Near‐Infrared Laser‐Triggered Nitric Oxide Nanogenerators for the Reversal of Multidrug Resistance in Cancer

The potential therapeutic implications of nitric oxide (NO) for diverse diseases have been under consideration for years; however, the development of precisely controllable NO generation system with potential for clinical application has remained elusive. Herein, intelligent near‐infrared (NIR) laser‐triggered NO nanogenerators for the treatment of multidrug‐resistant (MDR) cancer are fabricated by integrating photothermal agents and heat‐sensitive NO donors into a single nanoparticle. Such nanogenerators can absorb 808 nm NIR photons and convert them into ample heat to trigger NO release. The generated NO molecules are demonstrated to successfully achieve multidrug‐resistance reversal by inhibiting the expression of P‐glycol protein. Consequently, the intracellular accumulation of doxorubicin is effectively increased, resulting in high toxicity to MDR cancer cells in vitro. By virtue of surface modification with targeting ligands, these nanoparticles are able to selectively accumulate in tumor tissue. The therapeutic effects of the nanogenerators are validated in a humanized MDR cancer model. The in vivo experiment indicates that the nanoparticles possess excellent tumor suppression functionality with few side effects upon NIR laser exposure. Therefore, this novel photothermal conversion‐based NO‐releasing platform is expected to be a potential alternative to clinical MDR cancer treatment and may provide insights with regard to other NO‐relevant medical treatments.     

Tumor‐Microenvironment‐Adaptive Nanoparticles Codeliver Paclitaxel and siRNA to Inhibit Growth and Lung Metastasis of Breast Cancer

Prolonged circulation, specific and effective uptake by tumor cells, and rapid intracellular drug release are three main factors for the drug delivery systems to win the battle against metastatic breast cancer. In this work, a tumor microenvironment‐adaptive nanoparticle co‐loading paclitaxel (PTX) and the anti‐metastasis siRNA targeting Twist is prepared. The nanoparticle consists of a pH‐sensitive core, a cationic shell, and a matrix metalloproteinase (MMP)‐cleavable polyethylene glycol (PEG) corona conjugated via a peptide linker. PEG will be cut away by MMPs at the tumor site, which endows the nanoparticle with smaller particle size and higher positive charge, leading to more efficient cellular uptake in tumor cells and higher intra‐tumor accumulation of both PTX and siRNA in the 4T1 tumor‐bearing mice models compared to the nanoparticles with irremovable PEG. In addition, acid‐triggered drug release in endo/lysosomes is achieved through the pH‐sensitive core. As a result, the MMP/pH dual‐sensitive nanoparticles significantly inhibit tumor growth and pulmonary metastasis. Therefore, this tumor‐microenvironment‐adaptive nanoparticle can be a promising codelivery vector for effective therapy of metastatic breast cancer due to simultaneously satisfying the requirements of long circulating time, efficient tumor cell targeting, and fast intracellular drug release.     

Multifunctional Shell–Core Nanoparticles for Treatment of Multidrug Resistance Hepatocellular Carcinoma

Multidrug resistance (MDR) is the main obstruction against the chemotherapy for hepatocellular carcinoma. Herein, a biodegradable multifunctional tumor‐targeted core–shell structural nanocarrier (RGD peptide functionalized nanoparticles, RGD‐NPs) is reported for treating MDR hepatocellular carcinoma, which consists of three components: pH‐triggered calcium phosphate shell, long circulation phosphatidylserine‐polyethylene glycol (PS‐PEG) core, and an active targeting ligand RGD peptide. Drug‐resistance inhibitor (verapamil, VER) and chemotherapeutic agent (mitoxantrone, MIT) are separately encapsulated into the outer shell layer and inner core layer to obtain VER and MIT loaded RGD‐NPs (VM‐RGD‐NPs). Due to the shell–core structure, the VER and MIT can release sequentially, thus synergistically weakening the efflux effect to MIT by MDR cells. Also, the calcium phosphate can trigger lysosomal escaping through the varied pH value. Together with the optimized internalization pathway in MDR tumor cells, the increased intracellular effective chemotherapeutic drug concentration can be realized, thus achieving the improved curative effect. In this system, the PEG extends the circulation time in vivo. Also, the peptide RGD distinctly increases the affinity to MDR tumors with respect to nontargeted nanoparticles. As a consequence, VM‐RGD‐NPs exhibit a significant synergistic effect toward the MDR hepatocellular carcinoma, providing a promising therapeutic approach for MDR tumor.     

Dual‐Targeting to Cancer Cells and M2 Macrophages via Biomimetic Delivery of Mannosylated Albumin Nanoparticles for Drug‐Resistant Cancer Therapy

Multidrug resistance (MDR) is an issue that is not only related to cancer cells but also associated with the tumor microenvironments. MDR involves the complicated cancer cellular events and the crosstalk between cancer cells and their surroundings. Ideally, an effective system against MDR cancer should take dual action on both cancer cells and tumor microenvironments. The authors find that both the drug‐resistant colon cancer cells and the protumor M2 macrophages highly express two nutrient transporters, i.e., secreted protein acidic and rich in cysteine (SPARC) and mannose receptors (MR). By targeting SPARC and MR, a system can act on both cancer cells and M2 macrophages. Herein the authors develop a mannosylated albumin nanoparticles with coencapsulation of different drugs, i.e., disulfiram/copper complex (DSF/Cu) and regorafenib (Rego). The results show that combination therapy of DSF/Cu and Rego efficiently inhibits the growth of drug‐resistant colon tumor, and the combination has not been reported yet for use in anticancer treatment. The system significantly improves the treatment outcomes in the animal model bearing drug‐resistant tumors. The therapeutic mechanisms involve enhanced apoptosis, upregulation of intracellular ROS, anti‐angiogenesis, and tumor‐associated macrophage “re‐education.” This strategy is characterized by dual targeting to and the simultaneous action on cancer cells and M2 macrophages, with biomimetic codelivery of a novel drug combination.     

High‐Drug‐Loading Mesoporous Silica Nanorods with Reduced Toxicity for Precise Cancer Therapy against Nasopharyngeal Carcinoma

Nanorod‐based drug delivery systems have attracted great interest because of their enhanced cell internalization capacity and improved drug loading property. Herein, novel mesoporous silica nanorods (MSNRs) with different lengths are synthesized and used as nanocarriers to achieve higher drug loading and anticancer activity. As expected, MSNRs‐based drug delivery systems can effectively enhance the loading capacity of drugs and penetrate into tumor cells more rapidly than spherical nanoparticles due to their greater surface area and trans‐membrane transporting rates. Interestingly, these tailored MSNRs also enhance the cellular uptake of doxorubicin (DOX) in cancer cells, thus significantly enhancing its anticancer efficacy for hundreds of times by inducing of cell apoptosis. Internalized MSNRs‐DOX triggers intracellular reactive oxygen species (ROS) overproduction, which subsequently activates p53 and mitogen‐activated protein kinases (MAPKs) pathways to promote cell apoptosis. MSNRs‐DOX nanosystem also shows prolonged blood circulation time in vivo. In addition, MSNRs‐DOX significantly inhibits in vivo tumor growth in nude mice model and effectively reduced its in vivo toxicity. Therefore, this study provides an effective and safe strategy for designing chemotherapeutic agents for precise cancer therapy.     

Double-Lock Nanomedicines Enable Tumor-Microenvironment-Responsive Selective Antitumor Therapy

A hybrid nanocarrier for reducing the off-target adverse effects of chemotherapy via selective drug delivery to the tumor cells is reported. The model active agent, combretastatin A4 (CA4) phosphate is deposited onto the magnetite (Fe₃O₄) nanoparticles as the core, followed by lipid coating as the shell. Upon nanocarrier administration and biodistribution to the tumor site, the high level of adenosine triphosphate in the extracellular space of tumor induces the cargo release via phosphate displacement. Then, the CA4 phosphate is dephosphorylated by the alkaline phosphatase that is overexpressed at the plasma membrane of certain tumor cells, resulting in enhanced intracellular uptake of hydrophobic CA4. These sequential two-step unlocking processes enable the preferable accumulation of CA4 within tumor cells. Such approach is applicable to a wide range of chemotherapeutics and is promising for efficacy enhancement and side-effect reduction of antitumor chemotherapy.     

Bioinspired Nanoparticles with NIR‐Controlled Drug Release for Synergetic Chemophotothermal Therapy of Metastatic Breast Cancer

Optimal nanosized drug delivery systems (NDDS) require long blood circulation and controlled drug release at target lesions for efficient anticancer therapy. Red blood cell (RBC) membrane‐camouflaged nanoparticles (NPs) can integrate flexibility of synergetic materials and highly functionality of RBC membrane, endowed with many unique advantages for drug delivery. Here, new near‐infrared (NIR)‐responsive RBC membrane‐mimetic NPs with NIR‐activated cellular uptake and controlled drug release for treating metastatic breast cancer are reported. An NIR dye is inserted in RBC membrane shells, and the thermoresponsive lipid is employed to the paclitaxel (PTX)‐loaded polymeric cores to fabricate the RBC‐inspired NPs. The fluorescence of dye in the NPs can be used for in vivo tumor imaging with an elongated circulating halftime that is 12.3‐folder higher than that of the free dye. Under the NIR laser stimuli, the tumor cellular uptake of NPs is significantly enhanced to 2.1‐fold higher than that without irradiation. The structure of the RBC‐mimetic NPs can be destroyed by the light‐induced hyperthermia, triggered rapid PTX release (45% in 30 min). These RBC‐mimetic NPs provide a synergetic chemophotothermal therapy, completely inhibited the growth of the primary tumor, and suppress over 98% of lung metastasis in vivo, suggesting it to be an ideal NDDS to fight against metastatic breast cancer.     

Cancer Cell Membrane‐Biomimetic Oxygen Nanocarrier for Breaking Hypoxia‐Induced Chemoresistance

The inadequate oxygen supply in solid tumor causes hypoxia, which leads to drug resistance and poor chemotherapy outcomes. To solve this problem, a cancer cell membrane camouflaged nanocarrier is developed with a polymeric core encapsulating hemoglobin (Hb) and doxorubicin (DOX) for efficient chemotherapy. The designed nanoparticles (DHCNPs) retain the cancer cell adhesion molecules on the surface of nanoparticles for homologous targeting and possess the oxygen‐carrying capacity of Hb for O₂‐interfered chemotherapy. The results show that DHCNPs not only achieve higher tumor specificity and lower toxicity by homologous targeting but also significantly reduce the exocytosis of DOX via suppressing the expressions of hypoxia‐inducible factor‐1α, multidrug resistance gene 1, and P‐glycoprotein, thus resulting in safe and high‐efficient chemotherapy. This work presents a new paradigm for targeted oxygen interference therapy by conquering hypoxia‐involved therapeutic resistance and achieves effective treatment of solid tumors.     

Camouflaging Nanoparticles with Brain Metastatic Tumor Cell Membranes: A New Strategy to Traverse Blood–Brain Barrier for Imaging and Therapy of Brain Tumors

Glioblastoma multiforme is one of the most fatal intracranial tumors with no effective treatment. The drug concentration in tumor sites is usually insufficient to reach therapeutic levels, due to poor blood–brain‐barrier (BBB) permeability and short biological half‐life. Inspired by the proneness of those malignant tumors to brain metastasis, a brain metastatic tumor cell membrane‐coated nanocarrier with core–shell structure is constructed to cross BBB for imaging and photothermal therapy of early brain tumors. The cell membranes as the shell are extracted from different metastatic tumor cells, which endow the nanoparticles with BBB‐crossing ability and long circulation. Indocyanine green (ICG)‐loaded polymeric nanoparticle as the core allows fluorescence imaging and phototherapy of brain tumors. The as‐prepared biomimetic nanoparticles display superb BBB penetration and effective suppression of tumor growth. These findings suggest the biomimetic nanotechnology provides a new insight for the design of BBB‐crossing nanomaterials and is promising to treat brain diseases.     

Paclitaxel‐Loaded Polymer Nanoparticles for the Reversal of Multidrug Resistance in Breast Cancer Cells

Novel paclitaxel‐loaded polymer nanoparticles were developed for circumventing multidrug resistance (MDR) of malignant cancerous diseases, which is an unsolved clinical problem in cancer chemotherapy. In many cases, MDR is due to the intrinsic or acquired expression of an efflux pump, the P‐170 glycoprotein (P‐gp). By encapsulating paclitaxel in a water‐soluble and biocompatible synthetic polyampholyte using a solid‐state reaction the highly water‐soluble paclitaxel‐loaded nanoparticles are formed. The resulting paclitaxel nanoparticles with an average diameter of 250 nm show a significant reversal of chemoresistance in the drug‐resistant variants (MCF7/ADR, MT3/ADR) by a factor of 100 or more. The novel paclitaxel nanoparticles enter MDR breast cancer cells by adsorptive endocytosis bypassing the P‐gp, preventing the efflux of paclitaxel and thus restoring the anti‐proliferative effect of paclitaxel.