Artificial intelligence-aided optical imaging for cancer theranostics.

The use of artificial intelligence (AI) to assist biomedical imaging have demonstrated its high accuracy and high efficiency in medical decision-making for individualized cancer medicine. In particular, optical imaging methods are able to visualize both the structural and functional information of tumors tissues with high contrast, low cost, and noninvasive property. However, no systematic work has been performed to inspect the recent advances on AI-aided optical imaging for cancer theranostics. In this review, we demonstrated how AI can guide optical imaging methods to improve the accuracy on tumor detection, automated analysis and prediction of its histopathological section, its monitoring during treatment, and its prognosis by using computer vision, deep learning and natural language processing. By contrast, the optical imaging techniques involved mainly consisted of various tomography and microscopy imaging methods such as optical endoscopy imaging, optical coherence tomography, photoacoustic imaging, diffuse optical tomography, optical microscopy imaging, Raman imaging, and fluorescent imaging. Meanwhile, existing problems, possible challenges and future prospects for AI-aided optical imaging protocol for cancer theranostics were also discussed. It is expected that the present work can open a new avenue for precision oncology by using AI and optical imaging tools.

Synthesis and Preclinical Evaluation of PSMA-Targeted 111In-Radioconjugates Containing a Mitochondria-Tropic Triphenylphosphonium Carrier.

Nuclear DNA is the canonical target for biological damage induced by Auger electrons (AE) in the context of targeted radionuclide therapy (TRT) of cancer, but other subcellular components might also be relevant for this purpose, such as the energized mitochondria of tumor cells. Having this in mind, we have synthesized novel DOTA-based chelators carrying a prostate-specific membrane antigen (PSMA) inhibitor and a triphenyl phosphonium (TPP) group that were used to obtain dual-targeted 111In-radioconjugates ([111In]In-TPP-DOTAGA-PSMA and [111In]In-TPP-DOTAGA-G3-PSMA), aiming to promote a selective uptake of an AE-emitter radiometal (111In) by PSMA+ prostate cancer (PCa) cells and an enhanced accumulation in the mitochondria. These dual-targeted 111In-radiocomplexes are highly stable under physiological conditions and in cell culture media. The complexes showed relatively similar binding affinities toward the PSMA compared to the reference tracer [111In]In-PSMA-617, in line with their high cellular uptake and internalization in PSMA+ PCa cells. The complexes compromised cell survival in a dose-dependent manner and in the case of [111In]In-TPP-DOTAGA-G3-PSMA to a higher extent than observed for the single-targeted congener [111In]In-PSMA-617. µSPECT imaging studies in PSMA+ PCa xenografts showed that the TPP pharmacophore did not interfere with the excellent in vivo tumor uptake of the "golden standard" [111In]In-PSMA-617, although it led to a higher kidney retention. Such kidney retention does not necessarily compromise their usefulness as radiotherapeutics due to the short tissue range of the Auger/conversion electrons emitted by 111In. Overall, our results provide valuable insights into the potential use of mitochondrial targeting by PSMA-based radiocomplexes for efficient use of AE-emitting radionuclides in TRT, giving impetus to extend the studies to other AE-emitting trivalent radiometals (e.g., 161Tb or 165Er) and to further optimize the designed dual-targeting constructs.

Amplification of Cerenkov luminescence using semiconducting polymers for cancer theranostics.

The therapeutic efficacy of photodynamic therapy is limited by the ability of light to penetrate tissues. Due to this limitation, Cerenkov luminescence (CL) from radionuclides has recently been proposed as an alternative light source in a strategy referred to as Cerenkov radiation induced therapy (CRIT). Semiconducting polymer nanoparticles (SPNs) have ideal optical properties, such as large absorption cross-sections and broad absorbance, which can be utilized to harness the relatively weak CL produced by radionuclides. SPNs can be doped with photosensitizers and have nearly 100% energy transfer efficiency by multiple energy transfer mechanisms. Herein, we investigated an optimized photosensitizer doped SPN as a nanosystem to harness and amplify CL for cancer theranostics. We found that semiconducting polymers significantly amplified CL energy transfer efficiency. Bimodal PET and optical imaging studies showed high tumor uptake and retention of the optimized SPNs when administered intravenously or intratumorally. Lastly, we found that photosensitizer doped SPNs have excellent potential as a cancer theranostics nanosystem in an in vivo tumor therapy study. Our study shows that SPNs are ideally suited to harness and amplify CL for cancer theranostics, which may provide a significant advancement for CRIT that are unabated by tissue penetration limits.

Nanoheterostructure by Liquid Metal Sandwich-Based Interfacial Galvanic Replacement for Cancer Targeted Theranostics.

Nanoheterostructures with exquisite interface and heterostructure design find numerous applications in catalysis, plasmonics, electronics, and biomedicine. In the current study, series core-shell metal or metal oxide-based heterogeneous nanocomposite have been successfully fabricated by employing sandwiched liquid metal (LM) layer (i.e., LM oxide/LM/LM oxide) as interfacial galvanic replacement reaction environment. A self-limiting thin oxide layer, which would naturally occur at the metal-air interface under ambient conditions, could be readily delaminated onto the surface of core metal (Fe, Bi, carbonyl iron, Zn, Mo) or metal oxide (Fe3 O4 , Fe2 O3 , MoO3 , ZrO2 , TiO2 ) nano- or micro-particles by van der Waals (vdW) exfoliation. Further on, the sandwiched LM layer could be formed immediately and acted as the reaction site of galvanic replacement where metals (Au, Ag, and Cu) or metal oxide (MnO2 ) with higher reduction potential could be deposited as shell structure. Such strategy provides facile and versatile approaches to design and fabricate nanoheterostructures. As a model, nanocomposite of Fe@Sandwiched-GaIn-Au (Fe@SW-GaIn-Au) is constructed and their application in targeted magnetic resonance imaging (MRI) guided photothermal tumor ablation and chemodynamic therapy (CDT), as well as the enhanced radiotherapy (RT) against tumors, have been systematically investigated.

Platinum Drug-Incorporating Polymeric Nanosystems for Precise Cancer Therapy.

Platinum (Pt) drugs are widely used in clinic for cancer therapy, but their therapeutic outcomes are significantly compromised by severe side effects and acquired drug resistance. With the emerging immunotherapy and imaging-guided cancer therapy, precise delivery and release of Pt drugs have drawn great attention these days. The targeting delivery of Pt drugs can greatly increase the accumulation at tumor sites, which ultimately enhances antitumor efficacy. Further, with the combination of Pt drugs and other theranostic agents into one nanosystem, it not only possesses excellent synergistic efficacy but also achieves real-time monitoring. In this review, after the introduction of Pt drugs and their characteristics, the recent progress of polymeric nanosystems for efficient delivery of Pt drugs is summarized with an emphasis on multi-modal synergistic therapy and imaging-guided Pt-based cancer treatment. In the end, the conclusions and future perspectives of Pt-encapsulated nanosystems are given.

Dual-Responsive Drug-Delivery System Based on PEG-Functionalized Pillararenes Containing Disulfide and Amido Bonds for Cancer Theranostics.

The construction of a smart drug-delivery system based on amphiphilic pillararenes with multiple responsiveness properties has become an important way to improve the efficacy of tumor chemotherapy. Here, a new PEG-functionalized pillararene (EtP5-SS-PEG) containing disulfide and amido bonds was designed and synthesized, which has been used to construct a novel supramolecular nanocarrier through a host-guest interaction with a perylene diimide derivative (PDI-2NH4 ) and their supramolecular self-assembly. This nanocarrier showed good drug loading capability, and dual stimulus responsiveness to enzyme and GSH (glutathione). After loading of doxorubicin (DOX), the prepared nanodrugs displayed efficient DOX release and outstanding cancer theranostics ability.

Nano-inspired smart medicines targeting brain cancer: diagnosis and treatment.

Cancer, despite being the bull's eye for the research community, accounts for a large number of morbidity and mortality. Cancer of the brain is considered the most intractable, with the least diagnosis rates, hence treatment and survival. Despite the extensive development of therapeutic molecules, their targeting to the diseased site is a challenge. Specially tailored nanoparticles can efficiently deliver drugs and genes to the brain to treat tumours and diseases. These nanotechnology-based strategies target the blood-brain barrier, the local space, or a specific cell type. These nanoparticles are preferred over other forms of targeted drug delivery due to the chances for controlled delivery of therapeutic cargo to the intended receptor. Targeted cancer therapy involves using specific receptor-blocking compounds that block the spreading or growth of cancerous cells. This review presents an account of the recent applications of nano-based cancer theragnostic, which deal in conjunct functionalities of nanoparticles for effective diagnosis and treatment of cancer. It commences with an introduction to tumours of the brain and their grades, followed by hurdles in its conventional diagnosis and treatment. The characteristic mechanism of nanoparticles for efficiently tracing brain tumour grade and delivery of therapeutic genes or drugs has been summarised. Nanocarriers like liposomes have been widely used and commercialized for human brain cancer treatment. However, nano-inspired structures await their translational recognition. The green synthesis of nanomaterials and their advantages have been discussed. The article highlights the challenges in the nano-modulation of brain cancer and its future outlook.

Advances in photoacoustic imaging aided by nano contrast agents: special focus on role of lymphatic system imaging for cancer theranostics.

Photoacoustic imaging (PAI) is a successful clinical imaging platform for management of cancer and other health conditions that has seen significant progress in the past decade. However, clinical translation of PAI based methods are still under scrutiny as the imaging quality and clinical information derived from PA images are not on par with other imaging methods. Hence, to improve PAI, exogenous contrast agents, in the form of nanomaterials, are being used to achieve better image with less side effects, lower accumulation, and improved target specificity. Nanomedicine has become inevitable in cancer management, as it contributes at every stage from diagnosis to therapy, surgery, and even in the postoperative care and surveillance for recurrence. Nanocontrast agents for PAI have been developed and are being explored for early and improved cancer diagnosis. The systemic stability and target specificity of the nanomaterials to render its theranostic property depends on various influencing factors such as the administration route and physico-chemical responsiveness. The recent focus in PAI is on targeting the lymphatic system and nodes for cancer diagnosis, as they play a vital role in cancer progression and metastasis. This review aims to discuss the clinical advancements of PAI using nanoparticles as exogenous contrast agents for cancer theranostics with emphasis on PAI of lymphatic system for diagnosis, cancer progression, metastasis, PAI guided tumor resection, and finally PAI guided drug delivery.

Theranostic doxorubicin encapsulated FeAu alloy@metal-organic framework nanostructures enable magnetic hyperthermia and medical imaging in oral carcinoma.

Metal-organic frameworks (MOFs) have emerged as attractive candidates in cancer theranostics due to their ability to envelop magnetic nanoparticles, resulting in reduced cytotoxicity and high porosity, enabling chemodrug encapsulation. Here, FeAu alloy nanoparticles (FeAu NPs) are synthesized and coated with MIL-100(Fe) MOFs to fabricate FeAu@MOF nanostructures. We encapsulated Doxorubicin within the nanostructures and evaluated the suitability of this platform for medical imaging and cancer theranostics. FeAu@MOF nanostructures (FeAu@MIL-100(Fe)) exhibited superparamagnetism, magnetic hyperthermia behavior and displayed DOX encapsulation and release efficiency of 69.95 % and 97.19 %, respectively, when stimulated with alternating magnetic field (AMF). In-vitro experiments showed that AMF-induced hyperthermia resulted in 90 % HSC-3 oral squamous carcinoma cell death, indicating application in cancer theranostics. Finally, in an in-vivo mouse model, FeAu@MOF nanostructures improved image contrast, reduced tumor volume by 30-fold and tumor weight by 10-fold, which translated to enhancement in cumulative survival, highlighting the prospect of this platform for oral cancer treatment.

Synthesis of Multifunctional Mn3O4-Ag2S Janus Nanoparticles for Enhanced T1-Magnetic Resonance Imaging and Photo-Induced Tumor Therapy.

The global burden of cancer is increasing rapidly, and nanomedicine offers promising prospects for enhancing the life expectancy of cancer patients. Janus nanoparticles (JNPs) have garnered considerable attention due to their asymmetric geometry, enabling multifunctionality in drug delivery and theranostics. However, achieving precise control over the self-assembly of JNPs in solution at the nanoscale level poses significant challenges. Herein, a low-temperature reversed-phase microemulsion system was used to obtain homogenous Mn3O4-Ag2S JNPs, which showed significant potential in cancer theranostics. Structural characterization revealed that the Ag2S (5-10 nm) part was uniformly deposited on a specific surface of Mn3O4 to form a Mn3O4-Ag2S Janus morphology. Compared to the single-component Mn3O4 and Ag2S particles, the fabricated Mn3O4-Ag2S JNPs exhibited satisfactory biocompatibility and therapeutic performance. Novel diagnostic and therapeutic nanoplatforms can be guided using the magnetic component in JNPs, which is revealed as an excellent T1 contrast enhancement agent in magnetic resonance imaging (MRI) with multiple functions, such as photo-induced regulation of the tumor microenvironment via producing reactive oxygen species and second near-infrared region (NIR-II) photothermal excitation for in vitro tumor-killing effects. The prime antibacterial and promising theranostics results demonstrate the extensive potential of the designed photo-responsive Mn3O4-Ag2S JNPs for biomedical applications.

Oncolytic Viruses in the Era of Omics, Computational Technologies, and Modeling: Thesis, Antithesis, and Synthesis.

Oncolytic viruses (OVs) are the frontier therapy for refractory cancers, especially in integration with immunomodulation strategies. In cancer immunovirotherapy, the many available "omics" and systems biology technologies generate at a fast pace a challenging huge amount of data, where apparently clashing information mirrors the complexity of individual clinical situations and OV used. In this review, we present and discuss how currently big data analysis, on one hand and, on the other, simulation, modeling, and computational technologies, provide invaluable support to interpret and integrate "omic" information and drive novel synthetic biology and personalized OV engineering approaches for effective immunovirotherapy. Altogether, these tools, possibly aided in the future by artificial intelligence as well, will allow for the blending of the information into OV recombinants able to achieve tumor clearance in a patient-tailored way. Various endeavors to the envisioned "synthesis" of turning OVs into personalized theranostic agents are presented.

Recent Advances in Imaging Agents Anchored with pH (Low) Insertion Peptides for Cancer Theranostics.

The acidic extracellular microenvironment has become an effective target for diagnosing and treating tumors. A pH (low) insertion peptide (pHLIP) is a kind of peptide that can spontaneously fold into a transmembrane helix in an acidic microenvironment, and then insert into and cross the cell membrane for material transfer. The characteristics of the acidic tumor microenvironment provide a new method for pH-targeted molecular imaging and tumor-targeted therapy. As research has increased, the role of pHLIP as an imaging agent carrier in the field of tumor theranostics has become increasingly prominent. In this paper, we describe the current applications of pHLIP-anchored imaging agents for tumor diagnosis and treatment in terms of different molecular imaging methods, including magnetic resonance T1 imaging, magnetic resonance T2 imaging, SPECT/PET, fluorescence imaging, and photoacoustic imaging. Additionally, we discuss relevant challenges and future development prospects.

Rare-Earth Doped Iron Oxide Nanostructures for Cancer Theranostics: Magnetic Hyperthermia and Magnetic Resonance Imaging.

Superparamagnetic iron oxide nanoparticles (SPIONs) have been extensively investigated during the last couple of decades because of their potential applications across various disciplines ranging from spintronics to nanotheranostics. However, pure iron oxide nanoparticles cannot meet the requirement for practical applications. Doping is considered as one of the most prominent and simplest techniques to achieve optimized multifunctional properties in nanomaterials. Doped iron oxides, particularly, rare-earth (RE) doped nanostructures have shown much-improved performance for a wide range of biomedical applications, including magnetic hyperthermia and magnetic resonance imaging (MRI), compared to pure iron oxide. Extensive investigations have revealed that bigger-sized RE ions possessing high magnetic moment and strong spin-orbit coupling can serve as promising dopants to significantly regulate the properties of iron oxides for advanced biomedical applications. This review provides a detailed investigation on the role of RE ions as primary dopants for engineering the structural and magnetic properties of Fe3 O4 nanoparticles to carefully introspect and correlate their impact on cancer theranostics with a special focus on magnetic hyperthermia and MRI. In addition, prospects for achieving high-performance magnetic hyperthermia and MRI are thoroughly discussed. Finally, suggestions on future work in these two areas are also proposed.

NIR-II Emissive Ru(II) Metallacycle Assisting Fluorescence Imaging and Cancer Therapy.

Despite the success of emissive Ruthenium (Ru) agents in biomedicine, problems such as the visible-light excitation/emission and single chemo- or phototherapy modality still hamper their applications in deep-tissue imaging and efficient cancer therapy. Herein, an second nearinfrared window (NIR-II) emissive Ru(II) metallacycle (Ru1000, λem  = 1000 nm) via coordination-driven self-assembly is reported, which holds remarkable deep-tissue imaging capability (≈6 mm) and satisfactory chemo-phototherapeutic performance. In vitro results indicate Ru1000 displays promising cellular uptake, good cancer-cell selectivity, attractive anti-metastasis properties, and remarkable anticancer activity against various cancer cells, including cisplatin-resistant A549 cells (IC50  = 3.4 × 10-6  m vs 92.8 × 10-6  m for cisplatin). The antitumor mechanism could be attributed to Ru1000-induced lysosomal membrane damage and mitochondrial-mediated apoptotic cell death. Furthermore, Ru1000 also allows the high-performance in vivo NIR-II fluorescence imaging-guided chemo-phototherapy against A549 tumors. This work may provide a paradigm for the development of long-wavelength emissive metallacycle-based agents for future biomedicine.

Ligand conjugated lipid-based nanocarriers for cancer theranostics.

Cancer is one of the major health-related issues affecting the population worldwide and subsequently accounts for the second-largest death. Genetic and epigenetic modifications in oncogenes or tumor suppressor genes affect the regulatory systems that lead to the initiation and progression of cancer. Conventional methods, including chemotherapy/radiotherapy/appropriate combinational therapy and surgery, are being widely used for theranostics of cancer patients. Surgery is useful in treating localized tumors, but it is ineffective in treating metastatic tumors, which spread to other organs and result in a high recurrence rate and death. Also, the therapeutic application of free drugs is related to substantial issues such as poor absorption, solubility, bioavailability, high degradation rate, short shelf-life, and low therapeutic index. Therefore, these issues can be sorted out using nano lipid-based carriers (NLBCs) as promising drug delivery carriers. Still, at most, they fail to achieve site-targeted drug delivery and detection. This can be achieved by selecting a specific ligand/antibody for its cognate receptor molecule expressed on the surface of the cancer cells. In this review, we have mainly discussed the various types of ligands used to decorate NLBCs. A list of the ligands used to design nanocarriers to target malignant cells has been extensively undertaken. The approved ligand-decorated lipid-based nanomedicines with their clinical status have been explained in tabulated form to provide a wider scope to the readers regarding ligand-coupled NLBCs.

Silver Mesoporous Silica Nanoparticles: Fabrication to Combination Therapies for Cancer and Infection.

The integration of silver nanoparticles (Ag NPs) with mesoporous silica nanoparticles (MSNs) protects the former from aggregation and promotes the controlled release of silver ions, resulting in therapeutic significance on cancer and infection. The unique size, shape, pore structure and silver distribution of silver mesoporous silica nanoparticles (Ag-MSNs) embellish them with the potential to perform combined imaging and therapeutic actions via modulating optical and drug release properties. Here, we comprehensively review the recent progress in the fabrication and application of Ag-MSNs for combination therapies for cancer and infection. We first elaborate on the fabrication of star-shaped structure, core-shell structure, and Janus structure Ag-MSNs. We then highlight Ag-MSNs as a multifunctional nanoplatform to surface-enhanced Raman scattering-based detection, non-photo-based cancer theranostics and photo-based cancer theranostics. In addition, we detail Ag-MSNs for combined antibacterial therapy via drug delivery and phototherapy. Overall, we summarize the challenges and future perspectives of Ag-MSNs that make them promising for diagnosis and therapy of cancer and infection.

Intracellular Enzyme-Instructed Self-Assembly of Peptides (IEISAP) for Biomedical Applications.

Despite the remarkable significance and encouraging breakthroughs of intracellular enzyme-instructed self-assembly of peptides (IEISAP) in disease diagnosis and treatment, a comprehensive review that focuses on this topic is still desirable. In this article, we carefully review the advances in the applications of IEISAP, including the development of various bioimaging techniques, such as fluorescence imaging, photoacoustic imaging, magnetic resonance imaging, positron-emission tomography imaging, radiation imaging, and multimodal imaging, which are successfully leveraged in visualizing cancer tissues and cells, bacteria, and enzyme activity. We also summarize the utilization of IEISAP in disease treatments, including anticancer, antibacterial, and antiinflammation applications, among others. We present the design, action modes, structures, properties, functions, and performance of IEISAP materials, such as nanofibers, nanoparticles, nanoaggregates, and hydrogels. Finally, we conclude with an outlook towards future developments of IEISAP materials for biomedical applications. It is believed that this review may foster the future development of IEISAP with better performance in the biomedical field.

Coordinating the Mechanisms of Action of Ferroptosis and the Photothermal Effect for Cancer Theranostics.

Combination therapy based on different mechanisms of cell death has shown promise in tumor therapy. However, when different modalities are integrated, the maximum synergy of the therapeutic effects is often lacking in the design. Herein, we report a cancer theranostic nanomedicine formula developed by considering the mechanisms of action of ferroptosis and the photothermal effect in combination therapy. The croconaine molecule was encapsulated as both a photothermal converter and an iron-chelating agent with BSA, thus leading to biocompatible and stable Cro-Fe@BSA nanoparticles (NPs). The Cro-Fe@BSA NPs in the tumor milieu showed an activated photothermal effect leading to enhanced radical formation owing to the temperature-dependent Fenton reaction kinetics, while radical formation during ferroptosis in turn prevented the heat-induced formation of heat shock proteins and thus the self-protection mechanism of cancer cells in response to heat. The activatable photoacoustic and magnetic resonance imaging performance of the Cro-Fe@BSA NPs also enabled safe and reliable cancer theranostics.

Suprasomes Based on Host-Guest Molecular Recognition: An Excellent Alternative to Liposomes in Cancer Theranostics.

Liposomes and polymersomes, typical vesicular drug delivery systems (DDSs), have faced some limitations in cancer theranostics. Suprasomes, supramolecular vesicles assembled from amphiphiles linked by noncovalent interactions, show potential as new generation of vesicular DDSs. We construct suprasomes based on host-guest recognition, by which the desired functions can be integrated into carriers without tedious synthesis. Photothermally active host-guest complex is formed between a functional guest and pillar[5]arene, which further self-assembles into hollow suprasomes. A supramolecular nanomedicine is developed by encapsulating cisplatin in the suprasomes. The obtained cisplatin@Suprasomes achieve excellent anticancer efficacy and anti-metastasis combining chemotherapy and photothermal therapy, which ablate the tumors without relapse and metastasis. This work demonstrates the facile functionalization of suprasomes, holding promise as alternatives to liposomes and polymersomes.

A Hybrid Supramolecular Polymeric Nanomedicine for Cascade-Amplified Synergetic Cancer Therapy.

Supramolecular nanomedicines have shown great merits in cancer therapy, but their clinical translation is hampered by monotonous therapeutic modality and unsatisfactory antitumor performance. Herein, a hybrid supramolecular polymeric nanomedicine (SNPs) is developed based on ß-cyclodextrin/camptothecin (CPT) host-guest molecular recognition and iron-carboxylate coordination. Iron ions stabilizing SNPs catalyze the conversion of intracellular hydrogen peroxide into highly toxic hydroxyl radical through a Fenton reaction, which further cleaves the thioketal linker of the supramolecular monomer to release potent CPT, thus amplifying the therapeutic efficacy by combining chemodynamic therapy and chemotherapy. The combination therapy stimulates antitumor immunity and promotes intratumoral infiltration of cytotoxic T lymphocytes by triggering immunogenic cell death. In synergy with PD-L1 checkpoint blockade, SNPs enables enhanced immune therapy and a long-term tumor remission.