Phage‐Enabled Nanomedicine: From Probes to Therapeutics in Precision Medicine

Both lytic and temperate bacteriophages (phages) can be applied in nanomedicine, in particular, as nanoprobes for precise disease diagnosis and nanotherapeutics for targeted disease treatment. Since phages are bacteria‐specific viruses, they do not naturally infect eukaryotic cells and are not toxic to them. They can be genetically engineered to target nanoparticles, cells, tissues, and organs, and can also be modified with functional abiotic nanomaterials for disease diagnosis and treatment. This Review will summarize the current use of phage structures in many aspects of precision nanomedicine, including ultrasensitive biomarker detection, enhanced bioimaging for disease diagnosis, targeted drug and gene delivery, directed stem cell differentiation, accelerated tissue formation, effective vaccination, and nanotherapeutics for targeted disease treatment. We will also propose future directions in the area of phage‐based nanomedicines, and discuss the state of phage‐based clinical trials.     

Advanced polymeric dendrimers in the management of Alzheimer's disease

In recent years, advanced polymeric dendrimers have emerged as a promising avenue for AD management. Dendrimers are highly branched, three-dimensional macromolecules with precise nanoarchitectures, making them ideal candidates for the delivery of therapeutic agents and diagnostic tools. Their unique properties, such as well-defined size, multifunctionality, and controlled surface chemistry, allow for the design of targeted and highly efficient drug delivery systems and diagnostic probes. This review aims to provide a comprehensive overview of the potential applications of advanced polymeric dendrimers in the management of Alzheimer's disease. We explored their role in drug delivery, diagnostics, and other therapeutic interventions for AD. Additionally, we will delve into the challenges and opportunities in utilizing dendrimers as a key player in the battle against this devastating disease. The review will begin by discussing the current state of Alzheimer's disease, including its pathological features, clinical manifestations, and existing treatment strategies. It will then transition to an in-depth examination of polymeric dendrimers, highlighting their structural characteristics, synthesis methods, and biocompatibility. Subsequently, the review will delve into the various ways in which dendrimers can be tailored for AD management, including drug encapsulation and delivery, enhanced blood–brain barrier penetration, and targeted diagnostic imaging. Furthermore, we explored the potential benefits of dendrimer-based therapies, such as improved drug efficacy, reduced side effects, and enhanced patient compliance. The review will also address the challenges associated with dendrimer-based approaches, including toxicity concerns, regulatory hurdles, and the need for rigorous clinical evaluation.     

Application of Dendrimers in Anticancer Diagnostics and Therapy

The application of dendrimeric constructs in medical diagnostics and therapeutics is increasing. Dendrimers have attracted attention due to their compact, spherical three-dimensional structures with surfaces that can be modified by the attachment of various drugs, hydrophilic or hydrophobic groups, or reporter molecules. In the literature, many modified dendrimer systems with various applications have been reported, including drug and gene delivery systems, biosensors, bioimaging contrast agents, tissue engineering, and therapeutic agents. Dendrimers are used for the delivery of macromolecules, miRNAs, siRNAs, and many other various biomedical applications, and they are ideal carriers for bioactive molecules. In addition, the conjugation of dendrimers with antibodies, proteins, and peptides allows for the design of vaccines with highly specific and predictable properties, and the role of dendrimers as carrier systems for vaccine antigens is increasing. In this work, we will focus on a review of the use of dendrimers in cancer diagnostics and therapy. Dendrimer-based nanosystems for drug delivery are commonly based on polyamidoamine dendrimers (PAMAM) that can be modified with drugs and contrast agents. Moreover, dendrimers can be successfully used as conjugates that deliver several substances simultaneously. The potential to develop dendrimers with multifunctional abilities has served as an impetus for the design of new molecular platforms for medical diagnostics and therapeutics.     

Dendrimer-based prodrugs: design, synthesis, screening and biological evaluation

Dendrimers are a new class of artificial macromolecules with well-defined hyperbranched structures which enable bio-active molecules such as drugs to be presented in a highly multi-valent fashion. Covalent conjugation of drugs to the surface of dendrimers can be easily achieved either by direct chemical reactions between dendrimers and drug molecules including esterification and amidation or through cleavable linkers, depending on the functional groups on the surface of dendrimers. The pharmacological properties of these dendrimer-based prodrugs such as biocompatibility, biodistribution, biostability, bioadhesion and biopermeability can be modulated by further modifying dendrimers with specific functional molecules to fit a specific medicinal purpose. In this mini-review, recent advances on the use of dendrimers as prodrug nano-scaffolds were briefly demonstrated. The design and synthesis of dendrimer-based prodrugs as well as screening their intrinsic properties in biological systems were fully discussed.     

Nanodiamonds: A Cutting-Edge Approach to Enhancing Biomedical Therapies and Diagnostics in Biosensing

Nanodiamonds (NDs) have garnered attention in the field of nanomedicine due to their unique properties. This review offers a comprehensive overview of NDs synthesis methods, properties, and their uses in biomedical applications. Various synthesis techniques, such as detonation, high-pressure, high-temperature, and chemical vapor deposition, offer distinct advantages in tailoring NDs′ size, shape, and surface properties. Surface modification methods further enhance NDs′ biocompatibility and enable the attachment of bioactive molecules, expanding their applicability in biological systems. NDs serve as promising nanocarriers for drug delivery, showcasing biocompatibility and the ability to encapsulate therapeutic agents for targeted delivery. Additionally, NDs demonstrate potential in cancer treatment through hyperthermic therapy and vaccine enhancement for improved immune responses. Functionalization of NDs facilitates their utilization in biosensors for sensitive biomolecule detection, aiding in precise diagnostics and rapid detection of infectious diseases. This review underscores the multifaceted role of NDs in advancing biomedical applications. By synthesizing NDs through various methods and modifying their surfaces, researchers can tailor their properties for specific biomedical needs. The ability of NDs to serve as efficient drug delivery vehicles holds promise for targeted therapy, while their applications in hyperthermic therapy and vaccine enhancement offer innovative approaches to cancer treatment and immunization. Furthermore, the integration of NDs into biosensors enhances diagnostic capabilities, enabling rapid and sensitive detection of biomolecules and infectious diseases. Overall, the diverse functionalities of NDs underscore their potential as valuable tools in nanomedicine, paving the way for advancements in healthcare and biotechnology.     

Molecular heterogeneity analysis of poly(amidoamine) dendrimer-based mono- and multifunctional nanodevices by capillary electrophoresis

Poly(amidoamine) (PAMAM) dendrimer-based nanodevices are of recent interest in targeted cancer therapy. Characterization of mono- and multifunctional PAMAM-based nanodevices remains a great challenge because of their molecular complexity. In this work, various mono- and multifunctional nanodevices based on PAMAM G5 (generation 5) dendrimer were characterized by UV-Vis spectrometry, (1)H NMR, size exclusion chromatography (SEC), and capillary electrophoresis (CE). CE was extensively utilized to measure the molecular heterogeneity of these PAMAM-based nanodevices. G5-FA (FA denotes folic acid) conjugates (synthesized from amine-terminated G5.NH(2) dendrimer, approach 1) with acetamide and amine termini exhibit bimodal or multi-modal distributions. In contrast, G5-FA and bifunctional G5-FA-MTX (MTX denotes methotrexate) conjugates with hydroxyl termini display a single modal distribution. Multifunctional G5.Ac(n)-FI-FA, G5.Ac(n)-FA-OH-MTX, and G5.Ac(n)-FI-FA-OH-MTX (Ac denotes acetamide; FI denotes fluorescein) nanodevices (synthesized from partially acetylated G5 dendrimer, approach 2) exhibit a monodisperse distribution. It indicates that the molecular distribution of PAMAM conjugates largely depends on the homogeneity of starting materials, the synthetic approaches, and the final functionalization steps. Hydroxylation functionalization of dendrimers masks the dispersity of the final PAMAM nanodevices in both synthetic approaches. The applied CE analysis of mono- and multifunctional PAMAM-based nanodevices provides a powerful tool to evaluate the molecular heterogeneity of complex dendrimer conjugate nanodevices for targeted cancer therapeutics.     

Target delivery of photo-triggered nanocarrier for externally activated chemo-photodynamic therapy of prostate cancer

Objective therapeutics such as photodynamic therapy (PDT) play an imperative role where targeted delivery of nanotherapeutics could achieve the highest level of therapeutic efficiency for the treatment of cancer. For an effective combination of chemotherapy and PDT, a multimodal-targeted system is vital to achieving effective therapeutic efficacy to counter cancer. In this study, an upconversion nanoparticle-based dual-mode nanocarrier was established where doxorubicin, a chemotherapeutic drug, and tetra carboxy zinc phthalocyanine, a reactive oxygen species (ROS) generator, were successfully embedded onto metal-organic framework (ZIF-8) for synergistic photodynamic therapy. For controlled drug release, amine-PEG was wrapped around UCNPs@MOF. In addition, targeting efficiency was enhanced by employing a prostate cancer-specific ligand (folic acid, FA), which is recognized by prostate-specific membrane antigen (PSMA). Indeed, the nanocomposite-coupled FA was uptaken more in LNCaP (PSMA positive) cells compared to DU145 (PSMA negative) cells. Interestingly, coating the nanocomposite with biocompatible polyethylene glycol significantly inhibited doxorubicin (DOX) release even under a lower pH condition. This effect is abrogated by near-infrared irradiation, whereupon NIR irradiation, the nanocomposite accelerates the production of ROS, as well as chemotherapeutic drug release. These results suggest that the release of DOX was more tightly controlled by a polymer coating. As observed by in vitro cytotoxicity experiment, LNCaP cells showed descending pattern in the cell viability than DU145 cells under the NIR irradiation condition. All these results, taken together, show a promising system for NIR-based targeted PDT where burst release of drug and ROS is achieved to improve the synergistic therapeutics.     

肽类树状大分子磁共振成像探针的合成与功能化

通过优化设计,合成了高产率的DTPA和DOTA配体.通过液相发散法制得第三代肽类树状大分子,其外围氨基分别用两种不同保护基团保护,且两种保护基团的个数比精确控制为18∶6,通过选择性脱去保护基团,其中一种氨基与DTPA、DOTA偶联,或与丁二酸酐反应,并与金属离子钆螯合,制得G3-18Gd-DTPA-6COOH,G3-...     

Emerging nanomedicine and prodrug delivery strategies for the treatment of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic and recurrent disease of the gastrointestinal tract, mainly including Crohn's disease (CD) and ulcerative colitis (UC). However, current approaches against IBD do not precisely deliver drugs to the inflammatory site, which leads to life-long medication and serious side effects that can adversely impact patients’ adherence. It is necessary to construct optimal drug delivery systems (DDSs) that can target drugs to the region of inflammation, thereby improve therapeutic efficacy and reduce side effects. With the burgeoning development of nanotechnology-based nanomedicines (NMs) and prodrug strategy, remarkable progresses in the treatment of IBD have been made in recent years. Herein, the latest advances are outlined at the intersection of IBD treatment and nanotherapeutics as well as prodrug therapy. First, the pathophysiological microenvironment of inflammatory sites of IBD is introduced in order to rationally design potential NMs and prodrugs. Second, the necessity of NMs for the IBD therapy is elaborated, and the representative nanotherapeutics via passive targeted and active targeted NMs developed to treat the IBD are overviewed. Furthermore, the emerging prodrug-based therapeutics are summarized, including 5-aminosalicylic acid-, amino acid-, and carbohydrate-conjugated prodrugs. Finally, the design considerations and perspectives of these NMs and prodrugs-driven IBD therapeutics in the clinical translation are spotlighted.     

Dendritic Polymers in Biomedical Applications: From Potential to Clinical Use in Diagnostics and Therapy

Dendrimers are characterized by a combination of high end‐group functionality and a compact, precisely defined molecular structure. These characteristics can be used in biomedical applications, for example, for the amplification or multiplication of effects on a molecular level, or to create extremely high local concentrations of drugs, molecular labels, or probe moieties. A brief summary of the current state of the art in the field is given, and focuses on the application of dendrimers both in diagnostics as well as in therapy. In diagnostics, dendrimers that bear Gd^III complexes are used as contrast agents in magnetic resonance imaging. DNA dendrimers have potential for routine use in high‐throughput functional genomic analysis, as well as for DNA biosensors. Dendrimers are also being investigated for therapeutics, for example, as carriers for controlled drug delivery, in gene transfection, as well as in boron neutron‐capture therapy. Furthermore, the antimicrobial activity of dendrimers has been studied.     

Artemisinin and Derivatives-Based Hybrid Compounds: Promising Therapeutics for the Treatment of Cancer and Malaria

Cancer and malaria are major health conditions around the world despite many strategies and therapeutics available for their treatment. The most used strategy for the treatment of these diseases is the administration of therapeutic drugs, which suffer from several shortcomings. Some of the pharmacological limitations associated with these drugs are multi-drug resistance, drug toxicity, poor biocompatibility and bioavailability, and poor water solubility. The currently ongoing preclinical studies have demonstrated that combination therapy is a potent approach that can overcome some of the aforementioned limitations. Artemisinin and its derivatives have been reported to exhibit potent efficacy as anticancer and antimalarial agents. This review reports hybrid compounds containing artemisinin scaffolds and their derivatives with promising therapeutic effects for the treatment of cancer and malaria.     

Light-guided tumor diagnosis and therapeutics: From nanoclusters to polyoxometalates

Malignant tumors, with the characteristics of easy metastasis and recurrence, are a serious threat to health of mankind. It is urgent to develop promising clinical cancer targeted agents with combination of rapid diagnosis and efficient therapies. Compared with the conventional photosensitizing agents, the recent advances of nanoagents based on transition metal-oxide clusters possess unique structural and electronic properties, greatly improving cancer survival rate, meanwhile, keeping high cont...     

Targeted Tumor Computed Tomography Imaging Using Low‐Generation Dendrimer‐Stabilized Gold Nanoparticles

We report a facile approach to fabricating low‐generation poly(amidoamine) (PAMAM) dendrimer‐stabilized gold nanoparticles (Au DSNPs) functionalized with folic acid (FA) for in vitro and in vivo targeted computed tomography (CT) imaging of cancer cells. In this study, amine‐terminated generation 2 PAMAM dendrimers were employed as stabilizers to form Au DSNPs without additional reducing agents. The formed Au DSNPs with an Au core size of 5.5 nm were covalently modified with the targeting ligand FA, followed by acetylation of the remaining dendrimer terminal amines to endow the particles with targeting specificity and improved biocompatibility. Our characterization data show that the formed FA‐modified Au DSNPs are stable at different pH values (5—8) and temperatures (4–50 °C), as well as in different aqueous media. MTT assay data along with cell morphology observations reveal that the FA‐modified Au DSNPs are noncytotoxic in the particle concentration range of 0–3000 nM . X‐ray attenuation coefficient measurements show that the CT value of FA‐modified Au DSNPs is much higher than that of Omnipaque (a clinically used CT contrast agent) at the same concentration of the radiodense elements (Au or iodine). Importantly, the FA‐modified Au DSNPs are able to specifically target a model cancer cell line (KB cells, a human epithelial carcinoma cell line) over‐expressing FA receptors and they enable targeted CT imaging of the cancer cells in vitro and the xenografted tumor model in vivo after intravenous administration of the particles. With the simple synthesis approach, easy modification, good cytocompatibility, and high X‐ray attenuation coefficient, the FA‐modified low‐generation Au DSNPs could be used as promising contrast agents for targeted CT imaging of different tumors over‐expressing FA receptors.     

Smart Nanocarriers as an Emerging Platform for Cancer Therapy: A Review

Cancer is a group of disorders characterized by uncontrolled cell growth that affects around 11 million people each year globally. Nanocarrier-based systems are extensively used in cancer imaging, diagnostics as well as therapeutics; owing to their promising features and potential to augment therapeutic efficacy. The focal point of research remains to develop new-fangled smart nanocarriers that can selectively respond to cancer-specific conditions and deliver medications to target cells efficiently. Nanocarriers deliver loaded therapeutic cargos to the tumour site either in a passive or active mode, with the least drug elimination from the drug delivery systems. This review chiefly focuses on current advances allied to smart nanocarriers such as dendrimers, liposomes, mesoporous silica nanoparticles, quantum dots, micelles, superparamagnetic iron-oxide nanoparticles, gold nanoparticles and carbon nanotubes, to list a few. Exhaustive discussion on crucial topics like drug targeting, surface decorated smart-nanocarriers and stimuli-responsive cancer nanotherapeutics responding to temperature, enzyme, pH and redox stimuli have been covered.     

Precise nanomedicine for intelligent therapy of cancer

Precise nanomedicine has been extensively explored for efficient cancer imaging and targeted cancer therapy, as evidenced by a few breakthroughs in their preclinical and clinical explorations. Here, we demonstrate the recent advances of intelligent cancer nanomedicine, and discuss the comprehensive understanding of their structure-function relationship for smart and efficient cancer nanomedicine including various imaging and therapeutic applications, as well as nanotoxicity. In particular, a few emerging strategies that have advanced cancer nanomedicine are also highlighted as the emerging focus such as tumor imprisonment, supramolecular chemotherapy, and DNA nanorobot. The challenge and outlook of some scientific and engineering issues are also discussed in future development. We wish to highlight these new progress of precise nanomedicine with the ultimate goal to inspire more successful explorations of intelligent nanoparticles for future clinical translations.     

Theranostic nanomedicine by surface nanopore engineering

Theranostic nanomedicine that integrates diagnostic and therapeutic agents into one nanosystem has gained considerable momentum in the field of cancer treatment. Among diverse strategies for achieving theranostic capabilities, surface-nanopore engineering based on mesoporous silica coating has attracted great interest because of their negligible cytotoxicity and chemically active surface that can be easily modified to introduce various functional groups(e.g.,-COOH,-NH_2,-SH, etc.) via silanization, which can satisfy various requirements of conjugating biological molecules or functional nanoparticles. In addition,the nanopore-engineered biomaterials possess large surface area and high pore volume, ensuring desirable loading of therapeutic guest molecules. In this review, we comprehensively summarize the synthetic procedure/paradigm of nanopore engineering and further broad theranostic applications. Such nanopore-engineering strategy endows the biocompatible nanocomposites(e.g., Au,Ag, graphene, upconversion nanoparticles, Fe_3O_4, MXene, etc.) with versatile functional moieties, which enables the development of multifunctional nanoplatforms for multimodal diagnostic bio-imaging, photothermal therapy, photodynamic therapy,targeted drug delivery, synergetic therapy and imaging-guided therapies. Therefore, mesoporous silica-based surface-nanopore engineering integrates intriguing unique features for broadening the biomedical applications of the single mono-functional nanosystem, facilitating the development and further clinical translation of theranostic nanomedicine.     

Theranostic Applications of Nanomaterials in Cancer: Drug Delivery, Image-Guided Therapy, and Multifunctional Platforms

Successful cancer management depends on accurate diagnostics along with specific treatment protocols. Current diagnostic techniques need to be improved to provide earlier detection capabilities, and traditional chemotherapy approaches to cancer treatment are limited by lack of specificity and systemic toxicity. This review highlights advances in nanotechnology that have allowed the development of multifunctional platforms for cancer detection, therapy, and monitoring. Nanomaterials can be used as MRI, optical imaging, and photoacoustic imaging contrast agents. When used as drug carriers, nanoformulations can increase tumor exposure to therapeutic agents and result in improved treatment effects by prolonging circulation times, protecting entrapped drugs from degradation, and enhancing tumor uptake through the enhanced permeability and retention effect as well as receptor-mediated endocytosis. Multiple therapeutic agents such as chemotherapy, antiangiogenic, or gene therapy agents can be simultaneously delivered by nanocarriers to tumor sites to enhance the effectiveness of therapy. Additionally, imaging and therapy agents can be co-delivered to provide seamless integration of diagnostics, therapy, and follow-up, and different therapeutic modalities such as chemotherapy and hyperthermia can be co-administered to take advantage of synergistic effects. Liposomes, metallic nanoparticles, polymeric nanoparticles, dendrimers, carbon nanotubes, and quantum dots are examples of nanoformulations that can be used as multifunctional platforms for cancer theranostics. Nanomedicine approaches in cancer have great potential for clinically translatable advances that can positively impact the overall diagnostic and therapeutic process and result in enhanced quality of life for cancer patients. However, a concerted scientific effort is still necessary to fully explore long-term risks, effects, and precautions for safe human use.     

Polymeric nanocarriers for cancer theranostics

Theranostics is an emerging area in nanomedicine where therapeutic and diagnostic platforms are integrated together to perform multiple functions such as disease diagnostic and therapy, noninvasive method to determine the targeted delivery of drugs, and evaluation of drug efficacy. This review gives an overview of the different therapeutic and diagnostic strategies used to construct a theranostic system. The importance of polymer‐based theranostic carriers is presented. The different types of polymeric carriers such as micelles, liposomes, dendrimers, and nanogels explored for theranostic applications are also presented. Copyright © 2017 John Wiley & Sons, Ltd.     

Synthesis and functional evaluation of DNA-assembled polyamidoamine dendrimer clusters for cancer cell-specific targeting

We sought to produce dendrimers conjugated to different biofunctional moieties (fluorescein [FITC] and folic acid [FA]), and then link them together using complementary DNA oligonucleotides to produce clustered molecules that target cancer cells that overexpress the high-affinity folate receptor. Amine-terminated, generation 5 polyamidoamine (G5 PAMAM) dendrimers are first partially acetylated and then conjugated with FITC or FA, followed by the covalent attachment of complementary, 5'-phosphate-modified 34-base-long oligonucleotides. Hybridization of these oligonucleotide conjugates led to the self-assembly of the FITC- and FA-conjugated dendrimers. In vitro studies of the DNA-linked dendrimer clusters indicated specific binding to KB cells expressing the folate receptor. Confocal microscopy also showed the internalization of the dendrimer cluster. These results demonstrate the ability to design and produce supramolecular arrays of dendrimers using oligonucleotide bridges. This will also allow for further development of DNA-linked dendrimer clusters as imaging agents and therapeutics.     

Targeted Nanocarriers for Imaging and Therapy of Vascular Inflammation

Vascular inflammation is a common, complex mechanism involved in pathogenesis of a plethora of disease conditions including ischemia-reperfusion, atherosclerosis, restenosis and stroke. Specific targeting of imaging probes and drugs to endothelial cells in inflammation sites holds promise to improve management of these conditions. Nanocarriers of diverse compositions and geometries, targeted with ligands to endothelial adhesion molecules exposed in inflammation foci are devised for this goal. Imaging modalities that employ these nanoparticle probes include radioisotope imaging, MRI and ultrasound that are translatable from animal to human studies, as well as optical imaging modalities that at the present time are more confined to animal studies. Therapeutic cargoes for these drug delivery systems include diverse anti-inflammatory agents, anti-proliferative drugs for prevention of restenosis, and antioxidants. This article reviews recent advances in the area of image-guided translation of targeted nanocarrier diagnostics and therapeutics in nanomedicine.