Low Systemic Toxicity Research Articles

Druggability, molecular targets, and nanocarrier delivery of natural triterpenoid celastrol against chronic diseases

Celastrol is an active compound from the root of Tripterygium wilfordii Hook F that shows great potential in the treatment of inflammation, cancer, neurodegeneration, diabetes, and obesity. However, the clinical application of celastrol has been hindered by its low bioavailability and severe systemic toxicity. The aim of this review was to discuss the druggability, molecular targets, and nanocarrier delivery of the natural triterpenoid, celastrol, against chronic diseases. We sequentially investigated the physicochemical properties of celastrol using online tools (pkCSM and SwissADME), reviewed the recent studies on the molecular mechanisms underlying the therapeutic effects of celastrol, and examined the potential of nanoparticle-mediated delivery systems for safe and effective delivery of celastrol. The cancer-related targets and pathways involved were further predicted through network pharmacologic analysis. This review provides molecular insights into the pharmacologic activities and molecular mechanisms underlying celastrol, as well as useful information for the selection of nanocarrier drug delivery system for the clinical delivery of celastrol against various chronic diseases.

Hybrid Homodimeric Prodrug Nanoassemblies for Low-Toxicity and Synergistic Chemophotodynamic Therapy of Melanoma

Synergistically active nanoparticles hold great promise for facilitating multimodal cancer therapy. However, strategies for their feasible manufacture and optimizing their formulations remain lacking. Herein, we developed hybrid homodimeric prodrug nanotherapeutics with tumor-restricted drug activation and chemophotodynamic pharmacology by leveraging the supramolecular nanoassembly of small molecules. The covalent dimerization of cytotoxic taxane chemotherapy via reactive oxygen species (ROS)-activated linker yielded a homodimeric prodrug, which was further coassembled with a ROS-generating dimeric photosensitizer. The nanoassemblies were readily refined in an amphiphilic PEGylation matrix for particle surface cloaking and in vivo intravenous injection. The nanoassemblies were optimized with favorable stability and combinatorial synergism to kill cancer cells. Upon near-infrared laser irradiation, the neighboring dimer photosensitizer generated ROS, subsequently triggering bond cleavage to facilitate drug activation, which in turn produced synergistic chemophotodynamic effects against cancer. In a preclinical model of melanoma, the intravenous administration of PEGylated nanoassemblies followed by near-infrared tumor irradiation led to significant tumor regression. Furthermore, animals treated with this efficient, photo-activatable nanotherapy exhibited low systemic toxicity even at high doses. This study describes a simple and cost-effective approach to integrate multimodal therapies by creating self-assembling small-molecule prodrugs for designing a combinatorial therapeutic nanosystem. We consider that this new paradigm holds substantial potential for advancing clinical translation.

Photothermal Responsive Microcarriers Encapsulated With Cangrelor and 5-Fu for Colorectal Cancer Treatment.

Localized chemotherapy is emerging as a potential strategy for cancer treatment due to its low systemic toxicity. However, the immune evasion of tumor cells and the lack of an intelligent design of the delivery system limit its clinical application. Herein, photothermal responsive microcarriers are designed by microfluidic electrospray for colorectal tumor treatment. The microcarriers loaded with Cangrelor, 5-FU and MXene (G-M@F/C+NIR) show sustained delivery of antiplatelet drug Cangrelor, thus inhibiting the activity of platelets, interactions of platelet-tumor cell, as well as the tumor cells invasion and epithelial-mesenchymal transition (EMT). In addition, the sustained delivery of chemotherapeutics 5-FU and the photothermal effect provided by MXene enable the microcarriers to inhibit tumor cells proliferation and migration. In vivo studies validate that the G-M@F/C+NIR microcarriers significantly inhibites tumor growth, decreased the expression of Ki-67 in tumor cells and vascular endothelial growth factor (VEGF) in the tumor microenvironment, while increased the expression of E-cadherin. It is believe that by means of the proposed photothermal responsive microcarriers, the synergistic strategy of platelet inhibition, chemotherapy, and photothermal therapy can find practical applications in cancer treatment.

Nanoparticles with Active Targeting Ability and Acid Responsiveness for an Enhanced Antitumor Effect of Docetaxel.

Docetaxel (DOC) is commonly used in cancer treatment, especially for breast cancer. However, there are severe side effects in clinical application. In order to deliver docetaxel more effectively, a novel, active targeting acid-responsive polymer called cRGD-PAE-PEG-DSPE was developed. The polymer structure incorporated poly(ethylene glycol) (PEG) as the hydrophilic segment, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) as the hydrophobic segment, and poly(β-amino ester) (PAE) as the acid-responsive group, which was grafted onto the PEG. Furthermore, c(RGDyC) was grafted onto PAE to confer active targeting capability. Through self-assembly, docetaxel was encapsulated in RAED@DOC. Through in vitro experiments, it was confirmed that RAED@DOC had good serum stability and acid responsiveness, as well as enhanced uptake by MDA-MB-231 cells. Additionally, the antitumor efficiency in vivo and histopathological analysis showed that RAED@DOC exhibited higher antitumor activity and lower systemic toxicity in comparison to free docetaxel. These results suggested that RAED@DOC had considerable potential clinical use.

Single protein encapsulated SN38 for tumor-targeting treatment

BackgroundThe alkaloid camptothecin analog SN38 is a potent antineoplastic agent, but cannot be used directly for clinical application due to its poor water solubility. Currently, the prodrug approach on SN38 has resulted in 3 FDA-approved cancer therapeutics, irinotecan, ONIVYDE, and Trodelvy. However, only 2–8% of irinotecan can be transformed enzymatically in vivo into the active metabolite SN38, which severely limits the drug’s efficacy. While numerous drug delivery systems have been attempted to achieve effective SN38 delivery, none have produced drug products with antitumor efficacy better than irinotecan in clinical trials. Therefore, novel approaches are urgently needed for effectively delivering SN38 to cancer cells with better efficacy and lower toxicity.MethodsBased on the unique properties of human serum albumin (HSA), we have developed a novel single protein encapsulation (SPE) technology to formulate cancer therapeutics for improving their pharmacokinetics (PK) and antitumor efficacy and reducing their side effects. Previous application of SPE technology to doxorubicin (DOX) formulation has led to a promising drug candidate SPEDOX-6 (FDA IND #, 152154), which will undergo a human phase I clinical trial. Using the same SPE platform on SN38, we have now produced two SPESN38 complexes, SPESN38-5 and SPESN38-8. We conducted their pharmacological evaluations with respect to maximum tolerated dose, PK, and in vivo efficacy against colorectal cancer (CRC) and soft tissue sarcoma (STS) in mouse models.ResultsThe lyophilized SPESN38 complexes can dissolve in aqueous media to form clear and stable solutions. Maximum tolerated dose (MTD) of SPESN38-5 is 250 mg/kg by oral route (PO) and 55 mg/kg by intravenous route (IV) in CD-1 mice. SPESN38-8 has the MTD of 45 mg/kg by IV in the same mouse model. PK of SPESN38-5 by PO at 250 mg/kg gave mouse plasma AUC0-∞ of 0.05 and 4.5 nmol × h/mL for SN38 and SN38 glucuronidate (SN38G), respectively, with a surprisingly high molar ratio of SN38G:SN38 = 90:1. However, PK of SPESN38-5 by IV at 55 mg/kg yielded much higher mouse plasma AUC0-∞ of 19 and 28 nmol × h/mL for SN38 and SN38G, producing a much lower molar ratio of SN38G:SN38 = 1.5:1. Antitumor efficacy of SPESN38-5 and irinotecan (control) was evaluated against HCT-116 CRC xenograft tumors. The data indicates that SPESN38-5 by IV at 55 mg/kg is more effective in suppressing HCT-116 tumor growth with lower systemic toxicity compared to irinotecan at 50 mg/kg. Additionally, SPESN38-8 and DOX (control) by IV were evaluated in the SK-LMS-1 STS mouse model. The results show that SPESN38-8 at 33 mg/kg is highly effective for inhibiting SK-LMS-1 tumor growth with low toxicity, in contrast to DOX’s insensitivity to SK-LMS-1 with high toxicity.ConclusionSPESN38 complexes provide a water soluble SN38 formulation. SPESN38-5 and SPESN38-8 demonstrate better PK values, lower toxicity, and superior antitumor efficacy in mouse models, compared with irinotecan and DOX.

Phytochemical-loaded Nanoparticles in COVID-19 Management

A phytochemical-loaded nanoparticle is an important therapeutic agent that aids in enhancing the bioavailability of phytochemicals of lower water solubility and delivering the phytochemicals to the site of infection in a targeted manner. This strategy has also been developed for the management of COVID-19. They can be used as antiviral medication carriers, causing the direct death of viral particles and imitating the host in order to neutralize viral processes. In the formulation of phytochemical-loaded nanoparticles against SARS-CoV-2, different categories of nanoparticles, including inorganic, lipid-based, and polymeric nanoparticles, are used. Numerous phytochemicals belonging to the classes of alkaloids, flavonoids, terpenes, terpenoids, saponins, glycosides, polyphenols, and lignans, that demonstrate effective antiviral properties are utilized for the phytochemical-loaded nanoparticles. This approach results in increased solubility and stability of the phytochemicals with lower systemic toxicity, in addition to site-specific delivery. The combination therapy delivers multiple therapeutic agents at the site of infection. It can also be administered directly to the respiratory system by inhalation delivery. Therefore, this approach can potentially inhibit the application of phytochemical-loaded nanoparticles for the treatment of COVID-19, which is still in its replication of the SARS-CoV-2 virus and reduces the severity of the disease. The infancy and a number of obstacles must be overcome prior to their widespread use.

In vitro evaluation and in vivo efficacy studies of a liposomal doxorubicin-loaded glycyrretinic acid formulation for the treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC), more than 800 000 cases reported annually, is the most common primary liver cancer globally. Doxorubicin hydrochloride (Dox-HCl) is a widely used chemotherapy drug for HCC, but efficacy and tolerability are limited, thus critical to develop delivery systems that can target Dox-HCl to the tumour site. In this study, liver-targeting ligand glycyrrhetinic acid (Gly) was conjugated to polyethylene glycol (PEG) via Steglich reaction and incorporated in liposomes, which were then loaded with Dox-HCl by pH gradient method. The optimal formulation Gly–Peg-Dox-ProLP-F6 showed high Dox-HCl encapsulation capacity (90.0%±1.85%), low particle size (120 ± 3.2 nm). Gly–Peg-Dox-ProLP-F6 formulation demonstrated substantially greater toxicity against HCC cells than commercial Dox-HCl formulation (greater against 1.14, 1.5, 1.24 fold against Hep G2, Mahlavu and Huh-7 cells, respectively), but was 1.86-fold less cytotoxic against non-cancerous cell line AML-12. It increased permeability from apical to basolateral (A–B) approximately 2-fold. Gly–Peg-Dox-ProLP-F6 demonstrated superior antitumor efficacy in mouse liver cancer model as evaluated by IVIS. Isolated mouse liver tissue contained 2.48-fold Dox more than Dox-HCl after administration of Gly–Peg-Dox-ProLP-F6, while accumulation in heart tissue was substantially lower. This Gly–Peg-Dox-ProLP-F6 formulation may improve HCC outcomes through superior liver targeting for enhanced tumour toxicity with lower systemic toxicity.

Design of carboxymethylcellulose-conjugated polymeric prodrug micelles for enhanced in vivo performance of docetaxel

Docetaxel (DTX) has become one of the most important cytotoxic drugs to treat cancer; nevertheless, its poor hydrophilicity and non-specific distribution of DTX lead to detrimental side effects. In this article, we devised carboxymethylcellulose (CMC)-conjugated polymeric prodrug micelles (mPEG-CMC-DTX PMs) for DTX delivery. The ester-bonded polymeric prodrug, mPEG-CMC-DTX, was synthesized and exhibited the capacity for self-assembling into polymeric micelles. The CMC is profusely substituted and acetylated to promote the coupling rate of DTX. Covalent binding of DTX and CMC through an ester bond can be hydrolyzed to dissociate the bond under the action of esterase in the tumor. The mPEG-CMC-DTX PMs displayed promoted drug loading (>50 %, wt), commendable stability, and sustained release behavior in vitro. The gradual release of the prodrug amplified the selectivity of cytotoxicity between normal cells and tumor cells, mitigating the systemic toxicity of mPEG-CMC-DTX PMs and enabling dose intensification. Notably, mPEG-CMC-DTX PMs demonstrated a superior antitumor efficacy and low systemic toxicity due to the elevated tolerance dosage (even at 40 mg/kg DTX). In summation, mPEG-CMC-DTX PMs harmonized the antitumor efficacy and toxicity of DTX. In essence, innovative perspectives for the rational design of CMC-conjugated polymeric prodrug micelles for the delivery of potently toxic drugs were proffered.

Arterial chemotherapy for hepatocellular carcinoma in China: consensus recommendations.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third leading cause of cancer-related deaths globally. Hepatic arterial infusion chemotherapy (HAIC) treatment is widely accepted as one of the alternative therapeutic modalities for HCC owing to its local control effect and low systemic toxicity. Nevertheless, although accumulating high-quality evidence has displayed the superior survival advantages of HAIC of oxaliplatin, fluorouracil, and leucovorin (HAIC-FOLFOX) compared with standard first-line treatment in different scenarios, the lack of standardization for HAIC procedure and remained controversy limited the proper and safe performance of HAIC treatment in HCC. Therefore, an expert consensus conference was held on March 2023 in Guangzhou, China to review current practices regarding HAIC treatment in patients with HCC and develop widely accepted statements and recommendations. In this article, the latest evidence of HAIC was systematically summarized and the final 22 expert recommendations were proposed, which incorporate the assessment of candidates for HAIC treatment, procedural technique details, therapeutic outcomes, the HAIC-related complications and corresponding treatments, and therapeutic scheme management.

Antiseptic Chitosan-Poly(hexamethylene) Biguanide Hydrogel for the Treatment of Infectious Wounds.

Topical wound infections create the ideal conditions for microbial colonization and growth in terms of moisture, temperature, and nutrients. When they are not protected, numerous types of bacteria from the internal microbiota and the external environment may colonize them, creating a polymicrobial population. Treatment of these wounds often necessitates the use of antibiotics that may have systemic harmful effects. Unlike antibiotics, topical antiseptics exhibit a wider range of activity and reduced systemic toxicity and resistance. In order to address this issue, we developed an antiseptic Chitosan-Poly (hexamethylene) Biguanide (CS-PHMB) hydrogel. The prepared hydrogel was characterized using Fourier Transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). SEM images showed the smooth morphology and characteristic FTIR peaks of PHMB and confirmed the incorporation of the antiseptic into the chitosan (CS) hydrogel. A Water Vapor Permeation Rate study confirms the moisture retention ability of the CS-PHMB hydrogel. Rheological studies proved the gel strength and temperature stability. The prepared hydrogel inhibited the growth of S. aureus, P. aeruginosa, E. coli, methicillin-resistant Staphylococcus aureus (MRSA), and K. pneumoniae, which confirms its antibacterial properties. It also inhibited biofilm formation for S. aureus and E. coli. CS-PHMB hydrogel is also found to be hemo- and cytocompatible in nature. Thus, the developed CS-PHMB hydrogel is a very potent candidate to be used for treating infectious topical wounds with low systemic toxicity.

The role of Her-2 in penile squamous cell carcinoma progression and cisplatin chemoresistance and potential for antibody-drug conjugate-based therapy

BackgroundCisplatin-based chemotherapy has been the first choice for advanced penile squamous cell carcinoma (PSCC) in the last decade, but its utility is limited by the low response rate, systemic toxicity, and chemoresistance, which contribute to a poor prognosis. There is no standard second-line therapy for advanced PSCC. Human epidermal growth factor receptor 2 (Her-2)-targeted antibody-drug conjugates (ADCs) are novel low-toxicity agents which have greatly improved clinical outcomes for several advanced cancers. We aimed to explore the expression pattern, clinical significance, and oncogenic roles of Her-2 and the therapeutic potential of Her-2-targeted ADCs in PSCC. MethodsHer-2 immunohistochemistry was performed for the largest single-centre PSCC cohort to date (367 patients). PSCC cell lines, cisplatin-resistant cell lines, subcutaneous xenograft, and footpad metastatic models were used to investigate the biological roles of Her-2 in PSCC progression. Cytotoxicity, apoptosis assays, and western blotting investigated the mechanism of Her-2 induced cisplatin-chemoresistance. The efficacy of Disitamab Vedotin (RC48), a Her-2-targeted ADC, was evaluated in PSCC. ResultsHer-2 was identified as an adverse prognostic indicator associated with advanced Tumor-Node-Metastasis (TNM) stages and poor survival with an immunohistochemical expression rate of approximately 47.7% (1+, 23.2%; 2+, 18.0%; 3+, 6.5%) in PSCC. Her-2 promotes cell proliferation, migration, invasion, tumour progression, and cisplatin resistance in PSCC. Mechanistically, Her-2 inhibits cisplatin-induced cell apoptosis by the activation of Akt phosphorylation at Ser473 and disrupts the balance between proapoptotic and antiapoptotic proteins. Meanwhile, cisplatin-resistant PSCC cells present aggressive oncogenic abilities and Her-2 upregulation. More importantly, RC48 displayed remarkable antitumor activities in both Her2-positive and cisplatin-resistant PSCC tumours. ConclusionOur study suggests that Her-2 is an available therapeutic biomarker for PSCC. Her-2-targeted ADC might have the potential to improve clinical outcomes in high-risk Her-2-positive advanced PSCC patients and provide precious second-line clinical choice for appropriate cisplatin-based chemoresistance patients.

Development and Study of Mosquitocidal and Antibacterial Properties of Typhonium trilobatum-Synthesized ZnO NPS and their Impact on the Predation Efficiency of Guppy Poecilia reticulata against the Dengue vector, Aedes aegypti

Dengue fever is an arbovirus spread mostly by Aedes mosquitos. Every year, there is an increase in the incidence of dengue infection and transmission. As a result, the need for an effective measure remains a top concern. The current work aims to assess the effectiveness of Typhonium trilobatum leaf extract synthesized zinc oxide nanoparticles (ZnO NPs) against the Dengue vector, Aedes aegypti. We synthesized zinc nanoparticles by reducing and stabilizing it using T. trilobatum leaf extract. UV-vis spectrophotometry, Fourier transform infrared spectroscopy, X-ray diffraction, energy dispersive X-ray analysis, field emission scanning electron microscopy, transmission electron microscopy and EDAX analysis were used for analyzing nanoparticles. T. trilobatum leaf extract and biosynthesized ZnONPs were extremely efficient against Ae. aegypti young instars, with LC50 values ranging from 36.633 ppm (larva I) to 102.436 ppm (pupa) and 1.555 ppm (larva I) to 6.906 ppm (pupa). The predation effectiveness of Poecillia reticulata guppy fish against A. aegypti I - IV instar larvae were 49.8 and 25.9 %, respectively. Predation was 78.3 and 39.8 % in ZnO-contaminated environments, respectively. The results of T. trilobatum leaf extract synthesized ZnONPs showed considerable larvicidal action with an increase in predatory potential of the guppy fish P. reticulata. To screen the antibacterial activities of T. trilobatum leaf extract and Biosynthesized ZnO NPs against Bacillus subtilis, Klebsiella pneumoniae, and Salmonella typhi, the agar disk diffusion and minimum inhibitory concentration procedures were used. The biosynthesized ZnO NPs showed excellent antibacterial effects against bacterial pathogens. Overall, our study suggests that T. trilobatum leaf extract synthesized ZnO NPs could be used in mosquito control as well as the creation of novel chemotherapeutic medicines with low systemic toxicity.

Effect of the Aqueous Extract of Chrysobalanus icaco Leaves on Maternal Reproductive Outcomes and Fetal Development in Wistar Rats.

Toxicological studies on medicinal plants are essential to ensure their safety and effectiveness in treating various diseases. Despite the species Chrysobalanus icaco L. being popularly used in the treatment of several diseases due to the pharmacological properties of its bioactive compounds, there are few studies in the literature regarding its toxicity regarding reproduction. Therefore, the purpose of this study was to assess the potential embryotoxic and teratogenic effects of the aqueous extract of C. icaco leaves (AECi) on Wistar rats. Animals were given AECi at doses of 100, 200, and 400 mg/kg during the pre-implantation and organogenesis periods. Data were analyzed using ANOVA followed by Tukey's test and Kruskal-Wallis. Pregnant rats treated during the pre-implantation period showed no signs of reproductive toxicity. Rats that received AECi at 100, 200, and 400 mg/kg during organogenesis did not exhibit any signs of maternal systemic toxicity or significant differences in gestational and embryotoxic parameters. Some skeletal changes were observed in the treated groups. Therefore, it can be suggested that AECi at doses of 100, 200, and 400 mg/kg is safe for treated animals and does not induce reproductive toxicity under the experimental conditions applied, but it also caused low systemic toxicity.

Paclitaxel prodrug-encapsulated polypeptide micelles with redox/pH dual responsiveness for cancer chemotherapy

Polypeptides are a highly promising carrier for delivering hydrophobic drugs, due to their excellent biocompatibility, non-toxicity, and non-immunogenicity. Herein, a redox and pH dual-responsive poly(ethylene glycol)-SS-b-polypeptide micelles encapsulated with disulfide bridged paclitaxel-pentadecanoic acid prodrug was developed for cancer chemotherapy. First of all, disulfide bridged paclitaxel-pentadecanoic acid prodrug (PTX-SS-COOH) and poly(ethylene glycol)-SS-b-polylysine-b-polyphenylalanine (mPEG-SS-b-PLys-b-PPhe, ESLP) were synthesized and confirmed via NMR, MS, FT-IR or GPC. After that, PTX-SS-COOH (PSH) embedded mPEG-SS-b-PLys-b-PPhe (ESLP/PSH) micelles were prepared by mixing method based on electrostatic interactions and hydrophobic forces. For comparison, mPEG-b-PLys-b-PPhe (ELP) was mixed with PTX-SS-COOH to generate another kind of micelles (ELP/PSH). The characterization of ESLP/PSH micelles through dynamic light scattering (DLS) and transmission electron microscopy (TEM) revealed a spherical structure with a diameter of approximately 170 nm. It is noteworthy that ESLP/PSH micelles displayed a high drug-loading rate of 22.84%, and excellent stability, which can be attributed to the specific interactions between the prodrug and copolymer. Drug release analysis demonstrated that the micelles exhibited a substantial release of PTX in the presence of GSH at pH 5.0, indicating a pH and redox dual responsiveness. In vivo pharmacokinetic study revealed the ESLP/PSH micelles had increased bioavailability and an extended circulation time. Ultimately, antitumor efficacy and systemic toxicity evaluation in 4 T1 tumor-bearing mice confirmed that ESLP/PSH micelles achieved the highest level of tumor growth inhibition (ca. 83%) and the lowest systemic toxicity in comparison with ELP/PSH micelles and commercialized Taxol®. Taken together, the dual responsive micelles represent a promising PTX formulation with potential clinical application in cancer chemotherapy.

Construction of Tumor Microenvironment‐Responsive Gene Carriers

AbstractPeptide‐ and polypeptide‐based self‐assembling gene delivery systems have received considerable attention owing to their inherent biocompatibility and bioactivity. Gene carriers based on elastin‐like polypeptides (ELPs) have been extensively studied because of their controllability and unique temperature responsiveness. The (EK)10‐PLGLAG‐Tat polypeptide sequence was selected for tumor gene delivery, with ELP serving as the hydrophobic core. In this sequence, a hydration layer can be formed on the surface of the carrier using the zwitterionic peptide segment (EK)10, which helps prevent the nonspecific adsorption of plasma proteins. Additionally, the MMP‐2 enzyme‐responsive PLGLAG peptide segment is responsible for exposing the cell‐penetrating peptide Tat specifically near tumor cells, facilitating the penetration of tumor cells. To introduce (EK)10‐PLGLAG‐Tat into the self‐assembling carrier while ensuring its bioactivity, a leucine zipper ZR/ZE with opposite charges was used to link it to the ELP. Because of its high specificity and low systemic toxicity, the carrier was named environmentally responsive gene carrier (ERGV). Experimental results demonstrated that the ERGV effectively removed (EK)10 in MMP‐2 overexpressed environments, altering the surface charge from negative to positive and facilitating ssDNA delivery into tumor cells. These findings highlight the potential of ERGVs as a safe and efficient method for targeted gene delivery to tumors.

Dynamically assembled nanomedicine based on host-guest molecular recognition for NIR laser-excited chemotherapy and phototheranostics.

Nanomedicines combining multimodal therapeutic modalities supply opportunities to eliminate tumors in a safe and efficient manner. However, the rigid encapsulation and covalent conjugation of different therapeutic reagents suffer from the complicated preparation process, premature drug leakage and severe adverse events. Herein, we report a self-enhanced supramolecular nanomedicine (SND) based on the host-guest molecular recognition between β-cyclodextrin (β-CD) and camptothecin (CPT) for trimodal synergistic chemotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT) using a single 670 nm near-infrared (NIR) laser. Thioketal bond and polyethylene glycol (PEG) segment are introduced into the structure of CPT-tk-PEG prodrug, thus the premature release of CPT is efficiently inhibited and the specific drug release is realized at tumor site where singlet oxygen (1O2)-generated PDT is performed. A boron dipyrromethene (BODIPY) theranostic agent is anchored onto β-CD, endowing SND with capabilities of fluorescence imaging, PDT and PTT. Benefiting from the supramolecular assembly, not only the solubility of CPT is improved by 40 times, but also the blood circulation time and tumor accumulation of SND are greatly promoted. In vivo, SND can effectively induce the immunogenic cell death (ICD) of tumor cells, thus performing prominent inhibition against both primary and distal tumors, and even anti-metastasis effect against liver without causing obvious systemic toxicity. STATEMENT OF SIGNIFICANCE: Although nanomedicines supply opportunities to eliminate tumors in an efficient manner, they usually suffer from premature drug leakage, complicated preparation process and severe side effects owing to the rigid encapsulation or covalent conjugation. Based on the host-guest molecular recognition, we developed a self-enhanced SND for synergistic chemotherapy, photodynamic therapy and photothermal therapy. Introduction of thioketal bond in CPT prodrug avoided the premature drug release, and the specific drug release was realized in the tumor cells. Profiting from the facile supramolecular assembly strategy, SND not only displayed a primary anticancer efficacy with a low systemic toxicity, but also efficiently inhibited the growth of distal tumors, contributing a vaccine-like function to eradicate the recurrent and metastatic tumors.

Multimodal Therapeutic Platforms Based on Self-Assembled Metallacycles/Metallacages for Cancer Radiochemotherapy.

Discrete organometallic complexes with defined structures are proceeding rapidly in combating malignant tumors due to their multipronged treatment modalities. Many innovative superiorities, such as high antitumor activity, extremely low systemic toxicity, active targeting ability, and enhanced cellular uptake, make them more competent for clinical applications than individual precursors. In particular, coordination-induced regulation of luminescence and photophysical properties of organic light-emitting ligands has demonstrated significant potential in the timely evaluation of therapeutic efficacy by bioimaging and enabled synergistic photodynamic therapy (PDT) or photothermal therapy (PTT). This review highlights instructive examples of multimodal radiochemotherapy platforms for cancer ablation based on self-assembled metallacycles/metallacages, which would be classified by functions in a progressive manner. Finally, the essential demands and some plausible prospects in this field for cancer therapy are also presented.

Sialic acid-decorated liposomes enhance the anti-cancer efficacy of docetaxel in tumor-associated macrophages

Tumor-associated macrophages (TAMs) in the tumor microenvironment potentially enhance tumor growth and invasion through various mechanisms and are thus an essential factor in tumor immunity. The highly expressed siglec-1 receptors on the surfaces of TAMs are potential targets for cancer drug delivery systems. Sialic acid (SA) is a specific ligand for siglec-1. In this study, the sialic acid-polyethylene glycol conjugate (DSPE-PEG2000-SA) was synthesized to modify the surface of liposomes and target TAMs by interacting with the siglec-1 receptor. Three docetaxel (DTX)-loaded liposomes, conventional (DTX-CL), DSPE-PEG2000-coated (DTX-PL), and DSPE-PEG2000-SA-coated (DTX-SAPL) liposomes, were prepared, with a particle size of <100 nm, uniform polydispersity index (PDI) values, negative zeta potential, and % encapsulation efficiency (EE) exceeding 95 %. Liposomes showed high stability after 3 months of storage at 4 °C without significant changes in particle size, PDI, zeta potential, or % EE. DTX was released from liposomes according to the Weibull model, and DTX-SAPL exhibited more rapid drug release than other liposomes. In vitro studies demonstrated that DTX-SAPL liposome exhibited a higher uptake and cytotoxicity on RAW 264.7 cells (TAM model) and lower toxicity on NIH3T3 cells (normal cell model) than other formulations. The high cell uptake ability was demonstrated by the role of the SA-SA receptor. Biodistribution studies indicated a high tumor accumulation of surface-modified liposomal formulations, particularly SA-modified liposomes, showing high signal accumulation at the tumor periphery, where TAMs were highly concentrated. Ex vivo imaging showed a significantly higher accumulation of SA-modified liposomes in the tumor, kidney, and heart than conventional liposomes. In the anti-cancer efficacy study, DTX-SAPL liposomes showed effective inhibition of tumor growth and relatively low systemic toxicity, as evidenced by the tumor volume, tumor weight, body weight values, and histopathological analysis. Therefore, DSPE-PEG2000-SA-coated liposomes could be promising carriers for DTX delivery targeting TAMs in cancer therapy.

Design, fabrication and evaluation of redox/pH dual‐responsive micelles for tumor targeting delivery and controlled release of paclitaxel

AbstractIn this study, a polymer with tumor targeting function and dual redox/pH sensitivity is designed and synthesized by integrating chitosan (CS), Poloxamer 407 (P407), cholesterol (CHO), folic acid (FA), and disulfide bonds into one molecule (P407‐CS(FA)‐SS‐CHO). The polymer can self‐assemble in water to form micelles and solubilize paclitaxel (PTX). The mean particle size of PTX‐loaded P407‐CS(FA)‐SS‐CHO micelles is 133 nm. In vitro drug release study demonstrates the acid and glutathione (GSH) triggered PTX release behavior of the micelles. In vitro and in vivo experiments demonstrate the excellent tumor growth inhibition efficacy and low systemic toxicity of the PTX‐loaded micelles. The P407‐CS(FA)‐SS‐CHO micelles will be potential intelligent drug carriers for PTX delivery.

Advance and Challenges in the Treatment of Skin Diseases with the Transdermal Drug Delivery System.

Skin diseases are among the most prevalent non-fatal conditions worldwide. The transdermal drug delivery system (TDDS) has emerged as a promising approach for treating skin diseases, owing to its numerous advantages such as high bioavailability, low systemic toxicity, and improved patient compliance. However, the effectiveness of the TDDS is hindered by several factors, including the barrier properties of the stratum corneum, the nature of the drug and carrier, and delivery conditions. In this paper, we provide an overview of the development of the TDDS from first-generation to fourth-generation systems, highlighting the characteristics of each carrier in terms of mechanism composition, penetration method, mechanism of action, and recent preclinical studies. We further investigated the significant challenges encountered in the development of the TDDS and the crucial significance of clinical trials.