Transdermal Delivery of Chemotherapeutics: Strategies, Requirements, and Opportunities.
TL;DR: In this paper, the authors discuss the advantages of transdermal route over oral and parenteral routes for popular chemotherapeutic drugs and also discuss a possible in silico approach, Formulating for Efficacy™, to design trans-dermal formulations that would probably be economical, robust, and more efficacious.
Abstract: Chemotherapeutic drugs are primarily administered to cancer patients via oral or parenteral routes. The use of transdermal drug delivery could potentially be a better alternative to decrease the dose frequency and severity of adverse or toxic effects associated with oral or parenteral administration of chemotherapeutic drugs. The transdermal delivery of drugs has shown to be advantageous for the treatment of highly localized tumors in certain types of breast and skin cancers. In addition, the transdermal route can be used to deliver low-dose chemotherapeutics in a sustained manner. The transdermal route can also be utilized for vaccine design in cancer management, for example, vaccines against cervical cancer. However, the design of transdermal formulations may be challenging in terms of the conjugation chemistry of the molecules and the sustained and reproducible delivery of therapeutically efficacious doses. In this review, we discuss the nano-carrier systems, such as nanoparticles, liposomes, etc., used in recent literature to deliver chemotherapeutic agents. The advantages of transdermal route over oral and parenteral routes for popular chemotherapeutic drugs are summarized. Furthermore, we also discuss a possible in silico approach, Formulating for Efficacy™, to design transdermal formulations that would probably be economical, robust, and more efficacious.
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TL;DR: In this paper , a review of protein corona and its impact on physico-chemical and biological properties of nanoparticles is presented, which can be used to optimize nanoparticles for in vivo application.
Abstract: Nanomedicine has a great potential to revolutionize the therapeutic landscape. However, up-to-date results obtained from in vitro experiments predict the in vivo performance of nanoparticles weakly or not at all. There is a need for in vitro experiments that better resemble the in vivo reality. As a result, animal experiments can be reduced, and potent in vivo candidates will not be missed. It is important to gain a deeper knowledge about nanoparticle characteristics in physiological environment. In this context, the protein corona plays a crucial role. Its formation process including driving forces, kinetics, and influencing factors has to be explored in more detail. There exist different methods for the investigation of the protein corona and its impact on physico-chemical and biological properties of nanoparticles, which are compiled and critically reflected in this review article. The obtained information about the protein corona can be exploited to optimize nanoparticles for in vivo application. Still the translation from in vitro to in vivo remains challenging. Functional in vitro screening under physiological conditions such as in full serum, in 3D multicellular spheroids/organoids, or under flow conditions is recommended. Innovative in vivo screening using barcoded nanoparticles can simultaneously test more than hundred samples regarding biodistribution and functional delivery within a single mouse.
8 citations
TL;DR: In this article , the advanced strategies of mineral drug delivery systems in tumor therapy are summarized and the therapeutic advantages and research progress of novel mineral drugs delivery systems are also discussed, and the authors hope that this will provide a useful reference for the design and application of new mineral drug deliver systems.
Abstract: Mineral drugs are an important constituent of traditional Chinese medicine (TCM). Taking minerals that contain heavy metals as drugs is a very national characteristic part of TCM. However, the safety and scientific nature of mineral drugs are controversial owing to their heavy metals and strong toxicity. In 2000, the Food and Drug Administration (FDA) authorized arsenic trioxide (ATO) as first-line therapy for acute promyelocytic leukemia. This makes the development and utilization of mineral drugs become a research hotspot. The development of nanomedicine has found a great prospect of mineral drugs in nano-delivery carriers. And that will hold promise to address the numerous biological barriers facing mineral drug formulations. However, the studies on mineral drugs in the delivery system are few at present. There is also a lack of a detailed description of mineral drug delivery systems. In this review, the advanced strategies of mineral drug delivery systems in tumor therapy are summarized. In addition, the therapeutic advantages and research progress of novel mineral drug delivery systems are also discussed. Here, we hope that this will provide a useful reference for the design and application of new mineral drug delivery systems.
7 citations
TL;DR: In this article , the authors developed MXD-loaded double emulsion nanoparticles (MXD-DE-NPs) using poly(D,L-lactide-co-glycolide; PLGA) and surfactants.
5 citations
TL;DR: In this paper , a simple, cost-effective approach for functionalizing multiwalled carbon nanotubes with the carbohydrate ligands, galactose (GA), mannose (MA) and lactose (LA), using lysine as a linker, was reported.
Abstract: Multiwalled carbon nanotubes (MWCNTs) are elongated, hollow cylindrical nanotubes made of sp2 carbon. MWCNTs have attracted significant attention in the area of drug delivery due to their high drug-loading capacity and large surface area. Furthermore, they can be linked to bioactive ligands molecules via covalent and noncovalent bonds that allow for the targeted delivery of anticancer drugs such as doxorubicin. The majority of methodologies reported for the functionalization of MWCNTs for drug delivery are quite complex and use expensive linkers and ligands. In the present study, we report a simple, cost-effective approach for functionalizing MWCNTs with the carbohydrate ligands, galactose (GA), mannose (MA) and lactose (LA), using lysine as a linker. The doxorubicin (Dox)-loaded functionalized MWCNTs were characterized using FT-IR, NMR, Raman, XRD and FE-SEM. The drug–loaded MWCNTs were evaluated for drug loading, drug release and cell toxicity in vitro, in breast cancer cells. The results indicated that the carbohydrate-modified lysinated MWCNTs had greater Dox loading capacity, compared to carboxylated MWCNTs (COOHMWCNTs) and lysinated MWCNTs (LyMWCNTs). In vitro drug release experiments indicated that the carbohydrate functionalized LyMWCNTs had higher Dox release at pH 5.0, compared to the physiological pH of 7.4, over 120 h, indicating that they are suitable candidates for targeting the tumor microenvironment as a result of their sustained release profile of Dox. Doxorubicin-loaded galactosylated MWCNTs (Dox-GAMWCNTs) and doxorubicin loaded mannosylated MWCNTs (Dox-MAMWCNTs) had greater anticancer efficacy and cellular uptake, compared to doxorubicin–loaded lactosylated MWCNTs (Dox-LAMWCNTs) and pure Dox, in MDA-MB231 and MCF7 breast cancer cells. However, neither the ligand conjugated multiwall blank carbon nanotubes (GAMWCNTs, MAMWCNTs and LAMWCNTs) nor the lysinated multiwalled blank carbon nanotubes produced significant toxicity in the normal cells. Our results suggest that sugar-tethered multiwalled carbon nanotubes, especially the galactosylated (Dox-GAMWCNTs) and mannosylated (Dox-MAMWCNTs) formulations, may be used to improve the targeted delivery of anticancer drugs to breast cancer cells.
5 citations
TL;DR: Testing whether drugs which inhibit the AKT3-associated gene, discoidin domain receptor tyrosine kinase 2 (DDR2) specifically targeted cells deficient in E-cadherin demonstrated heightened sensitivity to dasatinib, a drug that targets multiple kinases including DDR2 and SRC.
Abstract: Simple Summary Inactivating mutations in the CDH1 gene, encoding the cell adhesion protein E-cadherin, cause hereditary diffuse gastric cancer syndrome (HDGC), as well as being a hallmark of sporadic diffuse gastric cancers and lobular breast cancers. We have previously identified AKT3 as a potential vulnerability in gastric cancers lacking CDH1 expression. This study aimed to test whether drugs which inhibit the AKT3-associated gene, discoidin domain receptor tyrosine kinase 2 (DDR2) specifically targeted cells deficient in E-cadherin. We demonstrated that cells and organoids lacking E-cadherin exhibited heightened sensitivity to dasatinib, a drug that targets multiple kinases including DDR2 and SRC. Abstract The CDH1 gene, encoding the cell adhesion protein E-cadherin, is one of the most frequently mutated genes in gastric cancer and inactivating germline CDH1 mutations are responsible for the cancer syndrome hereditary diffuse gastric cancer (HDGC). CDH1-deficient gastric cancers exhibit high AKT serine/threonine kinase 3 (AKT3) expression, but specific drugs against this AKT isoform are not available. We therefore used two publicly available datasets to identify AKT3-associated genes which could be used to indirectly target AKT3. Reactome analysis identified an enrichment of extracellular matrix remodelling genes in AKT3-high gastric cancers. Of the 51 genes that were significantly correlated with AKT3 (but not AKT1), discoidin domain receptor tyrosine kinase 2 (DDR2) showed the strongest positive association. Treatment of isogenic human cells and mouse gastric and mammary organoids with dasatinib, a small molecule inhibitor of multiple kinases including SRC, BCR-ABL and DDR2, preferentially slowed the growth and induced apoptosis of E-cadherin-deficient cells. Dasatinib treatment also preferentially slowed the growth of gastric and mammary organoids harbouring both Cdh1 and Tp53 mutations. In organoid models, dasatinib treatment was associated with decreased phosphorylation of total AKT, with a stronger effect seen in Cdh1-deficient organoids. Treatment with combinations of dasatinib and an inhibitor of AKT, MK2206, enhanced the effect of dasatinib in breast MCF10A cells. In conclusion, targeting the DDR2-SRC-AKT3 axis with dasatinib represents a promising approach for the chemoprevention and chemotherapy of gastric and breast cancers lacking E-cadherin.
4 citations
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TL;DR: In the United States, the cancer death rate has dropped continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment as mentioned in this paper.
Abstract: Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2017) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2018) were collected by the National Center for Health Statistics. In 2021, 1,898,160 new cancer cases and 608,570 cancer deaths are projected to occur in the United States. After increasing for most of the 20th century, the cancer death rate has fallen continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment. This translates to 3.2 million fewer cancer deaths than would have occurred if peak rates had persisted. Long-term declines in mortality for the 4 leading cancers have halted for prostate cancer and slowed for breast and colorectal cancers, but accelerated for lung cancer, which accounted for almost one-half of the total mortality decline from 2014 to 2018. The pace of the annual decline in lung cancer mortality doubled from 3.1% during 2009 through 2013 to 5.5% during 2014 through 2018 in men, from 1.8% to 4.4% in women, and from 2.4% to 5% overall. This trend coincides with steady declines in incidence (2.2%-2.3%) but rapid gains in survival specifically for nonsmall cell lung cancer (NSCLC). For example, NSCLC 2-year relative survival increased from 34% for persons diagnosed during 2009 through 2010 to 42% during 2015 through 2016, including absolute increases of 5% to 6% for every stage of diagnosis; survival for small cell lung cancer remained at 14% to 15%. Improved treatment accelerated progress against lung cancer and drove a record drop in overall cancer mortality, despite slowing momentum for other common cancers.
9,661 citations
TL;DR: It is suggested that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.
Abstract: Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.
4,786 citations
TL;DR: Signal transducer and activator of transcription proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer, and STAT3 is a promising target to redirect inflammation for cancer therapy.
Abstract: Commensurate with their roles in regulating cytokine-dependent inflammation and immunity, signal transducer and activator of transcription (STAT) proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer. Persistently activated STAT3 and, to some extent, STAT5 increase tumour cell proliferation, survival and invasion while suppressing anti-tumour immunity. The persistent activation of STAT3 also mediates tumour-promoting inflammation. STAT3 has this dual role in tumour inflammation and immunity by promoting pro-oncogenic inflammatory pathways, including nuclear factor-kappaB (NF-kappaB) and interleukin-6 (IL-6)-GP130-Janus kinase (JAK) pathways, and by opposing STAT1- and NF-kappaB-mediated T helper 1 anti-tumour immune responses. Consequently, STAT3 is a promising target to redirect inflammation for cancer therapy.
3,564 citations
Journal Article•
TL;DR: Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis, and Pharmacologically,Curcumin has been found to be safe.
Abstract: Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over the last 50 years has indicated this polyphenol can both prevent and treat cancer. The anticancer potential of curcumin stems from its ability to suppress proliferation of a wide variety of tumor cells, down-regulate transcription factors NF- κB, AP-1 and Egr-1; down-regulate the expression of COX2, LOX, NOS, MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules and cyclin D1; down-regulate growth factor receptors (such as EGFR and HER2); and inhibit the activity of c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases. In several systems, curcumin has been described as a potent antioxidant and anti-inflammatory agent. Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis. Pharmacologically, curcumin has been found to be safe. Human clinical trials indicated no dose-limiting toxicity when administered at doses up to 10 g/day. All of these studies suggest that curcumin has enormous potential in the prevention and therapy of cancer. The current review describes in detail the data supporting these studies. Curcumin, derived from turmeric (vernacular name: Haldi), is a rhizome of the plant Curcuma longa. The medicinal use of this plant has been documented in Ayurveda (the Indian
2,453 citations
TL;DR: The new HPV-oriented model of cervical carcinogenesis should gradually replace older morphological models based only on cytology and histology, and can minimise the incidence of cervical cancer, and the morbidity and mortality it causes, even in low-resource settings.
2,429 citations