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Modern functional foods are designed to provide health benefits beyond basic nutrition. They are enriched with bioactive ingredients like probiotics, vitamins, minerals, and antioxidants. These foods support overall health, enhance immune function, and help prevent chronic diseases. Milk proteins and tea are known to influence satiety and regulate body weight. Studies have shown that green tea polyphenols, namely, (-)-epigallocatechin gallate (EGCG), and whey proteins, predominantly lactoferrin (LF) from milk, play a role in regulating satiety. This study aims to investigate the effect of conjugating EGCG with apo-lactoferrin (Apo-LF) and assessing these effects on satiety through monitoring glucagon-like peptide-1 (GLP-1) regulation in a human colon (NCI-H716) cell line. Apo-LF-EGCG conjugates were synthesized and characterized in terms of structural and functional properties. The effect on GLP-1 regulation was assessed by real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) to monitor gene and protein expressions, respectively. The results revealed that the protein-polyphenol interaction occurs through the complex formation of hydrogen bonds at the O-H and carbonyl groups of EGCG. The conjugates also showed a significant up-regulation of gene and protein expression levels of GLP-1 while also preventing EGCG from degradation, thereby preserving its antioxidant properties. The Apo-LF-EGCG conjugates increase satiety via increasing GLP-1 secretion in human colon cells while simultaneously retaining the antioxidant properties of EGCG. Therefore, these conjugates show potential for use as dietary supplements to enhance satiety.
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Bone is one of the most prevalent sites of metastases in various epithelial malignancies, including breast cancer and this metastasis to bone often leads to severe skeletal complications in women due to its osteolytic nature. To address this, we devised a novel drug delivery approach using an Alendronate (ALN) functionalized self-assembled porous crystalsomes for concurrent targeting of Oleanolic acid (OA) and ALN (ALN + OA@NCs) to bone metastasis. Initially, the conjugation of both PEG-OA and OA-PEG-ALN with ALN and OA was achieved, and this conjugation was then self-assembled into porous crystalsomes (ALN + OA@NCs) by nanoemulsion crystallization. The reconstruction of a 3D single particle using transmission electron microscopy ensured the crystalline porous structure of ALN + OA@NCs, was well aligned with characteristic nanoparticle attributes including size distribution, polydispersity, and zeta potential. Further, ALN + OA@NCs showed enhanced efficacy in comparison to OA@NCs suggesting the cytotoxic roles of ALN towards cancer cells, followed by augmentation ROS generation (40.81%), mitochondrial membrane depolarization (57.20%), and induction of apoptosis (40.43%). We found that ALN + OA@NCs facilitated inhibiting osteoclastogenesis and bone resorption followed by inhibited osteolysis. In vivo activity of ALN + OA@NCs in the 4 T1 cell-induced tibia model rendered a reduced bone loss in the treated mice followed by restoring bone morphometric markers which were further corroborated bone-targeting effects of ALN + OA@NCs to reduce RANKL-stimulated osteoclastogenesis. Further, In vivo intravenous pharmacokinetics showed the improved therapeutic profile of the ALN + OA@NCs in comparison to the free drug, prolonging the levels of the drug in the systemic compartment by reducing the clearance culminating the higher accumulation at the tumor site. Our finding proposed that ALN + OA@NCs can effectively target and treat breast cancer metastasis to bone and its associated complications.
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Alendronato , Neoplasias Óseas , Nanopartículas , Osteólisis , Tibia , Alendronato/administración & dosificación , Alendronato/farmacocinética , Alendronato/química , Animales , Osteólisis/prevención & control , Osteólisis/tratamiento farmacológico , Femenino , Nanopartículas/química , Nanopartículas/administración & dosificación , Tibia/efectos de los fármacos , Tibia/patología , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Porosidad , Línea Celular Tumoral , Humanos , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/farmacocinética , Ácido Oleanólico/administración & dosificación , Ácido Oleanólico/farmacocinética , Ácido Oleanólico/química , Ácido Oleanólico/análogos & derivados , Ratones Endogámicos BALB C , Ratones , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patologíaRESUMEN
This study aimed to evaluate the potential therapeutic effects of Piper chaba (PC) growing in the northern region of India, having differences in the phytochemicals, nutritional content, antimicrobial and antioxidant properties by reducing power assay (RPA), 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, phosphomolybdate assay, and antidiabetic potential by α-amylase assay with change in the geographical location. Outcomes of the gas chromatography-mass spectrometry (GC-MS) analysis revealed that phytochemicals such as piperine (46.69%), kusunokinin (8.9%), and sitostenone (7.57%) are the prominent compounds found in PC. The plant has also shown a good nutritional value, i.e., iron (11.25 mg), calcium (147 mg), and vitamin C (9.30 mg) per 100 g. PC has a higher phenolic content than other species (â 13.75 g/100 g plant powder). Among the four tested bacterial strains, the extract is best responsive toward Escherichia coli (35 ± 0.68 mm) which is more than the standard ciprofloxacin (24 ± 0.8 mm). Similarly, among two tested fungal strains, Saccharomyces cerevisiae shows the best zone of inhibition (ZOI) (27.5 ± 0.8 mm), which is greater than tat of standard amphotericin (20.25 ± 0.28 mm). The DDPH method demonstrated the highest antioxidant activity (â 42.61 ± 1.82 µg/ml). IC50 for the antidiabetic potential of PC was found to be 23.09 ± 0.3 µg/ml against α-amylase assay. A molecular docking study revealed that three compounds, piperine, sitostenone and kusunokinin, showed strong binding affinity toward bacterial tyrosyl-tRNA synthetases, fungal dihydrofolate reductase, and α-amylase, respectively. Therefore, the findings of the current study indicate that PC can be considered as a source of food and medicines, either in the form of traditional preparations or as pure active constituents. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03996-7.
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In this study, we have proposed a novel approach that combines hyaluronic acid (HA), folic acid (FA), and celastrol (CLS) within a polymeric micelle system (CLS-HF/MLs), offering a dual-action strategy against breast cancer. Polymeric mixed micelles were prepared through the thin-film hydration method, and comprehensive quality control parameters were established, encompassing particle size, polydispersity index, zeta potential, surface morphology, encapsulation efficiency, drug content, in vitro drug release, and storage stability assessment. The average particle size of CLS-HF/MLs micelles was found to be 120 nm and their drug loading and encapsulation efficiencies were 15.9 % and 89.52 %, respectively. The in vitro release data showed that the CLS-HF/MLs targeted mixed micelles displayed a prolonged release profile compared to the free drug. Additionally, the stability of the developed polymeric mixed micelles was maintained for up to 8 weeks of storage in terms of particle size and drug content. Furthermore, both flow cytometry and confocal laser scanning microscopy studies indicated a significant enhancement in the cellular uptake efficiency and cytotoxicity of CLS-HF/MLs mixed micelles against MCF-7 cell line. In terms of pharmacokinetic analysis, the half-life and AUC values of CLS-HF/MLs mixed micelles were found to be approximately 4.71- and 7.36-folds higher than the values of free drug (CLS), respectively. The CLS-HF/MLs micelles exhibited remarkable antitumor efficacy (almost complete ablation of the 4 T1-cell bearing tumor xenografts mouse model) due to the dual receptor (CD44 and folate) targeting effects with minimal side effects. When considering the cumulative findings of our present research, it becomes evident that mixed micelles designed for chemotherapy offer a promising and potentially effective therapeutic avenue for the treatment of breast cancer.
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Antineoplásicos , Liberación de Fármacos , Ácido Fólico , Ácido Hialurónico , Micelas , Triterpenos Pentacíclicos , Polímeros , Triterpenos , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Humanos , Femenino , Triterpenos/química , Triterpenos/administración & dosificación , Triterpenos/farmacocinética , Triterpenos/farmacología , Células MCF-7 , Polímeros/química , Ácido Fólico/química , Ácido Fólico/administración & dosificación , Ácido Hialurónico/química , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Tamaño de la Partícula , Ratones , Portadores de Fármacos/química , Ratones Desnudos , Ratones Endogámicos BALB C , Ratas Sprague-Dawley , Supervivencia Celular/efectos de los fármacos , Estabilidad de MedicamentosRESUMEN
Cancer treatment has seen significant advancements with the introduction of Onco-immunotherapies (OIMTs). Although some of these therapies have received approval for use, others are either undergoing testing or are still in the early stages of development. Challenges persist in making immunotherapy widely applicable to cancer treatment. To maximize the benefits of immunotherapy and minimize potential side effects, it's essential to improve response rates across different immunotherapy methods. A promising development in this area is the use of extracellular vesicles (EVs) as novel delivery systems. These small vesicles can effectively deliver immunotherapies, enhancing their effectiveness and reducing harmful side effects. This article discusses the importance of integrating nanomedicines into OIMTs, highlighting the challenges with current anti-OIMT methods. It also explores key considerations for designing nanomedicines tailored for OIMTs, aiming to improve upon existing immunotherapy techniques. Additionally, the article looks into innovative approaches like biomimicry and the use of natural biomaterial-based nanocarriers (NCs). These advancements have the potential to transform the delivery of immunotherapy. Lastly, the article addresses the challenges of moving OIMTs from theory to clinical practice, providing insights into the future of using advanced nanotechnology in cancer treatment.
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Vesículas Extracelulares , Inmunoterapia , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Inmunoterapia/métodos , Animales , Nanomedicina/métodosRESUMEN
A nanozyme is a nanoscale material having enzyme-like properties. It exhibits several superior properties, including low preparation cost, robust catalytic activity, and long-term storage at ambient temperatures. Moreover, high stability enables repetitive use in multiple catalytic reactions. Hence, it is considered a potential replacement for natural enzymes. Enormous research interest in nanozymes in the past two decades has made it imperative to look for better enzyme-mimicking materials for biomedical applications. Given this, research on metal-organic frameworks (MOFs) as a potential nanozyme material has gained momentum. MOFs are advanced hybrid materials made of inorganic metal ions and organic ligands. Their distinct composition, adaptable pore size, structural diversity, and ease in the tunability of physicochemical properties enable MOFs to mimic enzyme-like activities and act as promising nanozyme candidates. This review aims to discuss recent advances in the development of MOF-based nanozymes (MOF-NZs) and highlight their applications in the field of biomedicine. Firstly, different enzyme-mimetic activities exhibited by MOFs are discussed, and insights are given into various strategies to achieve them. Modification and functionalization strategies are deliberated to obtain MOF-NZs with enhanced catalytic activity. Subsequently, applications of MOF-NZs in the biosensing and therapeutics domain are discussed. Finally, the review is concluded by giving insights into the challenges encountered with MOF-NZs and possible directions to overcome them in the future. With this review, we aim to encourage consolidated efforts across enzyme engineering, nanotechnology, materials science, and biomedicine disciplines to inspire exciting innovations in this emerging yet promising field.
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In recent years, Onco-immunotherapies (OIMTs) have been shown to be a potential therapy option for cancer. Several immunotherapies have received regulatory approval, while many others are now undergoing clinical testing or are in the early stages of development. Despite this progress, a large number of challenges to the broad use of immunotherapies to treat cancer persists. To make immunotherapy more useful as a treatment while reducing its potentially harmful side effects, we need to know more about how to improve response rates to different types of immunotherapies. Nanocarriers (NCs) have the potential to harness immunotherapies efficiently, enhance the efficiency of these treatments, and reduce the severe adverse reactions that are associated with them. This article discusses the necessity to incorporate nanomedicines in OIMTs and the challenges we confront with current anti-OIMT approaches. In addition, it examines the most important considerations for building nanomedicines for OIMT, which may improve upon current immunotherapy methods. Finally, it highlights the applications and future scenarios of using nanotechnology.
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Sistemas de Liberación de Medicamentos , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Inmunoterapia , NanomedicinaRESUMEN
In this study, novel solid lipid particles containing the adjuvant lipid monophosphoryl lipid A (termed 'SLN-A') were synthesised. The SLN-A particles were able to efficiently bind and form complexes with a DNA vaccine encoding the urease alpha subunit of Helicobacter pylori. The resultant nanoparticles were termed lipoplex-A. In a mouse model of H. pylori infection, the lipoplex-A nanoparticles were used to immunise mice, and the resultant immune responses were analysed. It was found that the lipoplex-A vaccine was able to induce high levels of antigen-specific antibodies and an influx of gastric CD4+ T cells in vaccinated mice. In particular, a prime with lipoplex-A and a boost with soluble UreA protein induced significantly high levels of the IgG1 antibody, whereas two doses of lipoplex-A induced high levels of the IgG2c antibody. In this study, lipoplex-A vaccination did not lead to a significant reduction in H. pylori colonisation in a challenge model; however, these results point to the utility of the system for delivering DNA vaccine-encoded antigens to induce immune responses and suggest the ability to tailor those responses.
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Helicobacter pylori , Liposomas , Nanopartículas , Vacunas de ADN , Animales , Ratones , Ureasa/genética , Modelos Animales de EnfermedadRESUMEN
Imprecise targeting of chemotherapeutic drugs often leads to severe toxicity during breast cancer therapy. To address this issue, we have devised a strategy to load dacarbazine (DC) into fucose-based carbon quantum dots (CQDs), which are subsequently coated with exosomes (Ex-DC@CQDs) derived from breast cancer cells. Nanoparticle tracking analysis and western blotting revealed that Ex-DC@CQDs retained the structural and functional characteristics of exosomes. We found that exosomes facilitated the transport of DC@CQDs to cancer cells via heparan sulfate proteoglycan (HSPG) receptors, followed by an augmented depolarization of the mitochondrial membrane potential, ROS generation, and induction of apoptosis leading to cell death. In vivo imaging and pharmacokinetic studies demonstrated enhanced antitumor targeting and efficacy compared to free DC which we attribute to an improved pharmacokinetic profile, a greater tumor accumulation via exosome-mediated- HSPG receptor-driven cell uptake, and sustained release of the Ex-DC@CQDs. Our findings may pave the way for the further development of biologically sourced nanocarriers for breast cancer targeting.
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Neoplasias de la Mama , Exosomas , Puntos Cuánticos , Humanos , Femenino , Puntos Cuánticos/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Exosomas/metabolismo , Dacarbazina , Proteoglicanos de Heparán Sulfato/metabolismo , Carbono/químicaRESUMEN
The detection and identification of biomolecules are essential in the modern era of medical diagnostics. Several approaches have been established, but they have significant limitations such as laborious and time-consuming sample preparation, analysis, and the need to use external probes which provide adequate but not desired levels of accuracy and sensitivity. Herein, we have explored successfully a non-invasive technique to detect and identifybiomolecules such as amino acids and proteins by utilizing their intrinsic fluorescence. The developed confocal microscopy method revealed high and photostable emission counts of these biomolecules including amino acids (tryptophan, phenylalanine, tyrosine, proline, histidine, cysteine, aspartic acid, asparagine, isoleucine, lysine, glutamic acid, arginine) and proteins (HSA, BSA) when they are excited with a green laser. The fluorescence lifetime of the samples enabled the identification and distinction of known and blind samples of biomolecules from each other. The developed optical technique is straightforward, non-destructive and does not require laborious labeling to identify specific proteins, and may serve as the basis for the development of a device that would quickly and accurately identify proteins at an amino acid level. Therefore, this approach would open an avenue for precise detection in imaging and at the same time increases our understanding of chemical dynamics at the molecular level.
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Alanina , Aminoácidos , Aminoácidos/análisis , Fluorescencia , Metionina , Leucina , Glicina , Cistina , Valina , Serina , Treonina , Proteínas , Tirosina , ArgininaRESUMEN
In the current study, we aimed to develop lyotropic crystalline nanoconstructs (LCNs) based on poly(l-glutamic acid) (PLG) with a two-tier strategy. The first objective was to confer pH-responsive charge conversion properties to facilitate the delivery of both doxorubicin (DOX) and buparvaquone (BPQ) in combination (B + D@LCNs) to harness their synergistic effects. The second goal was to achieve targeted delivery to sigma receptors within the tumor tissues. To achieve this, we designed a pH-responsive charge conversion system using a polymer consisting of poly(ethylenimine), poly(l-lysine), and poly(l-glutamic acid) (PLG), which was then covalently coupled with methoxybenzamide (MBA) for potential sigma receptor targeting. The resulting B + D@LCNs were further modified by surface functionalization with PLG-MBA to confer both sigma receptor targeting and pH-responsive charge conversion properties. Our observations indicated that at physiological pH 7.4, P/B + D-MBA@LCNs exhibited a negative charge, while under acidic conditions (pH 5.5, characteristic of the tumor microenvironment), they acquired a positive charge. The particle size of P/B + D-MBA@LCNs was determined to be 168.23 ± 2.66 nm at pH 7.4 and 201.23 ± 1.46 nm at pH 5.5. The crystalline structure of the LCNs was confirmed through small-angle X-ray scattering (SAXS) diffraction patterns. Receptor-mediated endocytosis, facilitated by P/B + D-MBA@LCNs, was confirmed using confocal laser scanning microscopy and flow cytometry. The P/B + D-MBA@LCNs formulation demonstrated a higher rate of G2/M phase arrest (55.20%) compared to free B + D (37.50%) and induced mitochondrial depolarization (59.39%) to a greater extent than P/B + D@LCNs (45.66%). Pharmacokinetic analysis revealed significantly improved area under the curve (AUC) values for both DOX and BPQ when administered as P/B + D-MBA@LCNs, along with enhanced tumor localization. Tumor regression studies exhibited a substantial reduction in tumor size, with P/B + D-MBA@LCNs leading to 3.2- and 1.27-fold reductions compared to B + D and nontargeted P/B + D@LCNs groups, respectively. In summary, this two-tier strategy demonstrates substantial promise for the delivery of a drug combination through the prototype formulation. It offers a potential chemotherapeutic option by minimizing toxic effects on healthy cells while maximizing therapeutic efficacy.
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Neoplasias de la Mama , Nanopartículas , Receptores sigma , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Ácido Glutámico , Dispersión del Ángulo Pequeño , Difracción de Rayos X , Doxorrubicina/química , Concentración de Iones de Hidrógeno , Receptores sigma/uso terapéutico , Nanopartículas/química , Portadores de Fármacos/química , Microambiente TumoralRESUMEN
Nanovesicles and bio-vesicles (BVs) have emerged as promising tools to achieve targeted cancer therapy due to their ability to overcome many of the key challenges currently being faced with conventional chemotherapy. These challenges include the diverse and often complex pathophysiology involving the progression of cancer, as well as the various biological barriers that circumvent therapeutic molecules reaching their target site in optimum concentration. The scientific evidence suggests that surface-functionalized nanovesicles and BVs camouflaged nano-carriers (NCs) both can bypass the established biological barriers and facilitate fourth-generation targeting for the improved regimen of treatment. In this review, we intend to emphasize the role of surface-functionalized nanovesicles and BVs camouflaged NCs through various approaches that lead to an improved internalization to achieve improved and targeted oncotherapy. We have explored various strategies that have been employed to surface-functionalize and biologically modify these vesicles, including the use of biomolecule functionalized target ligands such as peptides, antibodies, and aptamers, as well as the targeting of specific receptors on cancer cells. Further, the utility of BVs, which are made from the membranes of cells such as mesenchymal stem cells (MSCs), white blood cells (WBCs), red blood cells (RBCs), platelets (PLTs) as well as cancer cells also been investigated. Lastly, we have discussed the translational challenges and limitations that these NCs can encounter and still need to be overcome in order to fully realize the potential of nanovesicles and BVs for targeted cancer therapy. The fundamental challenges that currently prevent successful cancer therapy and the necessity of novel delivery systems are in the offing.
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Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Ligandos , Péptidos/uso terapéuticoRESUMEN
Graphene quantum dots (GQDs) are prepared and characterized via X-ray diffraction (XRD), UV-Visible spectroscopy, atomic force microscopy (AFM), transmission electron microscopy (TEM) and photoluminescence (PL). GQDs are doped (5 mg and 10 mg) in the lyotropic liquid crystalline (LLC) lamellar and hexagonal phases to prepare GQD/LLC nanocolloids. Polarizing optical microscopy and X-ray diffraction measurement reveals that GQDs do not affect the lamellar and hexagonal LLC structures and may organize on their interface. Pure LLC phases and nanocolloids are studied for steady and dynamic rheological behavior. LLC phases and GQD/LLC nanocolloids possess shear thinning and frequency dependent liquid viscoelastic behavior. A complex moduli study of LLCs and GQD/LLC nanocolloids is carried out which indicates the gel to viscous transition in LLCs and GQD/LLC nanocolloids as a function of frequency. LLC phases and GQD/LLC nanocolloids are tested for antibacterial activity against Listeria ivanovii. The effect of surfactant concentration, LLC phase geometry and GQD concentration has been studied and discussed. A probable mechanism for the strong antimicrobial activity of LLCs and GQD/LLC nanocolloids is presented considering intermolecular interactions. The viscoelastic behavior and strong antibacterial activity (inhibition zone 49.2 mm) of LLCs and GQD/LLC nanocolloids make them valuable candidates for lubrication, cleaning, cosmetics and pharmaceutical applications.
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Grafito , Cristales Líquidos , Puntos Cuánticos , Antibacterianos/farmacología , Microscopía de Fuerza AtómicaRESUMEN
This study is focused to highlight the phytochemical, nutrient content and in vitro antioxidant capacity of the wildly growing plant Calyptocarpus vialis (CV) of the Asteraceae family collected from the Garhwal region of India. Phytochemical and nutritional analysis of CV is done by qualitative and quantitative methods. Fourier-transform infrared spectroscopy (FT-IR) analysis confirmed the presence of phenols, alkanes, aliphatic primary amines, carboxylic acids, nitrile, aromatics and alcohols. Gas chromatography and mass spectroscopy (GC-MS) revealed the presence of terpenoids, plant sterols and phenols such as phytol (14.9%), stigmasterol (10.02%), viridiflorol (4.19%), squalene (2.54%) and various other phytochemicals. The plant's study reveals the existence of numerous nutritious elements, including proteins, vitamins, carbohydrates and amino acids. It also revealed the presence of the huge amount of phenolic content â13.49 g in a 100-g dried CV plant sample. The antioxidant potential of methanolic extract of CV was estimated using DPPH (2, 2-diphenyl-1-picrylhydrazyl) free radical scavenging assay, phosphomolybdate assay and reducing power assay. The highest percentage of antioxidant activity determined from three assays is 74 to 87% for 1 mg of dry extract. It is observed that the CV extract act as a good antioxidant when compared to other plants of the Asteraceae family even at very low concentration of the sample. Hence, CV found in the foothills of Himalayas can be further explored as a source of potent bioactive compounds and natural and economical antioxidant for biomedical and immunity-boosting applications.
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Metal-organic frameworks (MOFs) are currently under progressive development as a tool for non-viral biomolecule delivery. Biomolecules such as proteins, lipids, carbohydrates, and nucleic acids can be encapsulated in MOFs for therapeutic purposes. The favorable physicochemical properties of MOFs make them an attractive choice for delivering a wide range of biomolecules including nucleic acids. Herein, a green fluorescence protein (GFP)-expressing plasmid DNA (pDNA) is used as a representative of a biomolecule to encapsulate within a Zn-based metal-organic framework (MOF) called a zeolitic imidazolate framework (ZIF). The synthesized biocomposites are coated with positively charged amino acids (AA) to understand the effect of surface functionalization on the delivery of pDNA to prostate cancer (PC-3) cells. FTIR and zeta potential confirm the successful preparation of positively charged amino acid-functionalized derivatives of pDNA@ZIF (i.e., pDNA@ZIFAA). Moreover, XRD and SEM data show that the functionalized derivates retain the pristine crystallinity and morphology of pDNA@ZIF. The coated biocomposites provide enhanced uptake of genetic material by PC-3 human prostate cancer cells. The AA-modulated fine-tuning of the surface charge of biocomposites results in better interaction with the cell membrane and enhances cellular uptake. These results suggest that pDNA@ZIFAA can be a promising alternative tool for non-viral gene delivery.
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Estructuras Metalorgánicas , Neoplasias de la Próstata , Zeolitas , Humanos , Masculino , Aminoácidos/genética , Zeolitas/química , ADN/química , Plásmidos/genética , Compuestos Orgánicos/química , Estructuras Metalorgánicas/química , Neoplasias de la Próstata/genéticaRESUMEN
Progesterone (PR) is an endogenous steroid hormone that activates the progesterone receptor (PgR) and is known to play a critical role in cancer progression. Herein, we report the development of cationic lipid-conjugated PR derivatives by covalently conjugating progesterone with cationic lipids of varying hydrocarbon chain lengths (n = 6-18) through a succinate linker. Cytotoxicity studies performed on eight different cancer cell lines reveal that PR10, one of the lead derivatives, exerts notable toxicity (IC50 = 4-12 µM) in cancer cells irrespective of their PgR expression status and remains largely nontoxic to noncancerous cells. Mechanistic studies show that PR10 induces G2/M-phase cell cycle arrest in cancer cells, leading to apoptosis and cell death by inhibiting the PI3K/AKT cell survival pathway and p53 upregulation. Further, in vivo study shows that PR10 treatment significantly reduces melanoma tumor growth and prolongs the overall survival of melanoma tumor-bearing C57BL/6J mice. Interestingly, PR10 readily forms stable self-aggregates of â¼190 nm size in an aqueous environment and exhibits selective uptake into cancerous cell lines. In vitro uptake mechanism studies in various cell lines (cancerous cell lines B16F10, MCF7, PC3, and noncancerous cell line HEK293) using endocytosis inhibition proves that PR10 nanoaggregates enter selectively into the cancer cells predominantly using macropinocytosis and/or caveolae-mediated endocytosis. Overall, this study highlights the development of a self-aggregating cationic derivative of progesterone with anticancer activity, and its cancer cell-selective accumulation in nanoaggregate form holds great potential in the field of targeted drug delivery.
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Melanoma , Progesterona , Ratones , Animales , Humanos , Progesterona/farmacología , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasas/metabolismo , Células HEK293 , Ratones Endogámicos C57BL , Apoptosis , Melanoma/tratamiento farmacológico , Lípidos/farmacología , Proliferación CelularRESUMEN
Telomerase, a ribonucleoprotein coded by the hTERT gene, plays an important role in cellular immortalization and carcinogenesis. hTERT is a suitable target for cancer therapeutics as its activity is highly upregulated in most of cancer cells but absent in normal somatic cells. Here, by employing the two Metal-Organic Frameworks (MOFs), viz. ZIF-C and ZIF-8, based biomineralization we encapsulate Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 plasmid system that targets hTERT gene (CrhTERT) in cancer cells. When comparing the two biocomposites, ZIF-C shows the better loading capacity and cell viability. The loaded plasmid in ZIF-C is highly protected against enzymatic degradation. CrhTERT@ZIF-C is efficiently endocytosed by cancer cells and the subcellular release of CrhTERT leads to telomerase knockdown. The resultant inhibition of hTERT expression decreases cellular proliferation and causing cancer cell death. Furthermore, hTERT knockdown shows a significant reduction in tumour metastasis and alters protein expression. Collectively we show the high potential of ZIF-C-based biocomposites as a promising general tool for gene therapy of different types of cancers.
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Neoplasias , Telomerasa , Zeolitas , Telomerasa/genética , Telomerasa/metabolismo , Zeolitas/metabolismo , Línea Celular , Imidazoles/farmacología , Terapia Genética , Neoplasias/genética , Neoplasias/terapiaRESUMEN
Chondroitin anchored crystalline nano-capsules bearing Imatinib (IMT), and simvastatin (SMV) was developed using Poly (L-lactic acid) (PLLA) by two-step method, i.e., firstly, by synthesizing chondroitin (CSA) anchored simvastatin (SMV) using cystamine as a spacer (SMV-SS-CSA) for disulfide triggered glutathione (GSH) sensitive release and secondly, by developing phenyl boronic ester grafted Pluronic F68 (PEPF) for H2O2 responsive release. By combining these conjugates, we have prepared crystalline nano-capsules (CNs) for preferential targeting of CD44 receptors. The developed CNs were spherical when characterized through SEM, TEM, and AFM for surface morphology, while changes in particle size and crystalline structure were confirmed through Quasi-Elastic light scattering (QELS) and Wide Angle X-ray Scattering (WAXS). The enhanced cellular uptake was noted in chondroitin-modified nano-capsules IMT/SMV-SS-CSA@CNs compared to unmodified nano-capsules IMT+SMV@CNs. IMT/SMV-SS-CSA@CNs displayed significantly higher G2/M phase arrest (76.9%) than unmodified nano-capsules. The prototype formulation (IMT/SMV-SS-CSA@CNs) showed an overall improved pharmacokinetic profile in terms of both half-life and AUC0-α. When tested in the 4T1 subcutaneously injected tumor-bearing Balb/c mice model, the tumor growth inhibition rate of IMT/SMV-SS-CSA@CNs was significantly higher (91%) than the IMT+SMV combination. Overall, the findings suggest that the proposed dual responsive chondroitin-modified drug delivery could have a step forward in achieving spatial and temporal targeting at the tumor site.