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In vivo inhibition of orthotopic HCC progression by enhanced anti‐angiogenic therapy via co‐delivery of PCN‐Len NPs and p(Man‐IMDQ) NRs in supramolecular hydrogel. a) Schedule for orthotopic Hepa1‐6 HCC treatment. b) Curves of mouse body weight. Data represent mean ± SD (n = 5). c) The weight of tumors at the 7th and 14th day after treatment. Data represent mean ± SD (n = 3). d) Photographs of resected tumor‐bearing livers after treatment for 7 and 14 days. e) Representative images for H&E staining of tumor tissue sections. Statistical significance was analyzed using two‐tailed Student's t‐test between two groups, **p <0.01 and *p <0.05.
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Anti‐angiogenic therapies targeting inhibition of vascular endothelial growth factor (VEGF) pathway show clinical benefit in hypervascular hepatocellular carcinoma (HCC) tumors. However, HCC expresses massive pro‐angiogenic factors in the tumor microenvironment (TME) in response to anti‐angiogenic therapy, recruiting tumor‐associated macrophages (T...
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... In terms of extra toxicity associated with NDDS, most studies found that LVN-NDDS had good biosafety profile and had negligible side effects compared with PBS. 36,39,40,43,[45][46][47][49][50][51][52]54 However, several studies reported that LVN-NDDS was primarily accumulated and distributed to the liver 36,42,43 and spleen 42 except for the tumor. Overall, these results demonstrate that LVN-NDDS can effectively kill cancer cells without causing significant toxicity. ...
Lenvatinib (LVN) is a potentially effective multiple-targeted receptor tyrosine kinase inhibitor approved for treating hepatocellular carcinoma, metastatic renal cell carcinoma and thyroid cancer. Nonetheless, poor pharmacokinetic properties including poor water solubility and rapid metabolic, complex tumor microenvironment, and drug resistance have impeded its satisfactory therapeutic efficacy. This article comprehensively reviews the uses of nanotechnology in LVN to improve antitumor effects. With the characteristic of high modifiability and loading capacity of the nano-drug delivery system, an active targeting approach, controllable drug release, and biomimetic strategies have been devised to deliver LVN to target tumors in sequence, compensating for the lack of passive targeting. The existing applications and advances of LVN in improving therapeutic efficacy include improving longer-term efficiency, achieving higher efficiency, combination therapy, tracking and diagnosing application and reducing toxicity. Therefore, using multiple strategies combined with photothermal, photodynamic, and immunoregulatory therapies potentially overcomes multi-drug resistance, regulates unfavorable tumor microenvironment, and yields higher synergistic antitumor effects. In brief, the nano-LVN delivery system has brought light to the war against cancer while at the same time improving the antitumor effect. More intelligent and multifunctional nanoparticles should be investigated and further converted into clinical applications in the future.
... Hydrogels are used in the treatment of HCC as flexible drug delivery systems. The degradation of hydrogels is carefully controlled by particular molecular processes in order to maximize the effectiveness of the therapy [18]. Fig. 2 depicts the molecular processes and pathway responsible for hydrogel breakdown in the therapy of HCC. ...
... However, surgery is incomplete as residual microtumors could lead to tumor recurrence [69,70]. Wang et al. constructed a supramolecular hydrogel loading oxidized dextran, anti-angiogenic nanomedicines and TAMs-reprogramming polyTLR7/8a nano-regulators for orthotopic liver cancer therapy [71]. Injectable hydrogels for local drug delivery have been recently developed for tumor recurrence after surgery [72,73]. ...
Multifunctional nanoparticles are of significant importance for synergistic multimodal antitumor activity. Herein, zinc oxide (ZnO) was used as pH-sensitive nanoparticles for loading the chemotherapy agent doxorubicin (DOX) and the photosensitizer agent indocyanine green (ICG), and biocompatible low-molecular-weight heparin (LMHP) was used as the gatekeepers for synergistic photothermal therapy/photodynamic therapy/chemotherapy/immunotherapy. ZnO was decomposed into cytotoxic Zn2+ ions, leading to a tumor-specific release of ICG and DOX. ZnO simultaneously produced oxygen (O2) and reactive oxygen species (ROS) for photodynamic therapy (PDT). The released ICG under laser irradiation produced ROS for PDT and raised the tumor temperature for photothermal therapy (PTT). The released DOX directly caused tumor cell death for chemotherapy. Both DOX and ICG also induced immunogenic cell death (ICD) for immunotherapy. The in vivo and in vitro results presented a superior inhibition of tumor progression, metastasis and recurrence. Therefore, this study could provide an efficient approach for designing multifunctional nanoparticles for synergistic multimodal antitumor therapy.
Tumor metastasis, the spread of tumor cells from their place of origin to surrounding tissues and then distant organs through vasculatures, is the major cause of cancer mortality. Despite the recent advances in therapeutic approaches for tumor metastasis, the therapeutic efficacy is still unsatisfactory. Fruitful treatment strategies for tumor metastasis largely depend on targeting tumor cells, the molecular and cellular features of circulating tumor cells, the TME, and the regulatory components of the TME. However, traditionally administered therapeutic agents in biological fluids are highly prone to inactivation, often fail to reach the target site, cause adverse effects, and exhibit poor pharmacokinetics with a short half-life. To overcome these limitations, hydrogel-based delivery systems are investigated as local depots for sustained and stable release to combat tumor metastasis. Herein, we review the extensive application of hydrogels in the local delivery systems of potential therapeutic agents for tumor metastasis therapy. This review summarizes the recent advances in tumor metastasis inhibition strategies and potential therapeutic approaches using hydrogels for the local delivery of various therapeutic agents.
The treatment of digestive system tumors presents challenges, particularly in immunotherapy, owing to the advanced immune tolerance of the digestive system. Nanomaterials have emerged as a promising approach for addressing these challenges. They provide targeted drug delivery, enhanced permeability, high bioavailability, and low toxicity. Additionally, nanomaterials target immunosuppressive cells and reshape the tumor immune microenvironment (TIME). Among the various cells in the TIME, tumor-associated macrophages (TAMs) are the most abundant and play a crucial role in tumor progression. Therefore, investigating the modulation of TAMs by nanomaterials for the treatment of digestive system tumors is of great significance. Here, we present a comprehensive review of the utilization of nanomaterials to modulate TAMs for the treatment of gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer. We also investigated the underlying mechanisms by which nanomaterials modulate TAMs to treat tumors in the digestive system. Furthermore, this review summarizes the role of macrophage-derived nanomaterials in the treatment of digestive system tumors. Overall, this research offers valuable insights into the development of nanomaterials tailored for the treatment of digestive system tumors.
Hepatocellular carcinoma (HCC) is acknowledged as an immunosuppressive neoplasm, whereby the inactive microenvironment facilitates immune tolerance and evasion of HCC. Post‐surgical resected liver cancer exhibits a proclivity for relapse, rendering prevention of recurrence challenging as it may transpire at any point subsequent to surgery. Among the various anti‐recurrence interventions, the primary clinical approach involving the administration of regimens atezolizumab and bevacizumab (A+T) is deemed the most efficacious in reversing the tumor microenvironment, albeit still lacking in complete satisfaction. Therefore, the objective is to utilize a recently developed block copolymer as a protective carrier for two specific monoclonal antibody drugs. Subsequently, a modified hemostatic hydrogel will be synthesized for application during hepatic surgery. The immunotherapy impact of this approach is significantly prolonged and intensified due to the combined hemostasis properties and controlled release of the constituents within the synthesized nanocomposite hydrogel. Furthermore, these nanocomposite hydrogels exhibit remarkable efficacy in preventing postoperative wound bleeding and substantially enhancing the safety of liver cancer resection. This research on the anti‐recurrence hydrogel system presents a novel therapeutic approach for addressing local recurrence of liver cancer, potentially offering a substantial contribution to the field of surgical treatment for liver cancer in the future.
The optimal treatment for tracheal tumors necessitates sequential tumor elimination and tracheal cartilage reconstruction. This study introduces an innovative inorganic nanosheet, MnO2/PDA@Cu, comprising manganese dioxide (MnO2) loaded with copper ions (Cu) through in situ polymerization using polydopamine (PDA) as an intermediary. Additionally, a specialized methacrylic anhydride modified decellularized cartilage matrix (MDC) hydrogel with chondrogenic effects is developed by modifying a decellularized cartilage matrix with methacrylic anhydride. The MnO2/PDA@Cu nanosheet is encapsulated within MDC‐derived microneedles, creating a photothermal‐controllable MnO2/PDA@Cu‐MDC microneedle. Effectiveness evaluation involved deep insertion of the MnO2/PDA@Cu‐MDC microneedle into tracheal orthotopic tumor in a murine model. Under 808 nm near‐infrared irradiation, facilitated by PDA, the microneedle exhibited rapid overheating, efficiently eliminating tumors. PDA's photothermal effects triggered controlled MnO2 and Cu release. The MnO2 nanosheet acted as a potent inorganic nanoenzyme, scavenging reactive oxygen species for an antioxidant effect, while Cu facilitated angiogenesis. This intervention enhanced blood supply at the tumor excision site, promoting stem cell enrichment and nutrient provision. The MDC hydrogel played a pivotal role in creating a chondrogenic niche, fostering stem cells to secrete cartilaginous matrix. In conclusion, the MnO2/PDA@Cu‐MDC microneedle is a versatile platform with photothermal control, sequentially combining antitumor, antioxidant, pro‐angiogenic, and chondrogenic activities to orchestrate precise tracheal tumor eradication and cartilage regeneration.
Combined chemotherapy and targeted therapy holds immense potential in the management of advanced gastric cancer (GC). GC tissues exhibit an elevated expression level of protein kinase B (AKT), which contributes to disease progression and poor chemotherapeutic responsiveness. Inhibition of AKT expression through an AKT inhibitor, capivasertib (CAP), to enhance cytotoxicity of paclitaxel (PTX) toward GC cells is demonstrated in this study. A cathepsin B‐responsive polymeric nanoparticle prodrug system is employed for co‐delivery of PTX and CAP, resulting in a polymeric nano‐drug BPGP@CAP. The release of PTX and CAP is triggered in an environment with overexpressed cathepsin B upon lysosomal uptake of BPGP@CAP. A synergistic therapeutic effect of PTX and CAP on killing GC cells is confirmed by in vitro and in vivo experiments. Mechanistic investigations suggested that CAP may inhibit AKT expression, leading to suppression of the phosphoinositide 3‐kinase (PI3K)/AKT signaling pathway. Encouragingly, CAP can synergize with PTX to exert potent antitumor effects against GC after they are co‐delivered via a polymeric drug delivery system, and this delivery system helped reduce their toxic side effects, which provides an effective therapeutic strategy for treating GC.
Despite the tremendous progress in cancer treatment in recent decades, cancers often become resistant due to multiple mechanisms, such as intrinsic or acquired multidrug resistance, which leads to unsatisfactory treatment effects or accompanying metastasis and recurrence, ultimately to treatment failure. With a deeper understanding of the molecular mechanisms of tumors, researchers have realized that treatment designs targeting tumor resistance mechanisms would be a promising strategy to break the therapeutic deadlock. Nanodelivery systems have excellent physicochemical properties, including highly efficient tissue‐specific delivery, substantial specific surface area, and controllable surface chemistry, which endow nanodelivery systems with capabilities such as precise targeting, deep penetration, responsive drug release, multidrug codelivery, and multimodal synergy, which are currently widely used in biomedical researches and bring a new dawn for overcoming cancer resistance. Based on the mechanisms of tumor therapeutic resistance, this review summarizes the research progress of nanodelivery systems for overcoming tumor resistance to improve therapeutic efficacy in recent years and offers prospects and challenges of the application of nanodelivery systems for overcoming cancer resistance.
