RESUMEN
The induction of anti-drug antibody (ADA) is a formidable challenge for protein-based therapy. Trichosanthin (TCS) as a class of ribosome-inactivating proteins is widely studied in tumor treatment. However, the immunogenicity can induce the formation of ADA, which can cause hypersensitivity reactions and neutralize the efficacy of TCS, thus limiting its clinical application in cancer therapy. Here, a promising solution to this issue is presented by co-administration of the rapamycin nanoparticles and TCS. PEGylated rapamycin amphiphilic molecule is designed and synthesized as a prodrug and a delivery carrier, which can self-assemble into a nanoparticle system with encapsulation of free rapamycin, a hydrophobic drug. It is found that co-injection of the PEGylated rapamycin nanoparticles and TCS could mitigate the formation of anti-TCS antibody via inducing durable immunological tolerance. Importantly, the combination of TCS and the rapamycin nanoparticles has an enhanced effect on inhibit the growth of breast cancer. This work provides a promising approach for protein toxin-based anticancer therapy and for promoting the clinical translation.
Asunto(s)
Nanopartículas , Tricosantina , Humanos , Sirolimus/farmacología , Sirolimus/uso terapéutico , Formación de Anticuerpos , Tricosantina/farmacología , Tricosantina/uso terapéutico , Anticuerpos , PolietilenglicolesRESUMEN
BACKGROUND: Acute lung injury (ALI) is a fatal respiratory disease caused by overreactive immune reactions (e.g., SARS-CoV-2 infection), with a high mortality rate. Its treatment is often compromised by inefficient drug delivery barriers and insufficient potency of the currently used drugs. Therefore, developing a highly effective lung-targeted drug delivery strategy is a pressing clinical need. RESULTS: In this study, the micro-sized inclusion cocrystal of asiatic acid/γ-cyclodextrin (AA/γCD, with a stoichiometry molar ratio of 2:3 and a mean size of 1.8 µm) was prepared for ALI treatment. The dissolution behavior of the AA/γCD inclusion cocrystals followed a "spring-and-hover" model, which meaned that AA/γCD could dissolve from the cocrystal in an inclusion complex form, thereby promoting a significantly improved water solubility (nine times higher than free AA). This made the cyclodextrin-based inclusion cocrystals an effective solid form for enhanced drug absorption and delivery efficiency. The biodistribution experiments demonstrated AA/γCD accumulated predominantly in the lung (Cmax = 50 µg/g) after systemic administration due to the micron size-mediated passive targeting effect. The AA/γCD group showed an enhanced anti-inflammatory therapeutic effect, as evidenced by reduced levels of pro-inflammatory cytokines in the lung and bronchoalveolar lavage fluids (BALF). Histological examination confirmed that AA/γCD effectively inhibited inflammation reactions. CONCLUSION: The micro-sized inclusion cocrystals AA/γCD were successfully delivered into the lungs by pulmonary administration and had a significant therapeutic effect on ALI.
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Lesión Pulmonar Aguda , Ciclodextrinas , Triterpenos Pentacíclicos , Humanos , Ciclodextrinas/química , Distribución Tisular , Sistemas de Liberación de Medicamentos , Lesión Pulmonar Aguda/tratamiento farmacológico , SolubilidadRESUMEN
Colorectal cancer (CRC) therapy is a big challenge, and seeking an effective and safe drug is a pressing clinical need. Gambogic acid is a potent antineoplastic agent without the drawback of bone marrow suppression. To improve its druggability (e.g., poor water solubility and tumor delivery), a lactoferrin-modified gambogic acid liposomal delivery system (LF-lipo) was developed to enhance the treatment efficacy of CRC. The LF-lipo can specifically bind LRP-1 expressed on colorectal cancer cells to enhance drug delivery to the tumor cells and yield enhanced therapeutic efficacy. The LF-lipo promoted tumor cell apoptosis and autophagy, reduced reactive oxygen species (ROS) levels in tumor cells, and inhibited angiogenesis; moreover, it could also repolarize tumor-associated macrophages from the M2 to M1 phenotype and induce ICD to activate T cells, exhibiting the capability of remodeling the tumor immune microenvironment. The liposomal formulation yielded an efficient and safe treatment outcome and has potential for clinical translation.
Asunto(s)
Neoplasias Colorrectales , Liposomas , Humanos , Liposomas/uso terapéutico , Lactoferrina , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Microambiente TumoralRESUMEN
Cancer is one of the most serious human diseases, causing millions of deaths worldwide annually, and, therefore, it is one of the most investigated research disciplines. Developing efficient anticancer tools includes studying the effects of different natural enzymes of plant and microbial origin on tumor cells. The development of various smart delivery systems based on enzyme drugs has been conducted for more than two decades. Some of these delivery systems have been developed to the point that they have reached clinical stages, and a few have even found application in selected cancer treatments. Various biological, chemical, and physical approaches have been utilized to enhance their efficiencies by improving their delivery and targeting. In this paper, we review advanced delivery systems for enzyme drugs for use in cancer therapy. Their structure-based functions, mechanisms of action, fused forms with other peptides in terms of targeting and penetration, and other main results from in vivo and clinical studies of these advanced delivery systems are highlighted.
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Antineoplásicos , Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Sistemas de Liberación de Medicamentos/métodos , Humanos , Neoplasias/tratamiento farmacológico , Péptidos/uso terapéuticoRESUMEN
Rationale: Surgical resection is a primary treatment for solid tumors, but high rates of tumor recurrence and metastasis post-surgery present significant challenges. Manganese (Mn2+), known to enhance dendritic cell-mediated cancer immunotherapy by activating the cGAS-STING pathway, has potential in post-operative cancer management. However, achieving prolonged and localized delivery of Mn2+ to stimulate immune responses without systemic toxicity remains a challenge. Methods: We developed a post-operative microenvironment-responsive dendrobium polysaccharide hydrogel embedded with Mn2+-pectin microspheres (MnP@DOP-Gel). This hydrogel system releases Mn2+-pectin microspheres (MnP) in response to ROS, and MnP shows a dual effect in vitro: promoting immunogenic cell death and activating immune cells (dendritic cells and macrophages). The efficacy of MnP@DOP-Gel as a post-surgical treatment and its potential for immune activation were assessed in both subcutaneous and metastatic melanoma models in mice, exploring its synergistic effect with anti-PD1 antibody. Result: MnP@DOP-Gel exhibited ROS-responsive release of MnP, which could exert dual effects by inducing immunogenic cell death of tumor cells and activating dendritic cells and macrophages to initiate a cascade of anti-tumor immune responses. In vivo experiments showed that the implanted MnP@DOP-Gel significantly inhibited residual tumor growth and metastasis. Moreover, the combination of MnP@DOP-Gel and anti-PD1 antibody displayed superior therapeutic potency in preventing either metastasis or abscopal brain tumor growth. Conclusions: MnP@DOP-Gel represents a promising drug-free strategy for cancer post-operative management. Utilizing this Mn2+-embedding and ROS-responsive delivery system, it regulates surgery-induced immune responses and promotes sustained anti-tumor responses, potentially increasing the effectiveness of surgical cancer treatments.
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Dendrobium , Hidrogeles , Manganeso , Ratones Endogámicos C57BL , Microesferas , Polisacáridos , Animales , Ratones , Hidrogeles/química , Manganeso/química , Polisacáridos/química , Polisacáridos/farmacología , Dendrobium/química , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Melanoma/inmunología , Melanoma/tratamiento farmacológico , Melanoma/terapia , Inmunoterapia/métodos , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Línea Celular Tumoral , Femenino , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Especies Reactivas de Oxígeno/metabolismo , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/farmacología , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Melanoma Experimental/tratamiento farmacológicoRESUMEN
Inflammatory bowel disease (IBD) is a chronic, life quality-reducing disease with no cures available yet. To develop an effective medication suitable for long-term use is an urgent but unmet need. Quercetin (QT) is a natural dietary flavonoid with good safety and multifaceted pharmacological activities against inflammation. However, orally administrated quercetin yields unproductive outcomes for IBD treatment because of its poor solubility and extensive metabolism in the gastrointestinal tract. In this work, a colon-targeted QT delivery system (termed COS-CaP-QT) was developed, of which the pectin (PEC)/Ca2+ microspheres were prepared and then crosslinked by oligochitosan (COS). The drug release profile of COS-CaP-QT was pH-dependent and colon microenvironment-responsive, and COS-CaP-QT showed preferential distribution in the colon. The mechanism study showed that QT triggered the Notch pathway to regulate the proliferation of T helper 2 (Th2) cells and group 3 innate lymphoid cells (ILC3s) and the inflammatory microenvironment was remodeled. The in vivo therapeutic results revealed that COS-CaP-QT could relieve the colitis symptoms and maintain the colon length and intestinal barrier integrity.
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Sistemas de Liberación de Medicamentos , Enfermedades Inflamatorias del Intestino , Humanos , Sistemas de Liberación de Medicamentos/métodos , Quercetina/farmacología , Quercetina/uso terapéutico , Preparaciones de Acción Retardada/farmacología , Inmunidad Innata , Pectinas/farmacología , Microesferas , Linfocitos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/metabolismo , Colon/metabolismo , Quitina/farmacologíaRESUMEN
Alleviating immunosuppression of the tumor microenvironment is an important strategy to improve immune checkpoint therapy. It is an urgent but unmet need to develop adjuvant therapeutics for assisting the mainstay immunotherapies. Trichosanthin is an approved gynecology drug in China and its immunomodulatory effects have drawn much attention as an old drug for new applications in cancer. In this work, a recombinant cell-penetrating trichosanthin (rTCS-LMWP) was prepared via genetic fusion of a cell-penetrating peptide sequence (LMWP) to trichosanthin aiming to overcome the intratumoral penetration and intracellular delivery challenges. The potential of trichosanthin as an adjuvant therapy was explored, including its effects on tumor cells, antigen-presenting cells, tumor immune microenvironment, and the synergistic effect in combination with anti-PD-1. The results revealed that rTCS-LMWP can stimulate the maturation of dendritic cells via activating the STING-TBK1-IRF3 pathway, repolarize the protumor M2-type macrophages, and upregulate the pro-inflammatory cytokine expression. Moreover, rTCS-LMWP can enhance anti-PD-1 therapeutic efficacy in a CT26-bearing mouse model. The synergistic effect involved the induction of immunogenic cell death in the tumors, the proliferation and functionalization of cytotoxic T cells, and the suppression of the immunosuppressive regulatory T cells. These findings indicate that trichosanthin can be developed as an immunomodulator to facilitate cancer immunotherapy.
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Neoplasias Colorrectales , Tricosantina , Animales , Ratones , Células Presentadoras de Antígenos , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Citocinas , Tricosantina/farmacología , Tricosantina/uso terapéutico , Microambiente TumoralRESUMEN
The development of cancer vaccines based on tumor-associated antigens is hurdled by lack of an efficient adjuvant and insufficient efficacy. To improve the efficacy of vaccines, a genetically-engineered method was employed in this work to achieve the codelivery of antigen and adjuvant to enhance immune responses. Trichosanthin is a plant-derived protein that possesses cancer immune stimulation function. A genetically engineered protein vaccine composed of trichosanthin (adjuvant) and legumain domain (a peptidic antigen) was constructed, which was further chemically modified with mannose for targeting dendritic cells (DCs). The method is facile and ready for scaling up for massive production. Such a "two-in-one" vaccine is advantageous for codelivery for augmenting the immune responses. The vaccine inhibited the tumors by triggering a robust cytotoxic T lymphocyte response in the orthotopic-breast-tumor mice. Furthermore, the vaccine was loaded into the temperature-sensitive hydrogel based on Pluronic F127 for implanting use in the post-surgical site. The sustained-released vaccine from the hydrogel inhibited not only the tumor recurrence but also the lung metastases of breast cancer. These findings demonstrated that it was a safe and effective vaccination for breast cancer immunotherapy in a prophylactical and therapeutical manner for remodeling the tumor immune microenvironment and arresting tumor growth.
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Vacunas contra el Cáncer , Neoplasias , Tricosantina , Ratones , Animales , Hidrogeles/farmacología , Células Dendríticas , Tricosantina/farmacología , Adyuvantes Inmunológicos/farmacología , Microambiente TumoralRESUMEN
There is a close connection between epigenetic regulation, cancer metabolism, and immunology. The combination of epigenetic therapy and immunotherapy provides a promising avenue for cancer management. As an epigenetic regulator of histone acetylation, panobinostat can induce histone acetylation and inhibit tumor cell proliferation, as well as regulate aerobic glycolysis and reprogram intratumoral immune cells. JQ1 is a BRD4 inhibitor that can suppress PD-L1 expression. Herein, we proposed a chemo-free, epigenetic-based combination therapy of panobinostat/JQ1 for metastatic colorectal cancer. A novel targeted binary-drug liposome was developed based on lactoferrin-mediated binding with the LRP-1 receptor. It was found that the tumor-targeted delivery was further enhanced by in situ formation of albumin corona. The lactoferrin modification and endogenous albumin adsorption contribute a dual-targeting effect on the receptors of both LRP-1 and SPARC that were overexpressed in tumor cells and immune cells (e.g., tumor-associated macrophages). The targeted liposomal therapy was effective to suppress the crosstalk between tumor metabolism and immune evasion via glycolysis inhibition and immune normalization. Consequently, lactic acid production was reduced and angiogenesis inhibited; TAM switched to an anti-tumor phenotype, and the anti-tumor function of the effector CD8+ T cells was reinforced. The strategy provides a potential method for remodeling the tumor immune microenvironment (TIME).
RESUMEN
Lung cancer is the top cause of cancer mortality in the world. Distant metastasis leads to high mortality. Abdominal metastasis of lung cancer is characterized by very poor prognosis and the median survival time is usually less than two months. Therefore, it is of clinical significance to develop a new effective method for the treatment of abdominal metastasis of lung cancer. Cell therapy has promoted the development of new technology and strategy in oncology. Macrophages, as an important component of solid tumors, have also attracted great attention as a promising strategy of cell therapy in oncology. However, the reinfusion of autologous macrophages would be easily "re-educated" by the tumor microenvironment into a phenotype that promotes tumor development. This work developed a potential therapy using celastrol nanoparticle-containing M1-like macrophages (NP@M1) as a combinatory therapeutic system. M1-like macrophages (M1Φ) not only can serve as a drug delivery carrier for celastrol but also as a biotherapeutic agent. In turn, the celastrol nanoparticles (NPs) can maintain an anticancer polarized status of M1Φ, and subsequently, the exocytosed NPs can also execute the tumor cell-killing effect. Such a system thus provides a "two-birds-one-stone" therapeutic strategy and a proof of concept for the currently incurable abdominal metastasis of lung cancer.
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Neoplasias Pulmonares , Nanopartículas , Neoplasias Peritoneales , Línea Celular Tumoral , Humanos , Inmunoterapia , Neoplasias Pulmonares/terapia , Macrófagos , Neoplasias Peritoneales/terapia , Microambiente TumoralRESUMEN
Sodium cellulose sulfates with various degree of substitution (DS) and degree of polymerization (DP) were synthesized by homogeneous sulfation of cellulose with different DP by using SO3/pyridine (Py) complex in N,N-dimethylacetamide/lithium chloride (DMA/LiCl). Sodium cellulose sulfate (SCS) samples obtained were free-radically depolymerized with hydrogen peroxide and copper (II) acetate at a controlled pH value of 7.5-8.0 and without control of the pH value (pH 2.5-4.0). The depolymerization process was studied with respect to changes in molecular mass, total DS, and substituent distribution of SCS. Elemental analysis, 13C NMR- and IR spectroscopic methods indicated that primary structures of SCS were retained with insignificant decreases in total sulfate content in the depolymerization. The depolymerization of SCS was randomly and obeyed pseudo first order kinetics under the conditions applied. SCS oligomers with low DP and very narrow molecular weight distribution were prepared by the depolymerization at pH 2.5-4.0.