Specific Target Sites Research Articles

X‐Ray‐Induced Drug Release for Cancer Therapy

AbstractDrug delivery systems (DDSs) are designed to deliver therapeutic agents to specific target sites while minimizing systemic toxicity. Recent developments in drug‐loaded DDSs have demonstrated promising characteristics and paved new pathways for cancer treatment. Light, a prevalent external stimulus, is widely utilized to trigger drug release. However, conventional light sources primarily concentrate on the ultraviolet (UV) and visible light regions, which suffer from limited biological tissue penetration. This limitation hinders applications for deep‐tissue tumor drug release. Given their deep tissue penetration and well‐established application technology, X‐rays have recently received attention for the pursuit of controlled drug release. With precise spatiotemporal and dosage controllability, X‐rays stand as an ideal stimulus for achieving controlled drug release in deep‐tissue cancer therapy. This article explores the recent advancements in using X‐rays for stimulus‐triggered drug release in DDSs and delves into their action mechanisms.

Mitochondria-anchoring self-assembled nanoparticles for multi-path energy depletion: A “nano bomb” in chemo-co-starvation therapy

As the main systemic treatment for triple-negative breast cancer (TNBC), the bleak medical prognosis of chemotherapy resulted in impaired life quality by tumor recurrence and metastasis. The feasible cancer starvation therapy could inhibit tumor progression by blocking energy supplements, however, the mono-therapeutic modality showed limited curing efficacy due to heterogeneity and abnormal energy metabolism of TNBC. Thus, the development of a synergistic nano-therapeutic modality involving different anti-tumor mechanisms to simultaneously transport medicines to the organelle where metabolism took place, might remarkably improve curing efficacy, targeting ability, and bio-safety. Herein, the hybrid BLG@TPGS NPs were prepared by doping multi-path energy inhibitors Berberine (BBR) and Lonidamine (LND) as well as the chemotherapeutic agent Gambogic acid (GA). Our research indicated that Nanobomb-BLG@TPGS NPs inherited the mitochondria targeting ability from BBR to accumulate precisely at the “energy factory” mitochondria, and then induce starvation therapy to efficiently eradicated cancer cells by coordinately powered off tumor cells via a “three-prone strategy” to cut off mitochondrial respiration, glycolysis, and glutamine metabolism. The inhibition of tumor proliferation and migration was enlarged by the synergistic combination with chemotherapy. Besides, apoptosis via mitochondria pathway and mitochondria fragmentation supported the hypothesis that NPs eliminated MDA-MB-231 cells by violently attacking MDA-MB-231 cells and especially the mitochondria. In summary, this synergistic chemo-co-starvation nanomedicine proposed an innovative site-specific targeting strategy for improved tumor treatment and decreased toxicity to normal tissues, which provided an option for clinical TNBC-sensitive treatment.

Investigation into the Binding Site of (-)-Spirobrassinin for Herbicidal Activity Using Molecular Docking and Molecular Dynamics Simulations

(-)-Spirobrassinin, a glucosinolate compound from Brassicaceae plants, has shown inhibitory effects on weeds. However, its specific target sites are not well explored. This study used molecular docking, molecular dynamics simulations, and biological experiments to investigate (-)-Spirobrassinin’s target sites. The inhibitory effects of (-)-Spirobrassinin were observed on various enzymes crucial for plant metabolic pathways, including dihydroxyacid dehydrogenase, 4-hydroxyphenylpyruvate dioxygenase, protoporphyrinogen oxidase, and acetolactate synthase. Additionally, it disrupts the metabolism of vital phytohormones, namely abscisic acid and gibberellin. Molecular dynamics simulations revealed stable interactions between (-)-Spirobrassinin and specific residues (Phe270 and Phe261) of the photosystem II D1, involving electrostatic, hydrophobic, and van der Waals forces. This study provides valuable insights into (-)-Spirobrassinin’s mode of action, highlighting its potential as a natural herbicide from Brassicaceae plants.

Unforeseen consequences of synergizing PEGylated rapamycin and quercetin in angiogenesis and metastasis inhibition: Turning failure into benefit

Cancer continues to be a significant health hazard to the patient’s body around the globe, with more than 19 million incidents in 2020 worldwide, according to the world health organization, and it is expected to surpass 30 million in 2040. The advancement of nanomedicine focuses on enhancing the anticancer drugs that suffer from poor water solubility, unspecific cytotoxicity, and unfavorable pharmacokinetic properties. The most promising nanocarriers would be biodegradable and biocompatible, making the anticancer drugs soluble, preventing their aggregation, and enabling site-specific targeting. Herein, we formulated a rational design of two anticancer drugs (PEGylated rapamycin and quercetin) in a single micellar nanosystem, the ideal nanocarrier for water-insoluble drugs. After encapsulation, cytotoxicity and cellular uptake were increased. The quercetin loaded PEGylated rapamycin micelles (QRPM) exhibited significantly higher in vitro cytotoxicity in breast cancer cells than free drugs, mainly because of higher cellular uptake achieved via micelles. Moreover, the pharmacodynamic investigations indicated that QRPM significantly inhibited tumor growth compared to free drugs and PEGylated rapamycin micelles. Generally, QRPM could dramatically enhance the antitumor activity. They might be a promising drug delivery platform for anti-angiogenesis, -migration, and -invasion therapy as the nanosystem dramatically inhibited them compared with free drugs.

Magnetic chitosan oligomer-sulfonate-stearic acid triple combination as cisplatin carrier for site-specific targeted on MCF-7 cancer cells: Preparation, characterization and in vitro experiments.

In this study, a new amphiphilic target-specific adsorbent, chitosan oligomer-sulfonate-stearic acid triple combination (S-Cho-SA), and magnetic chitosan oligomer-sulfonate-stearic acid triple combination (M-S-Cho-SA) by oleic acid (OA)-modified Fe3 O4 via hydrophobic interaction are fabricated. By modifying the nanoparticle surfaces and having the ability to magnetically allow the target region, these particles attract attention as important particles used in targeting mechanisms in cancer therapy. With magnetic nanoparticles and an external magnetic field, it is possible to transport therapeutic agents to the target site and keep them in the desired effect zone for a longer period of time. These new adsorbents are characterized by scanning electron microscopy (SEM), attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy, nuclear magnetic resonance (NMR), X-ray diffraction (XRD), vibrating sample magnetometer (VSM), and thermogravimetric analysis (TG/DTA). After chemical characterization, it is complexed with cisplatin (CDDP). The magnetic adsorbents were loaded with high efficiency (>50%), and the release experiments exhibited that cisplatin is released more at pH 4.5 compared with pH 7.4 at 37°C. It showed better drug release results under a magnetic field for magnetic adsorbents (36% for pH 4.5 and 3.6% for pH 7.4). The biocompatibility of the prepared adsorbents was demonstrated via the XTT assay in MCF-7 cell lines. The results also exhibited that S-Cho-SA and M-S-Cho-SA were biocompatible, and free cisplatin and cisplatin-complexed adsorbents showed an antiproliferative effect. The results showed that these new cisplatin-loaded (M-S-Cho-SA) nanoparticles are good candidates for thermotherapy in cancer treatment in the future, as they can provide selectivity by site-specific targeting and hold onto an alternative magnetic field due to the magnetic nature of the nanoparticles.

Programmed antigen capture-harnessed dendritic cells by margination-hitchhiking lung delivery.

Adoptive T cells and immunotherapy suppress the most destructive metastatic tumors and prevent tumor recurrence by inducing T lymphocytes. However, the heterogeneity and immune privilege of invasive metastatic clusters often reduce immune cell infiltration and therapeutic efficacy. Here, the red blood cells (RBC)-hitchhiking mediated lung metastasis delivery of multi-grained iron oxide nanostructures (MIO) programming the antigen capture, dendritic cell harnessing, and T cell recruitment is developed. MIO is assembled to the surface of RBCs by osmotic shock-mediated fusion, and reversible interactions enable the transfer of MIO to pulmonary capillary endothelial cells by intravenous injection by squeezing RBCs at the pulmonary microvessels. RBC-hitchhiking delivery revealed that >65% of MIOs co-localized in tumors rather than normal tissues. In alternating magnetic field (AMF)-mediated magnetic lysis, MIO leads to the release of tumor-associated antigens, namely neoantigens and damage-associated molecular patterns. It also acted as an antigen capture agent-harnessed dendritic cells delivers these antigens to lymph nodes. By utilizing site-specific targeting, erythrocyte hitchhiker-mediated delivery of MIO to lung metastases improves survival and immune responses in mice with metastatic lung tumors.

Transformable Neuropeptide Prodrug with Tumor Microenvironment Responsiveness for Tumor Growth and Metastasis Inhibition of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) has the worstprognosis among all breast cancer subtypes due to lack of specific target sites and effective treatments. Herein, a transformable prodrug (DOX-P18) based on neuropeptide Y analogue with tumor microenvironment responsiveness is developed for TNBC treatment. The prodrug DOX-P18 can achieve reversible morphological transformation between monomers and nanoparticles through the manipulation of protonation degree in different environments. It can self-assemble into nanoparticles to enhance the circulation stability and drug delivery efficiency in the physiological environment while transforming from nanoparticles to monomers and being endocytosed into the breast cancer cells in the acidic tumor microenvironment. Further, the DOX-P18 can precisely be enriched in the mitochondria, and efficiently activated by matrix metalloproteinases. Then, the cytotoxic fragment (DOX-P3) can subsequently be diffused into the nucleus, generating a sustained cell toxicity effect. In the meanwhile, the hydrolysate residue P15 can assemble into nanofibers to construct nest-like barriers for the metastasis inhibition of cancer cells. After intravenous injection, the transformable prodrug DOX-P18 demonstrated superior tumor growth and metastasis suppression with much better biocompatibility and improved biodistribution compared to free DOX. As a novel tumor microenvironment-responsive transformable prodrug with diversified biological functions, DOX-P18 shows great potential in smart chemotherapeutics discovery for TBNC.

Cell penetrating peptides-functionalized Licochalcone-A-loaded PLGA nanoparticles for ocular inflammatory diseases: Evaluation of in vitro anti-proliferative effects, stabilization by freeze-drying and characterization of an in-situ forming gel

Licochalcone-A (Lico-A) PLGA NPs functionalized with cell penetrating peptides B6 and Tet-1 are proposed for the treatment of ocular anti-inflammatory diseases. In this work, we report the in vitro biocompatibility of cell penetrating peptides-functionalized Lico-A-loaded PLGA NPs in Caco-2 cell lines revealing a non-cytotoxic profile, and their anti-inflammatory activity against RAW 264.7 cell lines. Given the risk of hydrolysis of the liquid suspensions, freeze-drying was carried out testing different cryoprotectants (e.g., disaccharides, alcohols, and oligosaccharide-derived sugar alcohol) to prevent particle aggregation and mitigate physical stress. As the purpose is the topical eye instillation of the nanoparticles, to reduce precorneal wash-out, increase residence time and thus Lico-A bioavailability, an in-situ forming gel based on poloxamer 407 containing Lico-A loaded PLGA nanoparticles functionalized with B6 and Tet-1 for ocular administration has been developed. Developed formulations remain in a flowing semi-liquid state under non-physiological conditions and transformed into a semi-solid state under ocular temperature conditions (35 °C), which is beneficial for ocular administration. The pH, viscosity, texture parameters and gelation temperature results met the requirements for ophthalmic formulations. The gel has characteristics of viscoelasticity, suitable mechanical and mucoadhesive performance which facilitate its uniform distribution over the conjunctiva surface. In conclusion, we anticipate the potential clinical significance of our developed product provided that a synergistic effect is achieved by combining the high anti-inflammatory activity of Lico-A delivered by PLGA NPs with B6 and Tet-1 for site-specific targeting in the eye, using an in-situ forming gel.

A Detail Insight of Wilson’s Disease and its Treatment

Wilson disease is a rare inherited autosomal recessive genetic disorder caused by abnormal copper accumulation in the body, particularly involving the brain, liver, eyes, and other vital organs. This is also known as hepatolenticular degeneration. It primarily affects the liver and basal ganglia of the brain, but it can affect other vital organs too. It results from a mutation in the gene encoding the Wilson disease protein (ATP7B). It results from a mutation in the gene encoding the Wilson disease protein (ATP7B). A healthy body excretes extra copper through urine after the liver filters it out. Wilson's disease prevents the liver from effectively removing the excess copper. The extra copper then builds up in organs such as the brain, liver, and eyes; which is the reason why symptoms are usually related to the brain and liver. One of the 23 chromosomes in humans, chromosome 13, has a gene that causes Wilson's disease. For six months, a 12-year-old kid with Wilson's disease complained of speech problems, swallowing issues, and general stiffness. About 97 percent of those with Wilson's illness have K-F rings. Vomiting, weakness, ascites, yellowing of the skin, and brain or neurological symptoms like tremors, muscle stiffness, difficulty speaking, personality changes, or visual hallucinations are only a few of the symptoms associated with the liver. Sunflower cataracts are visible in 1 in 5 patients with Wilson's illness. One in 90 people in the general population are carriers of Wilson's illness. A liver biopsy, clinical evaluation, blood testing, urine tests, and a challenging diagnosis are all required. The family members of persons with the condition may be screened via genetic testing. For Wilson's disease to be stopped in its tracks, early detection is essential. Treatment can be done by both ayurvedic remedies using herbs and allopathy using drugs with specific target sites important for managing Wilson disease. WD can be treated with Copper chelating agents and Herbs act as a supporting treatment. Some drugs are still in the clinical trial phase.
 Keywords: Kayser-Fleischer rings, Wilson disease (WD), ALXN1840, d-Penicillinase, Vatavyadhi.

Current and emerging trends in oro-dental healthcare and cranio-maxillo-facial surgery

Dentistry is an ever-evolving field that has seen significant advances in recent years. This article sheds light on some of the current and emerging trends in oral health care, including digital dentistry, regenerative medicine, and the use of lasers. For example, digital dentistry involves the use of computer-aided design and manufacturing technology, which enables more accurate and efficient production of dental devices. On the other hand, regenerative medicine and nanoDentistry can be considered promising area that combines the use of stem cells, growth factors, biomaterials, and nanotechnology to regenerate damaged tissue and improve treatment outcomes. Lasers are increasingly being used in dentistry for a range of applications, including the treatment of gum disease and teeth whitening. Other developing technologies such as 3D printing and artificial intelligence are also being increasingly incorporated into dentistry, providing improved treatment options for our patients. Last yet definitely would/will not least, controlled drug delivery systems are being developed to deliver drugs to specific target sites in a localized and sustained manner, reducing the risk of adverse effects. Currently, these emerging trends are transforming the landscape of odontology and beyond. Hence, in this mini-Review, we explore such trends in oro-dental and cranio-maxillo-facial indications to highlight the potential benefits, advancements, and opportunities of applications for improved patient care.

NANOSPONGES - A REVOLUTIONARY TARGETED DRUG DELIVERY NANOCARRIER: A REVIEW

Effective targeted drug delivery systems have long been a dream, but have been largely hampered by the complex chemistries involved in developing new systems. The creation of novel colloidal carriers known as nanosponges has the potential to resolve these issues. An innovative and developing technology called nanosponge provides regulated medication delivery for topical application. Highly porous nanosponges have a unique capacity to entrap active molecules and have the advantage of programmable release. Nanosponges are small three-dimensional porous structures about the size of nanometer that can contain many different drugs. These tiny sponges can move throughout the body until they meet a specific target site and attach to surfaces and begin to release the drug in a controlled and predictable manner. Because the drug can be delivered to a specific target site instead of circulating throughout the body, it is more effective for a given specific dose. They are easy to make and safe for biological use. Different types of cyclodextrins can be cross-linked using a carbonyl or a dicarboxylate chemical as a cross-linker to create nanosponges. This groundbreaking technology has been extensively investigated for the delivery of medications for oral, topical, and parental administrations. Vaccines, antibodies, proteins, and enzymes can all be effectively transported via Nanosponges. The current review emphasizes the methods, advantages, disadvantages, characterization, and applications of nanosponges.

Starships are active eukaryotic transposable elements mobilized by a new family of tyrosine recombinases

Transposable elements in eukaryotic organisms have historically been considered "selfish," at best conferring indirect benefits to their host organisms. The Starships are a recently discovered feature in fungal genomes that are, in some cases, predicted to confer beneficial traits to their hosts and also have hallmarks of being transposable elements. Here, we provide experimental evidence that Starships are indeed autonomous transposons, using the model Paecilomyces variotii, and identify the HhpA "Captain" tyrosine recombinase as essential for their mobilization into genomic sites with a specific target site consensus sequence. Furthermore, we identify multiple recent horizontal gene transfers of Starships, implying that they jump between species. Fungal genomes have mechanisms to defend against mobile elements, which are frequently detrimental to the host. We discover that Starships are also vulnerable to repeat-induced point mutation defense, thereby having implications on the evolutionary stability of such elements.

PASTE, Don't Cut: Genome Editing Tool Looks Beyond CRISPR and Prime

PASTE, Don't Cut: Genome Editing Tool Looks Beyond CRISPR and Prime

Rolling circle extension-assisted loop-mediated isothermal amplification (Rol-LAMP) method for locus-specific and visible detection of RNA N6-methyladenosine.

N6-methyladenosine (m6A) is the most prevalent RNA modification in eukaryotic mRNAs. Currently available detection methods for locus-specific m6A marks rely on RT-qPCR, radioactive methods, or high-throughput sequencing. Here, we develop a non-qPCR, ultrasensitive, isothermal, and naked-eye visible method for m6A detection based on rolling circle amplification (RCA) and loop-mediated isothermal amplification (LAMP), named m6A-Rol-LAMP, to verify putative m6A sites in transcripts obtained from the high-throughput data. When padlock probes hybridize to the potential m6A sites on targets, they are converted to circular form by DNA ligase in the absence of m6A modification, while m6A modification hinders the sealing of padlock probes. Subsequently, Bst DNA polymerase-mediated RCA and LAMP allow the amplification of the circular padlock probe to achieve the locus-specific detection of m6A. Following optimization and validation, m6A-Rol-LAMP can ultra-sensitively and quantitatively determine the existence of m6A modification on a specific target site as low as 100 amol under isothermal conditions. Detections of m6A can be performed on rRNA, mRNA, lincRNA, lncRNAand pre-miRNA from biological samples with naked-eye observations after dye incubation. Together, we provide a powerful tool for locus-specific detection of m6A, which can simply, quickly, sensitively, specifically, and visually determine putative m6A modification on RNA.

CRGD-Functionalized Silk Fibroin Nanoparticles: A Strategy for Cancer Treatment with a Potent Unselective Naphthalene Diimide Derivative

Developing drug delivery systems to target cytotoxic drugs directly into tumor cells is still a compelling need with regard to reducing side effects and improving the efficacy of cancer chemotherapy. In this work, silk fibroin nanoparticles (SFNs) have been designed to load a previously described cytotoxic compound (NDI-1) that disrupts the cell cycle by specifically interacting with non-canonical secondary structures of DNA. SFNs were then functionalized on their surface with cyclic pentapeptides incorporating the Arg-Gly-Asp sequence (cRGDs) to provide active targeting toward glioma cell lines that abundantly express ανβ3 and ανβ5 integrin receptors. Cytotoxicity and selective targeting were assessed by in vitro tests on human glioma cell lines U373 (highly-expressing integrin subunits) and D384 cell lines (low-expressing integrin subunits in comparison to U373). SFNs were of nanometric size (d50 less than 100 nm), round shaped with a smooth surface, and with a negative surface charge; overall, these characteristics made them very likely to be taken up by cells. The active NDI-1 was loaded into SFNs with high encapsulation efficiency and was not released before the internalization and degradation by cells. Functionalization with cRGDs provided selectivity in cell uptake and thus cytotoxicity, with a significantly higher cytotoxic effect of NDI-1 delivered by cRGD-SFNs on U373 cells than on D384 cells. This manuscript provides an in vitro proof-of-concept of cRGD-silk fibroin nanoparticles' active site-specific targeting of tumors, paving the way for further in vivo efficacy tests.

Modeling mitochondrial DNA diseases: from base editing to pluripotent stem-cell-derived organoids.

Mitochondrial DNA (mtDNA) diseases are multi-systemic disorders caused by mutations affecting a fraction or the entirety of mtDNA copies. Currently, there are no approved therapies for the majority of mtDNA diseases. Challenges associated with engineering mtDNA have in fact hindered the study of mtDNA defects. Despite these difficulties, it has been possible to develop valuable cellular and animal models of mtDNA diseases. Here, we describe recent advances in base editing of mtDNA and the generation of three-dimensional organoids from patient-derived human-induced pluripotent stem cells (iPSCs). Together with already available modeling tools, the combination of these novel technologies could allow determining the impact of specific mtDNA mutations in distinct human cell types and might help uncover how mtDNA mutation load segregates during tissue organization. iPSC-derived organoids could also represent a platform for the identification of treatment strategies and for probing the in vitro effectiveness of mtDNA gene therapies. These studies have the potential to increase our mechanistic understanding of mtDNA diseases and may open the way to highly needed and personalized therapeutic interventions.

Biodegradable polymeric nanoparticles: The novel carrier for controlled release drug delivery system

In the recent decades, polymers are widely used as biomaterials due to their favourable properties such as good biocompatibility, easy design and preparation, structural varieties and interesting bio-mimetic character. The use of biodegradable polymeric nanoparticles (NPs) for controlled drug delivery has shown significant therapeutic potential. Concurrently, targeted delivery technologies are becoming increasingly important as a scientific area of investigation. The current review entails an in-depth discussion of biodegradable polymeric nanoparticles with respect to types, formulation aspects as well as site-specific drug targeting using various ligands modifying the surface of polymeric nanoparticles with special insights to the field of oncology. Ultimately the goal of polymeric nanoparticle drug delivery is the emergence of a nano-fabricated therapeutic drug release device with the capacity to enough hold and release of various active agents on demand.

Nanoparticle drug delivery systems for synergistic delivery of tumor therapy.

Nanoparticle drug delivery systems have proved anti-tumor effects; however, they are not widely used in tumor therapy due to insufficient ability to target specific sites, multidrug resistance to anti-tumor drugs, and the high toxicity of the drugs. With the development of RNAi technology, nucleic acids have been delivered to target sites to replace or correct defective genes or knock down specific genes. Also, synergistic therapeutic effects can be achieved for combined drug delivery, which is more effective for overcoming multidrug resistance of cancer cells. These combination therapies achieve better therapeutic effects than delivering nucleic acids or chemotherapeutic drugs alone, so the scope of combined drug delivery has also been expanded to three aspects: drug-drug, drug-gene, and gene-gene. This review summarizes the recent advances of nanocarriers to co-delivery agents, including i) the characterization and preparation of nanocarriers, such as lipid-based nanocarriers, polymer nanocarriers, and inorganic delivery carriers; ii) the advantages and disadvantages of synergistic delivery approaches; iii) the effectual delivery cases that are applied in the synergistic delivery systems; and iv) future perspectives in the design of nanoparticle drug delivery systems to co-deliver therapeutic agents.

The Technologist's Dilemma

The Technologist's Dilemma

Active Hydrophilic Graphene Oxide Nanocomposites Delivery Mediated by Adipose-Derived Stem Cell for Elevated Photothermal Therapy of Breast Cancer.

Graphene oxide (GO) and its derivatives have recently been identified as promising candidates for early disease diagnosis and therapy. However, the physiological stability and precise launch requirements present limitations on further clinical practices. Adipose-derived stem cells (ADSCs) were employed as an unobstructed biological vehicle to address the validate this ADSC-based tumor-targeting system for highly efficient GO delivery combined with two-stage NIR radiation for superior tumor ablation. GO was modified with poly-ethylene glycol (PEG) and folic acid (FA). Afterward, the GO nanocomposite was internalized into ADSCs. The GO-PEG-FA-laden ADSCs were injected into the tail veins of the tumor-bearing mice. Subsequently, first-stage NIR radiation was utilized to disrupt the ADSCs for GO-PEG-FA release. After this, the heat generated by secondary-stage NIR radiation destroy the malignant cells and shrink the tumor, and the cascade process could be recycled until complete tumor ablation if necessary. The GO-PEG-FA nanocomposite exhibited negligible cytotoxicity and could be internalized into ADSCs to target specific tumor sites after 32 days of intravenous injection. The nanocomposite was released from the ADSCs and taken up into cancer cells again with the assistance of FA after the first dose of near-infrared radiation. Then, the second radiation dose could directly strike the cancer cell for cancer ablation. In summary, we reported a stem cell-based anticancer system that used GO-PEG-FA-laden ADSCs for breast cancer therapy through NIR treatment in mice potentially opens a new avenue not only to address precise drug targeting in tumor therapy, but also future clinical practice in diverse areas.