Tumor Tissue Penetration Research Articles

A nanotheranostics with hypoxia-switchable fluorescence and photothermal effect for hypoxia imaging-guided immunosuppressive tumor microenvironment modulation

Modulating the immunosuppressive tumor immune microenvironment (TIME) is considered a promising strategy for cancer treatment. However, effectively modulating the immunosuppressive TIME within hypoxic zones remains a significant challenge. In this work, we developed a hypoxia-responsive amphiphilic drug carrier using boron-dipyrromethene (BODIPY) dye-modified chitosan (CsB), and then fabricated a hypoxia-targeted nanotheranostic system, named CsBPNs, through self-assembly of CsB and pexidartinib (5-((5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl), PLX3397), an immunotherapeutic drug targeting tumor-associated macrophages (TAMs), for synergistic photothermal/immunotherapy and hypoxia imaging. CsBPNs demonstrated uniform size, good stability, and hypoxia-switchable fluorescence and photothermal effects, enabling deep penetration and hypoxia imaging capacities in three-dimensional tumor cell spheres and tumor tissues. In vitro and in vivo experiments showed that CsBPNs under laser irradiation promoted TAMs repolarization, reversed the immunosuppressive TIME, and enhanced the therapeutic outcome of PLX3397 in solid tumors by facilitating deep delivery into hypoxic regions and synergistic photothermal therapy. This work provides a new strategy for detecting and modulating the immunosuppressive TIME in hypoxic zones, potentially enabling more precise and effective photo-immunotherapy in the future.

Biomimetic Nanosensitizer Potentiates Efficient Glioblastoma Gene-Radiotherapy through Synergistic Hypoxia Mitigation and PLK1 Silencing.

Postoperative radiotherapy currently stands as the cornerstone of glioblastoma (GBM) treatment. Nevertheless, low-dose radiotherapy has been proven ineffective for GBM, due to hypoxia in the GBM microenvironment, which renders the resistance to radiation-induced cell death. Moreover, the overexpression of the PLK1 gene in glioma cells enhances GBM proliferation, invasion, metastasis, and resistance to radiation. This study introduced a hybrid membrane-camouflaged biomimetic lipid nanosensitizer (CNL@miPA), which efficiently encapsulated gold nanoclusters (PA) and miR-593-5p by a chimeric membrane derived from lipids, cancer cells, and natural killer cells. CNL@miPA exhibited exceptional blood-brain barrier and tumor tissue penetration, effectively ameliorating hypoxia and synergizing with radiotherapy. By enabling prolonged miRNA circulation in the bloodstream and achieving high enrichment at the tumor site, CNL@miPA significantly suppressed tumor growth in combination treatment, thereby significantly extending the survival period of treated mice. Overall, the developed biomimetic nanosensitizer represented an efficient and multifunctional targeted delivery system, offering a novel strategy for gene-radiotherapy of GBM.

Adaptive Size Evolution of an MOFs-in-MOF Nanovehicle for Enhanced Nucleus-Targeted Tumor Chemotherapy.

A metal-organic frameworks (MOFs)-in-MOF nanovehicle (160 nm), which was constructed with newly prepared ultrasmall Cu(I)Cu(II)-BTC MOFs (UCMs, 2.95 nm) loaded with doxorubicin (DOX) and a nuclear localization signal (NLS) peptide as multicores (UCMDNs) and ZIF-8 as the shell MOF, was proposed to cross layers of biological barriers with adaptive size evolution capacity for achieving efficient nucleus-targeted drug delivery. It first enhanced tumor tissue penetration through its larger nanosize effect. Then the acidic tumor environment made the ZIF-8 shell degrade, releasing small-sized UCMDNs to enter into the cell and into the nucleus under the guidance of NLS. Furthermore, due to the distinct surface structural characteristics of UCMs, UCMDNs remained stable in the cytoplasm and collapsed in the nucleus due to the DOX-DNA interaction to deliver DOX precisely. It showed superior performance in the nucleus-directed delivery of DOX (delivery efficiency up to 56.7%) and a high tumor growth inhibition rate (96.4%), offering promising prospects in tumor chemotherapy.

Cascade catalyzed dual-responsive Gold-Ferri “bomb-like” nanoreactors for positive feedback penetrating in sequential targeted triple glioblastoma therapy

Glioblastoma (GBM) is the most common malignant primary brain tumor, with an overall median survival of less than two years after resection. The urgent goal in pre-clinical investigations is to develop effective therapeutic strategies to prolong the GBM patients’ survival and improve the poor prognosis. Although various inorganic nanoplatforms have been applied in GBM treatment, they still face obstacles such as poor brain targeting, low tumor effective penetration, and serious monotherapy resistance. Here, we designed an environmental-dependent tumor-killing nanoreactor (RFcAD) with a gold-ferri nanoagglomerates form structure that effectively inhibits GBM proliferation via catalyzing reactive oxygen species (ROS) generation, exhausting glucose, and NIR-based photothermal therapy. With iRGD decoration, RFcAD can effectively penetrate the blood–brain barrier and target GBM. The “bomb-like” structured RFcAD exhibited a glutathione (GSH)-responsive release of toxicity agent DM1 and pH-dependent nanoagglomerates degradation with gold particles and superparamagnetic iron oxide nanoparticles (SPIONS) release. Gold particles and SPIONS destroy GBM cells as chemodynamic therapy agents via exhibiting a glucose oxidase (GOx)-like and peroxide (POx)-like catalytic ability to generate cytotoxic ROS and exhaust intracellular glucose, respectively. Synergistic with DM1-based chemotherapy and NIR-induced photothermal therapy, RFcAD can significantly reduce GBM proliferation both in vitro and in vivo. This work highlights that the RFcAD nanoreactor can benefit GBM inhibition by improving tumor targeting, tissue penetration, and cytotoxicity.

Quantitative Three-Dimensional Imaging Analysis of HfO2 Nanoparticles in Single Cells via Deep Learning Aided X-ray Nano-Computed Tomography.

It is crucial for understanding mechanisms of drug action to quantify the three-dimensional (3D) drug distribution within a single cell at nanoscale resolution. Yet it remains a great challenge due to limited lateral resolution, detection sensitivities, and reconstruction problems. The preferable method is using X-ray nano-computed tomography (Nano-CT) to observe and analyze drug distribution within cells, but it is time-consuming, requiring specialized expertise, and often subjective, particularly with ultrasmall metal nanoparticles (NPs). Furthermore, the accuracy of batch data analysis through conventional processing methods remains uncertain. In this study, we used radioenhancer ultrasmall HfO2 nanoparticles as a model to develop a modular and automated deep learning aided Nano-CT method for the localization quantitative analysis of ultrasmall metal NPs uptake in cancer cells. We have established an ultrasmall objects segmentation method for 3D Nano-CT images in single cells, which can highly sensitively analyze minute NPs and even ultrasmall NPs in single cells. We also constructed a localization quantitative analysis method, which may accurately segment the intracellularly bioavailable particles from those of the extracellular space and intracellular components and NPs. The high bioavailability of HfO2 NPs in tumor cells from deeper penetration in tumor tissue and higher tumor intracellular uptake provide mechanistic insight into HfO2 NPs as advanced radioenhancers in the combination of quantitative subcellular image analysis with the therapeutic effects of NPs on 3D tumor spheroids and breast cancer. Our findings unveil the substantial uptake rate and subcellular quantification of HfO2 NPs by the human breast cancer cell line (MCF-7). This revelation explicates the notable efficacy and safety profile of HfO2 NPs in tumor treatment. These findings demonstrate that this 3D imaging technique promoted by the deep learning algorithm has the potential to provide localization quantitative information about the 3D distributions of specific molecules at the nanoscale level. This study provides an approach for exploring the subcellular quantitative analysis of NPs in single cells, offering a valuable quantitative imaging tool for minute amounts or ultrasmall NPs.

A Multifunctional Rocket‐Like Microneedle System with Thrusters for Self‐Promoted Deep Drug Penetration and Combination Treatment in Melanoma

AbstractPhotodynamic therapy (PDT) proves highly effective in addressing melanoma, and its synergy with targeted therapy offers a promising avenue in tumor treatment. However, the therapeutic outcome is largely impeded by the challenge of current photosensitizers and targeted drugs in reaching deep tumor tissues. Herein, a dually‐layered “microneedle rocket” termed PcNP/TRA‐HA‐Tyr/CLG‐MN is designed. The upper layer of the microneedle (MN) is composed of photodynamically active mesoporous silica nanoparticles, featuring photosensitizers covalently bonded to them. Within the mesopores of these nanoparticles lies trametinib (TRA), a compound that specifically targets the hyperactive MEK pathway present in melanoma cells. The lower layer is composed of an enzyme‐mediated hyaluronic acid‐tyramine hydrogel (HA‐Tyr/CLG) with collagenase (CLG), serving as rocket thrusters for remodeling the extracellular matrix (ECM) in tumor microenvironment. Among the three types of MNs prepared, the PcNP/TRA‐HA‐Tyr(II)/CLG‐MN exhibits the deepest penetration in tumor tissues and the longest retention time in vivo. Notably, the administrations of PcNP/TRA‐HA‐Tyr(II)/CLG‐MN alongside light irradiation significantly suppress the growth of A375‐xenografted tumors in mice. Together, the strategy of combining mesoporous silica nanoparticles, enzymatically cross‐linked hydrogels and CLG‐mediated ECM remodeling enables deep drug penetration and efficacious combination treatment against melanoma, showcasing significant potential in the realm of cancer nanomedicine.

Necroptosis-Mediated Synergistic Photodynamic and Glutamine-Metabolic Therapy Enabled by a Biomimetic Targeting Nanosystem for Cholangiocarcinoma.

Targeted delivery of glutamine metabolism inhibitors holds promise for cholangiocarcinoma therapy, yet effective delivery vehicles remain a challenge. This study reports the development of a biomimetic nanosystem, termed R-CM@MSN@BC, integrating mesoporous organosilicon nanoparticles with reactive oxygen species-responsive diselenide bonds for controlled release of the glutamine metabolism inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and the photosensitizer Ce6. Erythrocyte membrane coating, engineered with Arg-Gly-Asp (RGD) peptides, not only enhanced biocompatibility but also improved tumor targeting and tissue penetration. Upon laser irradiation, R-CM@MSN@BC executed both photodynamic and glutamine-metabolic therapies, inducing necroptosis in tumor cells and triggering significant immunogenic cell death. Time-of-flight mass cytometry analysis revealed that R-CM@MSN@BC can remodel the immunosuppressive tumor microenvironment by polarizing M1-type macrophages, reducing infiltration of M2-type and CX3CR1+ macrophages, and decreasing T cell exhaustion, thereby increasing the effectiveness of anti-programmed cell death ligand 1 immunotherapy. This strategy proposed in this study presents a viable and promising approach for the treatment of cholangiocarcinoma.

Cancer cell membrane cloaked fluorescent liposomes loaded with metal-phenolic complex nanoparticles for combinatorial therapy against breast cancer

The development of innovative strategies for effective cancer treatment remains a critical research focus. In this study, we present a novel approach by designing cancer cell membrane-cloaked fluorescent liposomes loaded with metal-phenolic complex nanoparticles for combinatorial therapy against breast cancer. This multifaceted therapeutic system leverages the unique properties of cancer cell membranes, fluorescent liposomes, and metal-phenolic complexes to create a highly targeted and versatile treatment platform. Cancer cell membranes serve as natural camouflage, allowing these nanoparticles to evade the immune system and specifically target breast cancer cells. The inclusion of fluorescent liposomes not only aids in real-time imaging of treatment progress but also enhances the therapeutic effect by providing photodynamic therapy. Metal-phenolic complexes provide a multifunctional payload, offering both thermally assisted cytotoxicity and the ability to modulate cellular pathways critical in cancer progression. The enhanced internalization found in 4T1 cell lines demonstrates the targeted efficiency of our nanosystem. We also observed a significant increase in intracellular reactive oxygen species (ROS), increased cell death, and a significant decrease in colony formation treated with the synthesized nanoparticles. Alteration in mitochondrial membrane potential indicated the onset of cellular apoptosis, which eventually resulted in cell death. The biomimetic CSpFeTA NPs exhibited remarkable deep tumor tissue penetration and apoptotic cell death assisted by NIR irradiation. The development of such a sophisticated nanosystem represents a significant advancement in cancer therapy, opening new avenues for personalized and effective breast cancer treatment.

Improving the pharmacokinetics, biodistribution and plasma stability of monobodies.

Cancer is a leading cause of death worldwide. Several targeted anticancer drugs entered clinical practice and improved survival of cancer patients with selected tumor types, but therapy resistance and metastatic disease remains a challenge. A major class of targeted anticancer drugs are therapeutic antibodies, but their use is limited to extracellular targets. Hence, alternative binding scaffolds have been investigated for intracellular use and better tumor tissue penetration. Among those, monobodies are small synthetic protein binders that were engineered to bind with high affinity and selectivity to central intracellular oncoproteins and inhibit their signaling. Despite their use as basic research tools, the potential of monobodies as protein therapeutics remains to be explored. In particular, the pharmacological properties of monobodies, including plasma stability, toxicity and pharmacokinetics have not been investigated. Here, we show that monobodies have high plasma stability, are well-tolerated in mice, but have a short half-life in vivo due to rapid renal clearance. Therefore, we engineered monobody fusions with an albumin-binding domain (ABD), which showed enhanced pharmacological properties without affecting their target binding: We found that ABD-monobody fusions display increased stability in mouse plasma. Most importantly, ABD-monobodies have a dramatically prolonged in vivo half-life and are not rapidly excreted by renal clearance, remaining in the blood significantly longer, while not accumulating in specific internal organs. Our results demonstrate the promise and versatility of monobodies to be developed into future therapeutics for cancer treatment. We anticipate that monobodies may be able to extend the spectrum of intracellular targets, resulting in a significant benefit to patient outcome.

Regulating Tumor-Associated Macrophage Polarization by Cyclodextrin-Modified PLGA Nanoparticles Loaded with R848 for Treating Colon Cancer.

This study aimed to develop a novel and feasible modification strategy to improve the solubility and antitumor activity of resiquimod (R848) by utilizing the supramolecular effect of 2-hydroxypropyl-beta-cyclodextrin (2-HP-β-CD). R848-loaded PLGA nanoparticles modified with 2-HP-β-CD (CD@R848@NPs) were synthesized using an enhanced emulsification solvent-evaporation technique. The nanoparticles were then characterized in vitro by several methods, such as scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, particle size analysis, and zeta potential analysis. Then, the nanoparticles were loaded with IR-780 dye and imaged using an in vivo imaging device to evaluate their biodistribution. Additionally, the antitumor efficacy and underlying mechanism of CD@R848@NPs in combination with an anti-TNFR2 antibody were investigated using an MC-38 colon adenocarcinoma model in vivo. The average size of the CD@R848@NPs was 376 ± 30 nm, and the surface charge was 21 ± 1 mV. Through this design, the targeting ability of 2-HP-β-CD can be leveraged and R848 is delivered to tumor-supporting M2-like macrophages in an efficient and specific manner. Moreover, we used an anti-TNFR2 antibody to reduce the proportion of Tregs. Compared with plain PLGA nanoparticles or R848, CD@R848@NPs increased penetration in tumor tissues, dramatically reprogrammed M1-like macrophages, removed tumors and prolonged patient survival. The new nanocapsule system is a promising strategy for targeting tumor, reprogramming tumor -associated macrophages, and enhancement immunotherapy.

Bispecific fibrous glue synergistically boosts vascular normalization and antitumor immunity for advanced renal carcinoma therapy

Immune checkpoint blockade therapy represented by programmed cell death ligand 1 (PD-L1) inhibitor for advanced renal carcinoma with an objective response rate (ORR) in patients is less than 20%. It is attributed to abundant tumoral vasculature with abnormal structure limiting effector T cell infiltration and drug penetration. We propose a bispecific fibrous glue (BFG) to regulate tumor immune and vascular microenvironments simultaneously. The bispecific precursor glue peptide-1 (pre-GP1) can penetrate tumor tissue deeply and self-assemble into BFG in the presence of neuropilin-1 (NRP-1) and PD-L1. The resultant fibrous glue is capable of normalizing tumoral vasculature as well as restricting immune escape. The pre-GP1 retains a 6-fold higher penetration depth than that of antibody in the multicellular spheroids (MCSs) model. It also shows remarkable tumor growth inhibition (TGI) from 19% to 61% in a murine advanced large tumor model compared to the clinical combination therapy. In addition, in the orthotopic renal tumor preclinical model, the lung metastatic nodules are reduced by 64% compared to the clinically used combination. This pre-GP1 provides a promising strategy to control the progression and metastasis of advanced renal carcinoma.

Abstract 6050: Targeting KRAS G12D mutant tumors with the PROTAC degrader RP03707

Abstract RAS oncogene mutations are prevalent in approximately 19% of cancer patients, with the most frequent alteration occurring in codon 12 of the KRAS gene, resulting in a variety of G12X oncoproteins. Recent advances in drug discovery have yielded several KRAS G12C inhibitors currently in clinical use, benefiting a subset of patients. However, addressing the high-prevalence G12D mutation remains a substantial unmet medical need. Targeted protein degradation using PROTAC molecules offers a promising approach for treating KRAS G12D-associated tumors, potentially providing superior efficacy and mitigating the development of resistance, a challenge frequently observed with KRAS G12C inhibitors in clinical settings. In the present study, we report a PROTAC compound RP03707 that efficiently induces the degradation of the KRAS G12D mutant protein and inhibits tumor growth. Treatment of AsPc-1 cells with RP03707 results in significant degradation of the KRAS G12D protein, with a DC50 value in the sub-nanomolar range. Within 24 hours, the compound eliminates over 90% of G12D proteins and effectively suppresses downstream cellular MAPK signaling. Additional in vitro experiments demonstrate that RP03707 inhibits cell proliferation in multiple KRAS G12D mutant cell lines, surpassing the anti-tumor efficacy of enzyme inhibitors. In a mouse GP2d xenograft tumor model, a single intravenous administration of RP03707 at 10 mpk results in excellent compound penetration and retention in tumor tissues, followed by 90% reduction of G12D protein levels for 7 days. Profound inhibition of tumor growth is observed not only in mouse GP2d xenograft but also in other mouse KRAS G12D tumor models, even when the compound is administered in low and infrequent doses. Moreover, RP03707 exhibits high selectivity for degrading the KRAS G12D protein and possesses favorable drug-like properties. RP03707, therefore, meets the criteria for advancing into drug development and represents a valuable therapeutic option for treating KRAS G12D-associated tumors. Citation Format: Xiang Ji, Huanping Li, Gang Wu, Qiguo Zhang, Xiaolin He, Yanpeng Wu, Bing Zong, Xiaojin Xu, Chao Liang, Beibei Wang, Yuwei Zhang, Qingyao Hu, Jiaxin Zhou, Weihui Guo, Bing Bai, Lin Wang, Jinchao Ai, Leduo Zhang, Honggui Zhou, Shihao Sun, Yijie Wang, Youhong Wang, Qiming Fan, Dawei Chen, Tianlun Zhou, Jiasheng Lu. Targeting KRAS G12D mutant tumors with the PROTAC degrader RP03707 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6050.

An FOF1-ATPase motor-embedded chromatophore as a nanorobot for overcoming biological barriers and targeting acidic tumor sites

Despite the booming progress of anticancer nanomedicines in the past two decades, precise tumor-targetability and sufficient tumor-accumulation are less successful and still require further research. To tackle this challenge, herein we present a biomolecular motor (FOF1-ATPase)-embedded chromatophore as nanorobot to efficiently overcome biological barriers, and thoroughly investigate its chemotactic motility, tumor-accumulation ability and endocytosis. Chromatophores embedded with FOF1-ATPase motors were firstly extracted from Thermus thermophilus, then their properties were fully characterized. Specifically, two microfluidic platforms (laminar flow microchip and tumor microenvironment (TME) microchip) were designed and developed to fully investigate the motility, tumor-accumulation ability and endocytosis of the chromatophore nanorobot (CN). The results from the laminar flow microchip indicated that the obtained CN possessed the strongly positive chemotaxis towards protons. And the TME microchip experiments verified that the CN had a desirable tumor-accumulation ability. Cellular uptake experiments demonstrated that the CN efficiently promoted the endocytosis of the fluorescence DiO into the HT-29 cells. And the in vivo studies revealed that the intravenously administered CN exhibited vigorous tumor-targetability and accumulation ability as well as highly efficient antitumor efficacy. All the results suggested that FOF1-ATPase motors-embedded CN could be promising nanomachines with powerful self-propulsion for overcoming physiological barriers and tumor-targeted drug delivery. Statement of significanceIn this study, we demonstrated that FOF1-ATPase-embedded chromatophore nanorobots exhibit a strong proton chemotaxis, which not only plays a key role in tumor-targetability and accumulation, but also promotes tumor tissue penetration and internalization. The results of in vitro and in vivo studies indicated that drug-loaded chromatophore nanorobots are capable to simultaneously accomplish tumor-targeting, accumulation, penetration and internalization for enhanced tumor therapy. Our study provides a fundamental basis for further study on FOF1-ATPase-embedded chromatophore as tumor-targeting drug delivery systems that have promising clinical applications. It offers a new and more efficient delivery vehicle for cancer related therapeutics.

Transmembrane modification of tumor vascular targeting peptide A7R as molecular cargo delivery tool

In recent years, targeting tumor angiogenesis has emerged as a prominent research focus in the treatment and prevention of tumor expansion. A7R (ATWLPPR) exhibits high affinity and specificity for VEGFR-2, which is overexpressed in various tumors. To enhance the tumor tissue and cell penetration capabilities of A7R, we substituted its non-critical amino acid with Arginine (R) and Glutamic acid (E), cyclized the mutant peptide, and linked it to the membrane permeation sequence using coordination principles. We designed and synthesized fifteen novel penetrating peptides that target tumor blood vessels and cells, followed by conducting various biological evaluations and cell imaging experiments. The results demonstrated that Cyclo-A7R-RRR and A7R-RLLRLLR exhibited excellent permeability towards tumor cells, with Cyclo-A7R-RRR showing superior serum stability compared to A7R. Furthermore, the modified peptides showed no toxicity towards HeLa cells, U251 cells, HuH-7 cells, and HEK293 cells under 10 μmol/L. Utilizing Cyclo-A7R-RRR or A7R-RLLRLLR for transmembrane delivery of drug molecules could significantly improve their efficacy. Our findings broaden the potential application scenarios of A7R in targeted tumor angiogenesis.

Self-Assembly of Heterogeneous Ferritin Nanocages for Tumor Uptake and Penetration.

Well-defined nanostructures are crucial for precisely understanding nano-bio interactions. However, nanoparticles (NPs) fabricated through conventional synthesis approaches often lack poor controllability and reproducibility. Herein, a synthetic biology-based strategy is introduced to fabricate uniformly reproducible protein-based NPs, achieving precise control over heterogeneous components of the NPs. Specifically, a ferritin assembly toolbox system is developed that enables intracellular assembly of ferritin subunits/variants in Escherichia coli. Using this strategy, a proof-of-concept study is provided to explore the interplay between ligand density of NPs and their tumor targets/penetration. Various ferritin hybrid nanocages (FHn) containing human ferritin heavy chains (FH) and light chains are accurately assembled, leveraging their intrinsic binding with tumor cells and prolonged circulation time in blood, respectively. Further studies reveal that tumor cell uptake is FH density-dependent through active binding with transferrin receptor 1, whereas in vivo tumor accumulation and tissue penetration are found to be correlated to heterogeneous assembly of FHn and vascular permeability of tumors. Densities of 3.7FH/100nm2 on the nanoparticle surface exhibit the highest degree of tumor accumulation and penetration, particularly in tumors with high permeability compared to those with low permeability. This study underscores the significance of nanoparticle heterogeneity in determining particle fate in biological systems.

Matrix-degrading soft-nanoplatform with enhanced tissue penetration for amplifying photodynamic therapeutic efficacy of breast cancer.

The dense extracellular matrix (ECM) in the tumor microenvironment forms an abnormal physical barrier, which impedes the delivery and penetration of nanomedicines and hinders their therapeutic efficacy. Herein, we synthesize matrix-degrading soft-nanocapsules composed of human serum albumin (HSA) and hyaluronidase (HAase) for overcoming the obstruction of ECM in the tumor microenvironment. The matrix-degrading human serum albumin/hyaluronidase soft-nanocapsules, referred to as HSA/HAase SNCs, possess a uniform diameter, inward hollow structure, and wrinkled morphology. In vitro biocompatibility results indicate that the HSA/HAase SNCs display no adverse effects on the viability of human umbilical vein endothelial cells (HUVECs), smooth muscle cells (SMCs), and mouse breast cancer (4T1) cells and do not induce hemolysis towards red blood cells (RBCs). The HSA/HAase SNCs exhibit a 1.4-fold increase in tumor cellular uptake compared to the stiff-counterparts and enhanced penetration in 4T1-, mouse colon carcinoma 26- (CT26-), and mouse pancreatic cancer- (PanO2-) multicellular spheroids. Thanks to the advanced biological properties, a photodynamic platform prepared by loading Ce6 in the HSA/HAase SNCs (HSA/HAase@Ce6) shows improved reactive oxygen species production, a stronger killing effect for cancer cells, and deeper penetration in tumor tissues. In vivo experiments show that HSA/HAase@Ce6 effectively inhibits tumor growth in breast cancer mouse models. RNA-seq analysis of the mice that received the treatment of HSA/HAase@Ce6 shows enrichment of signaling pathways associated with ECM-degradation, which demonstrates that the matrix-degrading nanocapsules overcome the ECM-induced physical barriers in tumors. Overall, the matrix-degrading soft-nanoplatform represents a highly promising strategy to overcome ECM-induced physical barriers and enhance the therapeutic efficacy of nanomedicines.

Combined Photothermal Chemotherapy for Effective Treatment Against Breast Cancer in Mice Model.

Breast cancer ranks among the most prevalent cancers in women, characterized by significant morbidity, disability, and mortality. Presently, chemotherapy is the principal clinical approach for treating breast cancer; however, it is constrained by limited targeting capability and an inadequate therapeutic index. Photothermal therapy, as a non-invasive approach, offers the potential to be combined with chemotherapy to improve tumor cellular uptake and tissue penetration. In this research, a mesoporous polydopamine-coated gold nanorod nanoplatform, encapsulating doxorubicin (Au@mPDA@DOX), was developed. This nanoplatform was constructed by surface coating mesoporous polydopamine (mPDA) onto gold nanorods, and doxorubicin (DOX) was encapsulated in Au@mPDA owing to π-π stacking between mPDA and DOX. The dynamic diameter, zeta potential, absorbance, photothermal conversion ability, and drug release behavior were determined. The cellular uptake, cytotoxicity, deep penetration, and anti-tumor effects were subsequently investigated in 4T1 cells. After that, fluorescence imaging, photothermal imaging and pharmacodynamics studies were utilized to evaluate the anti-tumor effects in tumor-bearing mice model. This nanoplatform exhibited high drug loading capacity, excellent photothermal conversion and, importantly, pH/photothermal dual-responsive drug release behavior. The in vitro results revealed enhanced photothermal-facilitated cellular uptake, drug release and tumor penetration of Au@mPDA@DOX under near-infrared irradiation. In vivo studies confirmed that, compared with monotherapy with either chemotherapy or photothermal therapy, the anti-tumor effects of Au@mPDA@DOX are synergistically improved. Together with good biosafety and biocompatibility, the Au@mPDA@DOX nanoplatform provides an alternative method for safe and synergistic treatment of breast cancer.

Nanomedicine as a multimodal therapeutic paradigm against cancer: on the way forward in advancing precision therapy.

Recent years have witnessed dramatic improvements in nanotechnology-based cancer therapeutics, and it continues to evolve from the use of conventional therapies (chemotherapy, surgery, and radiotherapy) to increasingly multi-complex approaches incorporating thermal energy-based tumor ablation (e.g. magnetic hyperthermia and photothermal therapy), dynamic therapy (e.g. photodynamic therapy), gene therapy, sonodynamic therapy (e.g. ultrasound), immunotherapy, and more recently real-time treatment efficacy monitoring (e.g. theranostic MRI-sensitive nanoparticles). Unlike monotherapy, these multimodal therapies (bimodal, i.e., a combination of two therapies, and trimodal, i.e., a combination of more than two therapies) incorporating nanoplatforms have tremendous potential to improve the tumor tissue penetration and retention of therapeutic agents through selective active/passive targeting effects. These combinatorial therapies can correspondingly alleviate drug response against hypoxic/acidic and immunosuppressive tumor microenvironments and promote/induce tumor cell death through various multi-mechanisms such as apoptosis, autophagy, and reactive oxygen-based cytotoxicity, e.g., ferroptosis, etc. These multi-faced approaches such as targeting the tumor vasculature, neoangiogenic vessels, drug-resistant cancer stem cells (CSCs), preventing intra/extravasation to reduce metastatic growth, and modulation of antitumor immune responses work complementary to each other, enhancing treatment efficacy. In this review, we discuss recent advances in different nanotechnology-mediated synergistic/additive combination therapies, emphasizing their underlying mechanisms for improving cancer prognosis and survival outcomes. Additionally, significant challenges such as CSCs, hypoxia, immunosuppression, and distant/local metastasis associated with therapy resistance and tumor recurrences are reviewed. Furthermore, to improve the clinical precision of these multimodal nanoplatforms in cancer treatment, their successful bench-to-clinic translation with controlled and localized drug-release kinetics, maximizing the therapeutic window while addressing safety and regulatory concerns are discussed. As we advance further, exploiting these strategies in clinically more relevant models such as patient-derived xenografts and 3D organoids will pave the way for the application of precision therapy.

Dual peptides-modified cationic liposomes for enhanced Lung cancer gene therapy by a gap junction regulating strategy

BackgroundGene therapy for lung cancer has emerged as a novel tumor-combating strategy for its superior tumor specificity, low systematical toxicity and huge clinical translation potential. Especially, the applications of microRNA shed led on effective tumor ablation by directly interfering with the crucial gene expression, making it one of the most promising gene therapy agents. However, for lung cancer therapy, the microRNA treatment confronted three bottlenecks, the poor tumor tissue penetration effect, the insufficient lung drug accumulation and unsatisfied gene transfection efficiency. To address these issues, an inhalable RGD-TAT dual peptides-modified cationic liposomes loaded with microRNA miR-34a and gap junction (GJ) regulation agent all-trans retinoic acid (ATRA) was proposed, which was further engineered into dry powder inhalers (DPIs).ResultsEquipped with a rough particle surface and appropriate aerodynamic size, the proposed RGD-TAT-CLPs/ARTA@miR-34a DPIs were expected to deposit into the deep lung and reach lung tumor lesions guided by targeting peptide RGD. Assisted by cellular transmembrane peptides TAT, the RGD-TAT-CLPs/ARTA@miR-34a was proven to be effectively internalized by cancer cells, enhancing gene transfection efficiency. Then, the GJ between tumor cells was upregulated by ARTA, facilitating the intercellular transport of miR-34a and boosting the gene expression in the deep tumor.ConclusionOverall, the proposed RGD-TAT-CLPs/ARTA@miR-34a DPIs could enhance tumor tissue penetration, elevate lung drug accumulation and boost gene transfection efficiency, breaking the three bottlenecks to enhancing tumor elimination in vitro and in vivo. We believe that the proposed RGD-TAT-CLPs/ARTA@miR-34a DPIs could serve as a promising pulmonary gene delivery platform for multiple lung local disease treatments.

Microwave-responsive gadolinium metal-organic frameworks nanosystem for MRI-guided cancer thermotherapy and synergistic immunotherapy

The clinical application of cancer immunotherapy is unsatisfied due to low response rates and systemic immune-related adverse events. Microwave hyperthermia can be used as a synergistic immunotherapy to amplify the antitumor effect. Herein, we designed a Gd-based metal-organic framework (Gd-MOF) nanosystem for MRI-guided thermotherapy and synergistic immunotherapy, which featured high performance in drug loading and tumor tissue penetration. The PD-1 inhibitor (aPD-1) was initially loaded in the porous Gd-MOF (Gd/M) nanosystem. Then, the phase change material (PCM) and the cancer cell membrane were further sequentially modified on the surface of Gd/MP to obtain Gd-MOF@aPD-1@CM (Gd/MPC). When entering the tumor microenvironment (TME), Gd/MPC induces immunogenic death of tumor cells through microwave thermal responsiveness, improves tumor suppressive immune microenvironment and further enhances anti-tumor ability of T cells by releasing aPD-1. Meanwhile, Gd/MPC can be used for contrast-enhanced MRI. Transcriptomics data revealed that the downregulation of MSK2 in cancer cells leads to the downregulation of c-fos and c-jun, and ultimately leads to the apoptosis of cancer cells after treatment. In general, Gd/MPC nanosystem not only solves the problem of system side effect, but also achieves the controlled drug release via PCM, providing a promising theranostic nanoplatform for development of cancer combination immunotherapy.