Accumulation In Tumor Tissue Research Articles

Intelligent micro/nanorobots for improved tumor therapy

AbstractA major bottleneck underlying nanomaterial‐based tumor therapy lies in complex biological environment and physiological barriers. Micro/nanorobots with the features of self‐propulsion and controllable navigation have gradually become a research hotspot in the tumor therapeutic community, exhibiting their advantages in efficient cargo loading, controllable cargo delivery, stimuli‐triggered cargo release, deeper tumor tissue penetration, and enhanced cargo accumulation in tumor tissue. In this review, the self‐propulsion and controllable navigation are introduced as two major properties of micro/nanorobots, in which micro/nanorobots are propelled by chemical reactions, physical fields, and biological systems and could be navigated by chemotaxis, remote magnetic guidance, and light. Then, the recent advances of micro/nanorobots for chemotherapy, immunotherapy, photothermal therapy, photodynamic therapy, chemodynamic therapy, and multimodal tumor therapy would be discussed. Finally, the perspective and challenges are also mentioned. It is expected that this review gives an insight into intelligent micro/nanorobots for improved tumor therapy, aiming for more extensive and in‐depth investigations, and final applications in the clinic.

A tumor-associated bacteria-responsive magnetic exosome as a clearable T1 contrast agent for targeted imaging of tumors

Bacteria can colonize and grow in tumors due to the hypoxic and immunosuppressive tumor microenvironment. Indeed, recent studies have revealed that bacteria are intrinsic and integral components of the tumors. Herein, a tumor-associated bacteria-responsive magnetic exosome (Exo@ESIONs) with switchable magnetic resonance imaging (MRI) property is developed for sensitive tumor imaging. The magnetic exosomes loaded with extremely small iron oxide nanoparticles (ESIONs) possess the excellent properties of long circulation in blood, high accumulation in tumor tissues and rapid response in the tumor microenvironment. Stimulated by the pore-forming toxins (PFTs) secreted from the bacteria in the tumors, the Exo@ESIONs can be disintegrated and the ESIONs are rapidly released, enabling dynamic switchable T2/T1 MRI of the tumors. As a result, the T1 contrast effect of the magnetic nanomaterials can be selectively enhanced in the tumor tissues, even the tumor size is as small as 10 mm3. Moreover, the ESIONs can be rapidly elimination from the body via renal clearance after the MRI to avoid the potential toxicity.

Artificial Base-Directed In Vivo Assembly of an Albumin-siRNA Complex for Tumor-Targeting Delivery.

RNA interference (RNAi) mediated by short interfering RNA (siRNA) is a promising method for cancer treatment, but the clinical application is hampered by several limitations, including metabolic instability, lack of tumor specificity, and poor cellular uptake. To meet these challenges, we have explored the possibility of structure modification of siRNA with artificial bases for property optimization. A series of siRNAs functionalized with different numbers of hydrophobic base F are prepared for screening. The interactions of plasma proteins with F-base-modified siRNA (F-siRNA) are investigated, and it is identified that the interaction with serum albumin is dominant. Experiments revealed that the introduction of F bases conferred modified siRNA with improved tumor-specific accumulation, prolonged circulatory retention time, and better tissue permeability. Mechanistic studies indicated that the F base induces the formulation of a stable siRNA-albumin complex, which transports siRNA to tumor tissues selectively owing to an enhanced permeability and retention (EPR) effect of albumin. The F base also facilitates the binding of siRNA to transport-associated proteins on the cell membrane, enabling its cellular internalization. Together, these data demonstrate that F base modification confers siRNA-enhanced cellular uptake and biostability and specific accumulation in tumor tissue, which provides a new approach for the development of siRNA-based cancer therapeutics.

Optimization of staging algorithm for newly detected prostate cancer by using PET/CT with <sup>68</sup>Ga-PSMA: a retrospective study

INTRODUCTION: Prostate cancer (PC) is the most common malignancy in men worldwide and ranks third in mortality. Improvement of the results of staging of newly detected prostate cancer is rightfully associated with the active use in clinical practice of positron emission tomography combined with computed tomography (PET/CT) with radiotracers based on prostate-specific membrane antigen (PSMA) ligands.OBJECTIVE: The aim of the study was to determine the capabilities of PET/CT with 68Ga-PSMA in evaluating the prevalence of newly diagnosed breast cancer in comparison with traditional imaging techniques (computed tomography, magnetic resonance imaging and bone scan) and to determine the role of this technology in the choice of treatment algorithm.MATERIALS AND METHODS: 120 patients aged 46 to 74 years (median age 62.5 years) with histologically verified prostate cancer underwent PET/CT with 68Ga-PSMA in our center to assess disease prevalence. The selection criteria for the study were: prostate-specific antigen (PSA) level of 5 ng/ml and above, presence of newly detected, histologically verified prostate cancer, no treatment, suspected metastatic lesion of pelvic and skeletal lymph nodes according to CT, MRI and OSG. All patients were divided into groups according to PSA level and Gleason score. Statistics: Statistical processing of the results was performed by methods of variance statistics using Statistica 10.0, GraphPad Prism 9.3.1. Wilcoxon-Mann-Whitney and Friedman tests for ANOVA were used to determine the significance of differences between comparison groups. The chi-square test with Yates correction was used to determine the reliability of intergroup differences for nominal measures (such as the presence of previous recurrences). The level of correlation was assessed using Spearman criterion.RESULTS: PET/CT imaging analysis in addition to MRI, CT, and OSG data showed TNM staging changes in 63 of 120 patients (52.3%) due to the detection of additional foci of metastatic lesions. Change of data about local spread of tumor with increasing of TNM stage due to detection of pathological RFP accumulation in seminal vesicles in 10 of 120 patients (8.3%), without structural changes using conventional imaging methods. In 20 of 64 patients (31.3%), PET/CT revealed lesions of regional lymph nodes (N) that were not visualized by conventional imaging methods due to their small size. Metastatic lesions of distant lymph nodes (M1a) and bones (M1b) undetected by CT, MRI, and OSG were found in 27 (22.5%) and 32 (26.7%) of 120 patients, respectively. At the same time, foci of pathological accumulation of 68Ga-PSMA in the bones without structural changes on CT were detected in 7 and 32 patients (21.8%).DISCUSSION: One of the objectives of this study was to compare the diagnostic capabilities of standard diagnostic imaging techniques, in particular MRI, CT and Bone scan, with the hybrid technology of PET/CT with 68Ga-PSMA to improve the accuracy of PCa staging in order to determine treatment tactics. The results demonstrate minimal superiority of PET/CT with 68Ga-PSMA over MRI in terms of sensitivity (96% and 94%, respectively) in assessing local disease prevalence. Tumor invasion of the seminal vesicles, in most cases, was detected in patients with a Gleason score greater than 8. At the same time there was a tendency for an increase in the level of radiotracer accumulation in the tumor tissue of the seminal vesicles depending on the differentiation group of PCa. Analysis of the histological material obtained after the prostatectomy demonstrated tumorous invasion of the seminal vesicles in 26 (37.1%) out of 70 operated patients. Coincidence of histological examination results with PET/CT data was found in 22 patients, with MRI data — in 20 patients. The sensitivity, specificity, positive predictive value, and negative predictive value of PET/CT were 85%, 92%, 85%, and 92%, while the corresponding values from MRI were as follows: 77%, 88%, 77%, and 88%. Analyzing the levels of 68Ga-PSMA uptake in the tumor tissue, we found that with increasing prostate differentiation group, there was a persistent increase in radiotracer accumulation in the prostate tumor tissue. We also evaluated the interrelation of RFP accumulation with PSA level. The patients with PCa with PSA level ≥10.0 ng/ml demonstrated high accumulation of radiotracer accumulation compared to those with PSA <10.0 ng/ml (p<0.001).CONCLUSIONS: The use of 68Ga-PSMA PET/CT in the staging of newly diagnosed and untreated cancers provides comprehensive information on the local, regional, and distant extent of the disease, and in some cases contributes to a change in TNM stage of the disease in a single study. The use of this method before planned surgical treatment of PCa can significantly reduce the risk of early postoperative relapse, especially in patients with a Gleason score of more than 7 and a PSA level greater than 20 ng/ml.

A Three-in-One Nanoscale Coordination Polymer for Potent Chemo-Immunotherapy.

The addition of immune checkpoint blockade to standard chemotherapy has changed the standards of care for some cancer patients. However, current chemo-immunotherapy strategies do not benefit most colorectal cancer patients and many triple-negative breast cancer patients. Here, the design of a three-in-one nanoscale coordination polymer (NCP), OX/GC/CQ, comprising prodrugs of oxaliplatin (OX), gemcitabine (GC), and 5-carboxy-8-hydroxyquinoline (CQ) for triple-modality chemo-immunotherapy is reported. OX/GC/CQ exhibits optimal pharmacokinetics and enhanced particle accumulation and drug release in acidic tumor tissues, wherein CQ greatly enhances immunogenic cell death induced by OX/GC and downregulates programmed cell death-ligand 1 expression in cancer cells. Consequently, OX/GC/CQ efficiently promotes infiltration and activity of cytotoxic T lymphocytes, while decreasing the proportion of immunosuppressive regulatory T cells. Intravenous injection of OX/GC/CQ reduces the growth of colorectal carcinoma and triple-negative breast cancer, prevents metastasis to lungs, and extends mouse survival by 30-40 days compared to free drugs. This work highlights the potential of NCPs in co-delivering synergistic chemo-immunotherapeutics for the treatment of advanced and aggressive cancers.

Targeted ferroptotic potency of ferrous oxide nanoparticles-diethyldithiocarbamate nanocomplex on the metastatic liver cancer.

Existing treatments are frequently ineffective in combating liver cancer (LC) due to its rapid growth, high metastatic potential, and chemoresistance. Thus, inducing ferroptosis, a new non-apoptotic regulated cell death-dependent massive iron overload-mediated lipid peroxidation, is an alternative effective approach for treating LC. The efficient trigger of ferroptosis requires blocking cellular antioxidant (anti-ferroptosis) response and selectivity to avoid harming other healthy tissues. In this study, green chemically synthesized ferrous oxide nanoparticles (F(II) NPs) were used for enhancing selective iron accumulation in tumor tissue, while diethyldithiocarbamate (DE) was for inhibiting the antioxidant system (glutathione and aldehyde dehydrogenase (ALDH) 2) which protects the tumor from damage-dependent lipid peroxides. Thus, F(II) NPs were used with DE as nanocomplex (DF(II) NPs) and its anti-LC activity compared to ferrous oxide DF(II). DF(II) NPs outperformed the typical complex of DF(II) in eradicating metastatic LC cells in HepG2 cells and a chemically induced metastatic LC animal model, as evidenced by flow cytometry, histological and immunohistochemical analyses, and α-fetoprotein depletion. The superior therapeutic potency-dependent ferroptotic activity of DF(II) NPs, attributed to their higher selective accumulation (∼77%) than DF(II) in tumor tissues (liver and lung), resulted in a strong elevation of cellular lipid peroxidation with extreme suppression of nuclear related factor 2 (Nrf2) transcriptional activity, glutathione (GSH), glutathione peroxidase 4, and ALDH2. Subsequently, a severe inhibition in the expression of oncogenes and metastatic cancer stem cell genes was recorded in DF(II) NPs-treated LC animal group. In contrast to DF(II), DF(II) NPs were able to normalize liver functions and did not show any variations in hematological and histological parameters in the blood and tissues of DF(II) NPs-treated normal mouse group. These findings validate the potency and safety of DF(II) nanocomplex as a promising nanodrug for combating metastatic LC.

Novel Liposomal Formulation of Baicalein for the Treatment of Pancreatic Ductal Adenocarcinoma: Design, Characterization, and Evaluation.

Pancreatic cancer (PC) is one of the deadliest cancers so there is an urgent need to develop new drugs and therapies to treat it. Liposome-based formulations of naturally-derived bioactive compounds are promising anticancer candidates due to their potential for passive accumulation in tumor tissues, protection against payload degradation, and prevention of non-specific toxicity. We chose the naturally-derived flavonoid baicalein (BAI) due to its promising effect against pancreatic ductal adenocarcinoma (PDAC) and encapsulated it into a liposomal bilayer using the passive loading method, with an almost 90% efficiency. We performed a morphological and stability analysis of the obtained BAI liposomal formulation and evaluated its activity on two-dimensional and three-dimensional pancreatic cell models. As the result, we obtained a stable BAI-encapsulated liposomal suspension with a size of 100.9 nm ± 2.7 and homogeneity PDI = 0.124 ± 0.02, suitable for intravenous administration. Furthermore, this formulation showed high cytotoxic activity towards AsPC-1 and BxPC-3 PDAC cell lines (IC50 values ranging from 21 ± 3.6 µM to 27.6 ± 4.1 µM), with limited toxicity towards normal NHDF cells and a lack of hemolytic activity. Based on these results, this new BAI liposomal formulation is an excellent candidate for potential anti-PDAC therapy.

The treatment of hepatocellular carcinoma with SP94 modified asymmetrical bilayer lipid-encapsulated Cu(DDC)2 nanoparticles facilitating Cu accumulation in the tumor

Background Copper diethyldithiocarbamate (Cu(DDC)2) has been demonstrated to possess excellent antitumor activity. However, the extremely poor water solubility of Cu(DDC)2 bring difficulty for its formulation research. In this study, we aim to develop a novel nanocarrier for Cu(DDC)2 delivery to overcome this obstacle and enhance antitumor activity. Methods The SP94 modified asymmetrical bilayer lipid-encapsulated Cu(DDC)2 nanoparticles (DCDP) was established by combining the method of inverse microemulsion aggregation and thin-film dispersion. In vitro cellular assays and in vivo tumor-xenograft experiments were conducted to evaluate the tumor chemotherapeutic effect of DCDP. And the vital role of copper ions played in DSF or DDC (DSF/DDC)-based cancer chemotherapy was also explored. Results DCDP with an encapsulation efficiency (EE%) of 74.0% were successfully prepared. SP94 modification facilitated cellular intake for DCDP, and promoted apoptosis to repress tumor cell proliferation (IC50, 200 nM). And DCDP effectively inhibited tumor growth with a high tumor inhibition rate of 74.84%. Furthermore, Cu(DDC)2 was found to facilitate the copper ion accumulation in tumor tissues, which is beneficial to therapy with high potency. Conclusion DCDP exhibited high-efficient tumor chemotherapeutic efficacy and provided a novel strategy for investigating the anticancer mechanism of Cu(DDC)2.

Bismuth nanoclusters on nitrogen-doped porous carbon nanoenzyme for cancer therapy.

Among the emerging cancer therapeutic methods, nanocatalytic therapy through the rational design of nanozymes is considered to be a promising strategy. However, high-performance nanozymes with the ability to catalyze the production of toxic substances to efficiently kill cancer cells are still highly desired. Herein, we fabricate bismuth nanoclusters loaded on nitrogen-doped porous carbon (Bi-NC) as a nanozyme for cancer therapy. The Bi-NC nanozyme displays both peroxidase (POD) and glutathione oxidase (GSHOx) biomimetic enzymatic activities, especially in a tumor microenvironment (TME), which catalyzes the production of hydroxyl radicals (·OH) and depletes antioxidant glutathione (GSH), simultaneously. Moreover, Bi-NC exhibits good photothermal conversion performance under near-infrared light irradiation. After surface modification with hyaluronic acid (HA) to improve the dispersity of nanoparticles and their accumulation in tumor tissues, Bi-NC@HA exhibits remarkable antitumor effects through the synergistic effect of catalytic and photothermal therapy. This work provides a new pathway for designing high-performance nanozymes for cancer catalytic therapy.

Impact of nanocarrier aggregation on EPR-mediated tumor targeting.

The aim of this study was to investigate the influence of excipients on retaining the particle size of methotrexate (MTX) loaded chitosan nanocarriers (CsNP) during lyophilization, which relates to the ability to enlarge the particle size and target specific areas. The nanocarriers were prepared using the ionic gelation technique with tripolyphosphate as a crosslinker. Three lyophilized formulations were used: nanosuspension without Lyoprotectant (NF), with mannitol (NFM), and with sucrose (NFS). The lyophilized powder intended for injection (PI) was examined to assess changes in particle size, product integrity, and comparative biodistribution studies to evaluate targeting ability. After lyophilization, NFS was excluded from in-vivo studies due to the product melt-back phenomenon. The particle size of the NF lyophile significantly increased from 176nm to 261nm. In contrast, NFM restricted the nanocarrier size to 194nm and exhibited excellent cake properties. FTIR, XRD, and SEM analysis revealed the transformation of mannitol into a stable β, δ polymorphic form. Biodistribution studies showed that the nanocarriers significantly increased MTX accumulation in tumor tissue (NF = 2.04 ± 0.27; NFM = 2.73 ± 0.19) compared to the marketed PI (1.45 ± 0.25μg), but this effect was highly dependent on the particle size. Incorporating mannitol yielded positive results in restricting particle size and favoring successful tumor targeting. This study demonstrates the potential of chitosan nanocarriers as promising candidates for targeted tumor drug delivery and cancer treatment.

Bioinspired nanovehicle of furoxans-oxaliplatin improves tumoral distribution for chemo-radiotherapy.

The spatiotemporal distribution of therapeutic agents in tumors remains an essential challenge of radiation-mediated therapy. Herein, we rationally designed a macrophage microvesicle-inspired nanovehicle of nitric oxide donor-oxaliplatin (FO) conjugate (M-PFO), aiming to promote intratumor permeation and distribution profiles for chemo-radiotherapy. FO was responsively released from M-PFO in intracellular acidic environments, and then be activated by glutathione (GSH) into active oxaliplatin and NO molecules in a programmed manner. M-PFO exhibited notable accumulation, permeation and cancer cell accessibility in tumor tissues. Upon radiation, the reactive peroxynitrite species (ONOO-) were largely produced, which could diffuse into regions over 400μm away from the tumor vessels and be detectable after 24h of radiation, thereby exhibiting superior efficacy in improving the spatiotemporal distribution in tumors versus common reactive oxygen species (ROS). Moreover, M-PFO mediated chemo-radiotherapy caused notable inhibition of tumor growth, with an 89.45% inhibition in HT-29 tumor models and a 92.69% suppression in CT-26 tumor models. Therefore, this bioinspired design provides an encouraging platform to improve intratumor spatiotemporal distribution to synergize chemo-radiotherapy.

Custom-built automated radiosynthesis platform for Al[18F]F radiochemistry and its application for clinical production

The construction of fully automated Al[18F]F radiochemistry can enhance the reproducibility and reliability of Al[18F]F-based radiopharmaceuticals while promoting translation from preclinical to clinical studies. However, commercially available automated radiosynthesizers possess several disadvantages pertaining to the performance of Al[18F]F radiochelation, including the presence of unsuitable sealed-heating for microvolume reactions, imprecise liquid handling and lack of a validated kit formulation for automatic production. In order to address these limitations, this study attempted to design, assemble and validate a custom-built radiosynthesizer for the production of clinical-grade Al[18F]F tracers. Due to the special design of the proposed interlinked sealed-heating, the microvolume solution of the reaction mixture was able to be heated above the boiling point without incurring significant volume change. Moreover, high efficiency for [18F]fluoride concentration was achieved with only 150 µL saline as the eluent with use of the syringe pump, allowing the replication of accurate liquid handling and finally minimizing the volume of the reaction mixture. A validated kit formulation was then developed to bolster the reproducibility and robustness of Al[18F]F chelation. Benefiting from the consumable kit formulation and automated processes optimization, the isolated radiochemical yield for the Al[18F]F tracer was found to be generally higher than those of the reported synthesizer. Furthermore, to demonstrate proof-of-concept, 18F-Alfatide II was then synthesized in large scale (up to 8.31 GBq) with high radiochemical purity (>99 %) and molar activity of 10.6–83.2 GBq/μmol. 18F-Alfatide II exhibited favorable pharmacokinetics in lung cancer patients for clinical trials, demonstrating high and specific accumulation in tumor tissues.

Nanotherapeutic Intervention in Photodynamic Therapy for Cancer.

The clinical need for photodynamic therapy (PDT) has been growing for several decades. Notably, PDT is often used in oncology to treat a variety of tumors since it is a low-risk therapy with excellent selectivity, does not conflict with other therapies, and may be repeated as necessary. The mechanism of action of PDT is the photoactivation of a particular photosensitizer (PS) in a tumor microenvironment in the presence of oxygen. During PDT, cancer cells produce singlet oxygen (1O2) and reactive oxygen species (ROS) upon activation of PSs by irradiation, which efficiently kills the tumor. However, PDT's effectiveness in curing a deep-seated malignancy is constrained by three key reasons: a tumor's inadequate PS accumulation in tumor tissues, a hypoxic core with low oxygen content in solid tumors, and limited depth of light penetration. PDTs are therefore restricted to the management of thin and superficial cancers. With the development of nanotechnology, PDT's ability to penetrate deep tumor tissues and exert desired therapeutic effects has become a reality. However, further advancement in this field of research is necessary to address the challenges with PDT and ameliorate the therapeutic outcome. This review presents an overview of PSs, the mechanism of loading of PSs, nanomedicine-based solutions for enhancing PDT, and their biological applications including chemodynamic therapy, chemo-photodynamic therapy, PDT-electroporation, photodynamic-photothermal (PDT-PTT) therapy, and PDT-immunotherapy. Furthermore, the review discusses the mechanism of ROS generation in PDT advantages and challenges of PSs in PDT.

Innovative Diagnostic Peptide-Based Technologies for Cancer Diagnosis: Focus on EGFR-Targeting Peptides.

Active targeting using biological ligands has emerged as a novel strategy for the targeted delivery of diagnostic agents to tumor cells. Conjugating functional targeting moieties with diagnostic probes can increase their accumulation in tumor cells and tissues, enhancing signal detection and, thus, the sensitivity of diagnosis. Due to their small size, ease of chemical synthesis and site-specific modification, high tissue penetration, low immunogenicity, rapid blood clearance, low cost, and biosafety, peptides offer several advantages over antibodies and proteins in diagnostic applications. Epidermal growth factor receptor (EGFR) is one of the most promising cancer biomarkers for actively targeting diagnostic and therapeutic agents to tumor cells due to its active involvement and overexpression in various cancers. Several peptides for EGFR-targeting have been identified in the last decades, which have been obtained by multiple means including derivation from natural proteins, phage display screening, positional scanning synthetic combinatorial library, and in silico screening. Many studies have used these peptides as a targeting moiety for diagnosing different cancers in vitro, in vivo, and in clinical trials. This review summarizes the progress of EGFR-targeting peptide-based assays in the molecular diagnosis of cancer.

Tumor microenvironment-responsive Zn/Cu nanoparticles for enhanced chemodynamic therapy

Chemodynamic therapy (CDT) has emerged as an effective and safe anticancer therapeutic strategy by catalytic generation of hydroxyl radicals via Fenton chemistry to kill notorious cancer cells. Herein, we decorated the Cu-based nanoparticles with pH-responsive ZnO nanoparticles to give new Zn/Cu nanoparticles (Zn/Cu NPs) which showed good biocompatibility and stability for enhanced therapeutic efficacy of CDT. The newly developed Zn/Cu NPs had a small size of ∼20 ​nm, which could prolong blood circulation time of NPs and facilitate their accumulation in tumor tissues. The mode of therapeutic mechanism was experimentally verified. Upon arriving at the acidic cancer cells, ZnO on Zn/Cu NPs dissolved leading to the release of Cu2+ ions which were then reduced by the overexpressed glutathione (GSH), yielding Cu+ ions. The presence of Cu+ ions favorably catalyzed the conversion of endogenous H2O2 into hydroxyl radicals by Fenton-like reactions. Such generated ROS would cause serious oxidative damage to cellular constituents resulting in cell death. Importantly, as the Zn/Cu NPs are pH sensitive, they exhibited much higher cytotoxicity against tumor cells than normal cells. In vivo studies also demonstrated that Zn/Cu NPs could effectively inhibit tumor growth without adverse side effects. Therefore, these Zn/Cu NPs hold great potential for direct and effective tumor therapy for personalized medicine applications.

Polylactic acid based polymeric nanoparticle mediated co-delivery of navitoclax and decitabine for cancer therapy

Combination chemotherapy with systemic administration of drugs in their free form can be challenging due to non-synchronized pharmacokinetics and sub-optimal tumor accumulation. The present study investigates a PLA-based block copolymeric nanocarrier for the co-delivery of navitoclax and decitabine (NAV/DCB NPs) for combination cancer therapy. NAV/DCB NPs exhibited potent in vitro synergistic cytotoxicity in both acute myeloid leukemia and breast cancer cell lines. Biodistribution studies of NAV/DCB NPs in tumor bearing mice, showed significant drug accumulation in tumor tissue and detectable quantities in plasma even after 48 h. Good hemocompatibility with reduced in vivo platelet toxicity indicated that encapsulation in PLA-based nanocarrier helped ameliorate navitoclax associated thrombocytopenia. In vivo biological activity of NAV/DCB NPs evaluated in xenograft AML and syngeneic breast cancer model, demonstrated potent tumor growth inhibition efficacy. PLA-based NAV/DCB dual NPs present a novel, safe and effective nanoformulation for combination cancer therapy in both solid tumors and hematologic malignancies.

Applications of Metallic Nanoparticles in the Skin Cancer Treatment.

Skin cancer is one of leading cancers globally, divided into two major categories including melanoma and nonmelanoma. Skin cancer is a global concern with an increasing trend, hence novel therapies are essential. The local treatment strategies play a key role in skin cancer therapy. Nanoparticles (NPs) exert potential applications in medicine with huge advantages and have the ability to overcome common chemotherapy problems. Recently, NPs have been used in nanomedicine as promising drug delivery systems. They can enhance the solubility of poorly water-soluble drugs, improve pharmacokinetic properties, modify bioavailability, and reduce drug metabolism. The high-efficient, nontoxic, low-cost, and specific cancer therapy is a promising goal, which can be achieved by the development of nanotechnology. Metallic NPs (MNPs) can act as important platforms. MNPs development seeks to enhance the therapeutic efficiency of medicines through site specificity, prevention of multidrug resistance, and effective delivery of therapeutic factors. MNPs are used as potential arms in the case of cancer recognition, such as Magnetic Resonance Imaging (MRI) and colloidal mediators for magnetic hyperthermia of cancer. The applications of MNPs in the cancer treatment studies are mostly due to their potential to carry a large dose of drug, resulting in a high concentration of anticancer drugs at the target site. Therefore, off-target toxicity and suffering side effects caused by high concentration of the drug in other parts of the body are avoided. MNPs have been applied as drug carriers for the of improvement of skin cancer treatment and drug delivery. The development of MNPs improves the results of many cancer treatments. Different types of NPs, such as inorganic and organic NPs have been investigated in vitro and in vivo for the skin cancer therapy. MNPs advantages mostly include biodegradability, electrostatic charge, good biocompatibility, high drug payload, and low toxicity. However, the use of controlled-release systems stimulated by electromagnetic waves, temperature, pH, and light improves the accumulation in tumor tissues and improves therapeutic outcomes. This study (2019-2022) is aimed at reviewing applications of MNPs in the skin cancer therapy.

ФОТОДИНАМИЧЕСКИ-АКТИВНЫЕ ПРЕПАРАТЫ В ЛЕЧЕНИИ РАЗЛИЧНЫХ ЗАБОЛЕВАНИЙ

A multifactorial effect on damaged tissues of the body in the process of a photosensitive reaction in photodynamic therapy is carried out. It includes the killing of pathologically altered cells with intensive production of reactive oxygen species, the effect on blood vessels and the activation of the body's immune system. The effectiveness of this method depends on the properties of photosensitizing drugs, namely, their selectivity, the ability to photoproduce reactive particles and ability to absorb in the near infrared spectrum. This review discusses three generations of photosensitizers. The first is the photodynamically active compound hematoporphyrin «Photofrin I». Taking into account the shortcomings of the first generation of drugs, such as: the complexity of the chemical composition, moderate photodynamic activity, a high degree of photosensitization of normal skin areas, insufficient selectivity and low optical absorption, second-generation photosensitizers were developed. These include Levulan, Foscan, Talaporfin and others. However, clinical trials of some of them have not been completed due to a number of reasons, to a greater extent, the low effectiveness of drugs or the financial costs of research. The third generation preparations were obtained using the methods of bioconjugation and encapsulation of photosensitizers of previous generations. To date, special attention is paid to the development of new systems for targeted delivery of photosensitizers, such as nanoparticles and monoclonal antibodies, which can significantly reduce the time required for targeted accumulation in tumor tissue.

A pH-Responsive Cluster Metal-Organic Framework Nanoparticle for Enhanced Tumor Accumulation and Antitumor Effect.

As a result of the deficient tumor-specific antigens, potential off-target effect, and influence of protein corona, metal-organic framework nanoparticles have inadequate accumulation in tumor tissues, limiting their therapeutic effects. In this work, a pH-responsive linker (L) is prepared by covalently modifying oleylamine (OA) with 3-(bromomethyl)-4-methyl-2,5-furandione (MMfu) and poly(ethylene glycol) (PEG). Then, the L is embedded into a solid lipid nanoshell to coat apilimod (Ap)-loaded zeolitic imidazolate framework (Ap-ZIF) to form Ap-ZIF@SLN#L. Under the tumor microenvironment, the hydrophilic PEG and MMfu are removed, exposing the hydrophobic OA on Ap-ZIF@SLN#L, increasing their uptake in cancer cells and accumulation in the tumor. The ZIF@SLN#L nanoparticle induces reactive oxygen species (ROS). Ap released from Ap-ZIF@SLN#L significantly promotes intracellular ROS and lactate dehydrogenase generation. Ap-ZIF@SLN#L inhibits tumor growth, increases the survival rate in mice, activates the tumor microenvironment, and improves the infiltration of macrophages and T cells in the tumor, as demonstrated in two different tumor-bearing mice after injections with Ap-ZIF@SLN#TL. Furthermore, mice show normal tissue structureof the main organs and the normal serum level in alanine aminotransferase and aspartate aminotransferase after treatment with the nanoparticles. Overall, this pH-responsive targeting strategy improves nanoparticle accumulation in tumors with enhanced therapeutic effects.

Mitochondria-targeting folic acid-modified nanoplatform based on mesoporous carbon and a bioactive peptide for improved colorectal cancer treatment

Oral colon-targeted drug delivery systems (OCDDs) are designed to deliver the therapeutic agents to colonic disease sites to improve the effectiveness of drug treatment, increase bioavailability, and reduce systemic side effects and are beneficial for the treatment of colorectal cancer (CRC) and inflammatory bowel disease (IBD). However, concerns about the biosafety of OCDDs are increasing, and changes in the physiological environment of the gastrointestinal tract can affect the therapeutic efficacy of the drug. Herein, we report about an orally administered colon-accumulating mitochondria-targeted drug delivery nanoplatform (M27-39@FA-MCNs), which was synthesized using the small peptide, M27-39, and folic acid (FA)-modified mesoporous carbon nanoparticles (FA-MCNs). The phenolic resin polymerized with phloroglucinol and formaldehyde (PF) was used for fabricating MCNs using a one-step soft-template method. Folic acid (FA) can be covalently combined with chitosan-modified MCNs to obtain FA-MCNs. The M27-39@FA-MCNs were stable with a spherical morphology and an average diameter of 129 nm. The cumulative release rate of M27-39@FA-MCNs in the artificial gastric fluid (pH = 1.2) and intestinal fluid (pH = 6.8) for 6 h was 87.77%. This nanoplatform maintains the advantages of both FA and MCNs to improve the bioactivity of M27-39 with high drug accumulation in colorectal tumor tissues and the ease of excretion, thus ameliorating its biosafety and targetability. Furthermore, M27-39@FA-MCNs induced tumor-cell apoptosis and inhibited tumor growth by disrupting mitochondrial energy metabolism and regulating the mitochondrial apoptosis signaling pathway and immune inflammatory response. Thus, such a mitochondria-targeting FA-modified nanoplatform based on mesoporous carbon and a bioactive peptide may provide a precise strategy for CRC treatment. Statement of significanceIn this study, we constructed an orally administered colon-accumulating mitochondria-targeted drug delivery nanoplatform (M27-39@FA-MCNs), which was synthesized using the small peptide (M27-39) and folic acid-modified mesoporous carbon nanoparticles (FA-MCNs). M27-39@FA-MCNs increased the targeting ability of M27-39 toward mitochondria and colon based on the properties of FA-MCNs; they also increased M27-39 accumulation and residence time in colon tumors. Oral administration of M27-39@FA-MCNs remarkably alleviated colorectal cancer (CRC) by targeting tumor cell mitochondria and interfering with the mitochondrial energy metabolism process, and inducing apoptosis related P53/Caspase-3 mitochondrial pathway activation. Therefore, M27-39@FA-MCNs may provide a safe and precise therapeutic strategy for CRC.