic strategy for cancer treatment. However, effective delivery of drugs in combination at the tumor site is marred by low bioavailability and systemic toxicity of individual drugs. Polymer therapeutics is indeed an upcoming approach for the combinational drug delivery in favor of better cancer management. Hence, the objective of our investigation was to develop a dual drug PEGylated system that carries two chemotherapeutic drugs simultaneously for effective treatment of cancer. In this regard, we have synthesized Pem-PEG-Gem, wherein pemetrexed (Pem) and gemcitabine (Gem) are conjugated to a heterobifunctional polyethylene glycol (PEG) polymer for the effective treatment of Non-Small Cell Lung Cancer (NSCLC). Our results demonstrate enhanced bioavailability of the individual drugs in Pem-PEG-Gem in comparison with the drugs in their native form. The developed Pem-PEG-Gem showed enhanced cell death with respect to their native counterparts when treated singly or in combination against NSCLC cells. This might be attributed to better cellular internalization through the process of macropinocytosis and synergistic cytotoxic action of Pem-PEG-Gem in NSCLC cells. Hence, we propose the above dual drug based polymer therapeutic approach suitable for better clinical application in the treatment of NSCLC.

Multifunctional nanoparticle-EpCAM aptamer bioconjugates: a paradigm for targeted drug delivery and imaging in cancer therapy.

The promising proposition of multifunctional nanoparticles for cancer diagnostics and therapeutics has inspired the development of theranostic approach for improved cancer therapy. Moreover, active targeting of drug carrier to specific target site is crucial for providing efficient delivery of therapeutics and imaging agents. In this regard, the present study investigates the theranostic capabilities of nutlin-3a loaded poly (lactide-co-glycolide) nanoparticles, functionalized with a targeting ligand (EpCAM aptamer) and an imaging agent (quantum dots) for cancer therapy and bioimaging. A wide spectrum of in vitro analysis (cellular uptake study, cytotoxicity assay, cell cycle and apoptosis analysis, apoptosis associated proteins study) revealed superior therapeutic potentiality of targeted NPs over other formulations in EpCAM expressing cells. Moreover, our nanotheranostic system served as a superlative bio-imaging modality both in 2D monolayer culture and tumor spheroid model. Our result suggests that, these aptamer-guided multifunctional NPs may act as indispensable nanotheranostic approach toward cancer therapy. FROM THE CLINICAL EDITOR: This study investigated the theranostic capabilities of nutlin-3a loaded poly (lactide-co-glycolide) nanoparticles functionalized with a targeting ligand (EpCAM aptamer) and an imaging agent (quantum dots) for cancer therapy and bioimaging. It was concluded that the studied multifunctional targeted nanoparticle may become a viable and efficient approach in cancer therapy.

Reversal of multidrug resistance in vitro by co-delivery of MDR1 targeting siRNA and doxorubicin using a novel cationic poly(lactide-co-glycolide) nanoformulation.

Over expression of drug efflux transporters such as P-glycoprotein (P-gp) cumulatively leading to multidrug resistance (MDR) embodies a major hindrance for successful cancer therapy. A paradigm nanomedicinal approach involving an anticancer drug and modulators of drug resistance within one multifunctional nanocarrier-based delivery system represent an ideal modality for the treatment of MDR. In this regards, we have developed a cationic polymeric nanoparticulate system loaded with MDR1-siRNA and doxorubicin. Results indicated augmented synergistic effect of combinational nanoformulation in overcoming MDR in MCF-7/ADR cells. Therefore, the above regime could be a promising co-delivery system for effective therapy of drug resistant breast cancer.

Magnetic nanoparticles: a novel platform for cancer theranostics.

Multifunctional nanoplatforms represent a cutting edge tool in biomedical applications as a result of their applicability in the concurrent monitoring of medical treatment. Magnetic nanoparticles (MNPs) have generated great interest in the field of cancer nanotheranostics owing to their intrinsic magnetic property that enables them to be used as contrast agents in magnetic resonance imaging and as a therapeutic system in conjunction with hyperthermia. In addition, the physical properties and biocompatibility of MNPs help them to act as efficient drug carriers for targeted therapeutic regimes. In this review, we have discussed the different theranostic applications of MNPs. Further, we have raised the current challenges associated with the clinical translation of MNPs along with future opportunities in this field.

Multimodal Treatment Eliminates Cancer Stem Cells and Leads to Long-Term Survival in Primary Human Pancreatic Cancer Tissue Xenografts.

PURPOSE: In spite of intense research efforts, pancreatic ductal adenocarcinoma remains one of the most deadly malignancies in the world. We and others have previously identified a subpopulation of pancreatic cancer stem cells within the tumor as a critical therapeutic target and additionally shown that the tumor stroma represents not only a restrictive barrier for successful drug delivery, but also serves as a paracrine niche for cancer stem cells. Therefore, we embarked on a large-scale investigation on the effects of combining chemotherapy, hedgehog pathway inhibition, and mTOR inhibition in a preclinical mouse model of pancreatic cancer. EXPERIMENTAL DESIGN: Prospective and randomized testing in a set of almost 200 subcutaneous and orthotopic implanted whole-tissue primary human tumor xenografts. RESULTS: The combined targeting of highly chemoresistant cancer stem cells as well as their more differentiated progenies, together with abrogation of the tumor microenvironment by targeting the stroma and enhancing tissue penetration of the chemotherapeutic agent translated into significantly prolonged survival in preclinical models of human pancreatic cancer. Most pronounced therapeutic effects were observed in gemcitabine-resistant patient-derived tumors. Intriguingly, the proposed triple therapy approach could be further enhanced by using a PEGylated formulation of gemcitabine, which significantly increased its bioavailability and tissue penetration, resulting in a further improved overall outcome. CONCLUSIONS: This multimodal therapeutic strategy should be further explored in the clinical setting as its success may eventually improve the poor prognosis of patients with pancreatic ductal adenocarcinoma.

Sustained wound healing activity of curcumin loaded oleic acid based polymeric bandage in a rat model.

Wound healing is an intricate multistage process that includes inflammation, cell proliferation, matrix deposition and remodeling phases. It is often associated with oxidative stress and consequent prolonged inflammation, resulting in impaired wound healing. Curcumin has been reported to improve wound healing in different animal models. In order to increase the efficacy of curcumin in the healing arena a curcumin loaded oleic acid based polymeric (COP) bandage was formulated. The in vivo wound healing potency was compared with void bandage and control (cotton gauze treatment) in a rat model. Biochemical parameters and histological analysis revealed increased wound reduction and enhanced cell proliferation in COP bandage treated groups due to its efficient free radical scavenging properties. Comparative acceleration in wound healing was due to early implementation of fibroblasts and its differentiation (increased level of α-smooth muscle actin). Western blotting and semiquantitative PCR analysis clearly indicate that COP bandage can efficiently quench free radicals leading to reduced antioxidative enzyme activity. Further evidence at mRNA and protein level indicates that our system is potent enough to reduce the inflammatory response mediated by the NFκB pathway during wound healing. With this background, we anticipate that such a versatile approach may seed new arena for topical wound healing in the near future.

Emerging role of nanocarriers to increase the solubility and bioavailability of curcumin.

INTRODUCTION: Curcumin is a safe, affordable and natural bioactive molecule of turmeric (Curcuma longa). It has gained considerable attention in recent years for its multiple pharmacological activities. However, its optimum pharmaceutical potential has been limited by its lack of aqueous solubility and poor bioavailability. To mitigate the above limitations, recently various nanostructured water-soluble delivery systems were developed to increase the solubility and bioavailability of curcumin. AREAS COVERED: Major reasons contributing to the low bioavailability of curcumin appear to be owing to its poor solubility, low absorption, rapid metabolism and rapid systemic elimination. The present review summarizes the strategies using curcumin in various nanocarrier delivery systems to overcome poor solubility and inconsistent bioavailability of curcumin and describes the current status and challenges for the future. EXPERT OPINION: The development of various drug delivery systems to deliver curcumin will certainly provide a step up towards augmenting the therapeutic activity of curcumin thereby increasing the solubility and bioavailability of curcumin. However, the future of such delivery technology will be highly dependent on the development of safe, non-toxic and non-immunogenic nanocarriers.

Reduced folate carrier independent internalization of PEGylated pemetrexed: a potential nanomedicinal approach for breast cancer therapy.

Pemetrexed has been widely used as an effective chemotherapeutic agent for the treatment of a variety of cancers including breast cancer. It is a multitargeted antifolate that gets transported to cells primarily by reduced folate carrier (RFC) and exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. The loss of RFC leads to impaired transport of pemetrexed, which in turn decreases its intracellular concentration and reduces its cytotoxic effect on cancer cells. Furthermore, the multidrug resistance (MDR) related proteins (MRPs) contribute to pemetrexed efflux from the cancer cells. These observations prompted us to develop PEGylated pemetrexed that follows an efficient cellular internalization route independent of RFC and simultaneously bypasses the MRP efflux mechanism for acting as an efficient chemotherapeutic agent. Thus, the present study focuses on PEGylation of pemetrexed for its superior therapeutic efficiency by evaluating its cellular uptake and retention by flow cytometry, confocal microscopy, and reversed-phase high-performance liquid chromatography (RP-HPLC) in breast cancer cell lines having RFC expression and lacking RFC expression, that is, MCF7 and MDA MB231, respectively. In addition, the treatment of PEGylated pemetrexed lead to enhanced cytotoxicity due to S-phase arrest and apoptosis in the above mentioned cell lines. Interestingly, the longer circulation time of PEGylated pemetrexed in animal model concomitant with the RFC independent uptake and enhanced cytotoxicity suggests it to be a potential candidate for cancer therapy in a clinical setting.

PEGylation of an osteoclast inhibitory peptide: suitable candidate for the treatment of osteoporosis.

Osteoporosis is a condition of bone loss due to excessive osteoclastic activity. Several protein factors, such as receptor activator of nuclear factor kappa-B (RANK), receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), have been identified that are important in the pathogenesis of osteoporosis. RANKL binds to RANK and activates the NF-κB pathway by interaction of its cytoplasmic domain with an intracellular adapter protein, TNF receptor associated factors 6 (TRAF 6). This interaction can be inhibited by cell-permeable peptides that prevent RANK-TRAF 6 interaction. However, similar to the peptides/proteins used in clinical setting, the effective application of this TRAF 6 Inhibitory peptide as a therapeutic agent is marred by several limitations for instance short half-life, rapid renal clearance and immunogenicity. In the present study, we have developed PEGylated TRAF 6 Inhibitory peptide by conjugating TRAF 6 Inhibitory peptide to linear PEG backbone that exhibits longer bioavailability in plasma in the animal model. Besides, it has an enhanced uptake at its site of action, i.e., bone marrow.

Antibacterial activity of doxycycline-loaded nanoparticles.

Doxycycline is a tetracycline antibiotic with a potent antibacterial activity against a wide variety of bacteria. However, poor cellular penetration limits its use for the treatment of infectious disease caused by intracellular pathogens. One potential strategy to overcome this problem is the use of nanotechnology that can help to easily target the intracellular sites of infection. The antibacterial activity of these antibiotics is enhanced by encapsulating it in polymeric nanoparticles. In this study, we describe the improvement of the entrapment efficiency of doxycycline hydrochloride (doxycycline)-loaded PLGA:PCL nanoparticles up to 70% with variation of different formulation parameters such as polymer ratio, amount of drug loading (w/w), solvent selection, electrolyte addition, and pH alteration in the formulation. We have evaluated the efficacy of these nanoparticles over native doxycycline against a strain of Escherichia coli (DH5α) through growth inhibition and colony counting. The results indicate that doxycycline-loaded nanoparticles have superior effectiveness compared to native doxycycline against the above bacterial strain, resulting from the sustained release of doxycycline from nanoparticles. These results are encouraging for the use of these doxycycline-loaded nanoparticles for the treatment of infections caused by doxycycline-sensitive bacteria.