Accumulation Of Nanoparticles In Tumors Research Articles

Reshaping Immunosuppressive Tumor Microenvironment Using Ferroptosis/Cuproptosis Nanosensitizers for Enhanced Radioimmunotherapy

AbstractRadiotherapy, a traditional cancer treatment, not only controls local tumor growth but also potentially induces immunogenic cell death, initiating systemic immune responses. However, radiotherapy resistance and immunosuppressive tumor microenvironments often limit the potency of radiation‐induced anti‐tumor immune responses, rendering them insufficient for clinical applications. Consequently, trimetallic nanoparticles are constructed with dual enzymatic activity, AuBiCu‐distearoyl phosphoethanolamine‐PEG nanoparticles (AuBiCu‐PEG NPs), to synergistically improve radiotherapy resistance through X‐ray deposition, hypoxia alleviation, and ferroptosis and cuproptosis induction. This approach promotes radiotherapy‐induced immunogenic cell death and boosts anti‐tumor immune responses. Furthermore, AuBiCu‐PEG NPs effectively reversed radiation‐induced upregulation of programmed cell death 1 ligand 1 (PD‐L1), inhibit tumor immune evasion, and reshaped the immune microenvironment. Non‐invasive and real‐time longitudinal monitoring of nanoparticle accumulation in tumors can be achieved using spectral computed tomography (CT) and photoacoustic (PA) imaging. In summary, the designed AuBiCu‐PEG NPs serve as promising nanoplatforms for immune microenvironment remodeling and can be used in multimodal molecular imaging‐guided ferroptosis‐cuproptosis‐enhanced radiotherapy.

The influence of various polymer coatings on the in vitro and in vivo properties of PLGA nanoparticles: Comprehensive study

Nanoparticles based on poly(lactic-co-glycolic acid) (PLGA) with various surface chemistry are widely used in biomedicine for theranostic applications. The nature of the external coating of nanoparticles has a significant influence on their efficiency as drug carriers or visualization agents. However, information about the mechanisms of nanoparticle accumulation in tumors and the influence of their surface properties on biodistribution is scarce due to the lack of systematic evaluation. Here we investigate the effect of different polymer coatings of the surface on in vitro and in vivo properties of PLGA nanoparticles. Namely, cell binding efficiency, cytotoxicity, efficiency of fluorescent bioimaging, and tumor accumulation were tested. The highest binding efficiency in vitro and cytotoxicity were observed for positively charged polymers. Interestingly, in vivo fluorescent visualization of tumor-bearing mice and quantitative measurements of biodistribution of magnetite-loaded nanoparticles indicated different dependences of accumulation in tumors on the coating of PLGA nanoparticles. This means that nanoparticle surface properties can simultaneously enhance imaging efficiency and decrease quantitative accumulation in tumors. The obtained data demonstrate the complexity of the dependence of nanoparticles’ effectiveness for theranostic applications on surface features. We believe that this study will contribute to the rational design of nanoparticles for effective cancer diagnostics and therapy.

Using imaging modalities to predict nanoparticle distribution and treatment efficacy in solid tumors: The growing role of ultrasound.

Nanomedicine in oncology has not had the success in clinical impact that was anticipated in the early stages of the field's development. Ideally, nanomedicines selectively accumulate in tumor tissue and reduce systemic side effects compared to traditional chemotherapeutics. However, this has been more successful in preclinical animal models than in humans. The causes of this failure to translate may be related to the intra- and inter-patient heterogeneity of the tumor microenvironment. Predicting whether a patient will respond positively to treatment prior to its initiation, through evaluation of characteristics like nanoparticle extravasation and retention potential in the tumor, may be a way to improve nanomedicine success rate. While there are many potential strategies to accomplish this, prediction and patient stratification via noninvasive medical imaging may be the most efficient and specific strategy. There have been some preclinical and clinical advances in this area using MRI, CT, PET, and other modalities. An alternative approach that has not been studied as extensively is biomedical ultrasound, including techniques such as multiparametric contrast-enhanced ultrasound (mpCEUS), doppler, elastography, and super-resolution processing. Ultrasound is safe, inexpensive, noninvasive, and capable of imaging the entire tumor with high temporal and spatial resolution. In this work, we summarize the in vivo imaging tools that have been used to predict nanoparticle distribution and treatment efficacy in oncology. We emphasize ultrasound imaging and the recent developments in the field concerning CEUS. The successful implementation of an imaging strategy for prediction of nanoparticle accumulation in tumors could lead to increased clinical translation of nanomedicines, and subsequently, improved patient outcomes. This article is categorized under: Diagnostic Tools In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery Emerging Technologies.

Synergistic reinforcement of immunogenic cell death and transformation of tumor-associated macrophages via an M1-type macrophage membrane-camouflaged ferrous-supply-regeneration nanoplatform

The immune system's role in tumor growth and spread has led to the importance of activating immune function in tumor therapy. We present a strategy using an M1-type macrophage membrane-camouflaged ferrous-supply-regeneration nanoplatform (M1mDDTF) to synergistically reinforce immunogenic cell death (ICD) and transform tumor-associated macrophages (TAMs) against tumors. The M1mDDTF nanoparticles consist of doxorubicin-loaded dendritic mesoporous silica nanoparticles chelated with FeIII-tannic acid (FeIIITA) and coated with M1-type macrophage membranes. In the acidic tumor microenvironment, FeIIITA releases Fe2+ and generates ·OH, aided by near infrared irradiation for enhanced doxorubicin release. Furthermore, the M1mDDTF nanoplatform not only directly kills tumor cells but stimulates ICD, which can increase the proportion of CD86+ CD80+ cells and promote dendritic cell maturation. Particularly, the M1mDDTF nanoplatform can also promote the gradual polarization of TAMs into the M1-type and promote tumor cell killing. This study demonstrates the safety and multifunctionality of M1mDDTF nanoparticles, highlighting their potential for clinical tumor treatment. Statement of significanceMalignant tumors are a global concern and a major cause of death. Nanoparticles' passive targeting is ineffective and hindered by reticuloendothelial system clearance. Therefore, enhancing nanoparticle accumulation in tumors while minimizing toxicity is a challenge. Coating nanoparticles with cell membranes enhances biocompatibility, immune evasion, and specific targeting. This approach has led to the development of numerous cell membrane-mimicking nanomaterials with remarkable properties and functions. This study developed an M1-type macrophage membrane-camouflaged ferrous-supply-regeneration nanoplatform, boosting immunogenic cell death and transforming tumor-associated macrophages. Tannic acid in the tumor microenvironment reduced Fe3+ to Fe2+, generating ·OH. M1mDDTF nanosystem induced M1-type macrophage polarization, inhibiting tumor growth and triggering immune cell death. Safe and versatile, these M1mDDTF nanoparticles hold promise for clinical tumor treatment.

Dual-Targeting Biomimetic Semiconducting Polymer Nanocomposites for Amplified Theranostics of Bone Metastasis.

Bone metastasis is a type of metastatic tumors that involves the spreads of malignant tumor cells into skeleton, and its diagnosis and treatment remain a big challenge due to the unique tumor microenvironment. We herein develop osteoclast and tumor cell dual-targeting biomimetic semiconducting polymer nanocomposites (SPFeNOC ) for amplified theranostics of bone metastasis. SPFeNOC contain semiconducting polymer and iron oxide (Fe3 O4 ) nanoparticles inside core and surface camouflaged hybrid membrane of cancer cells and osteoclasts. The hybrid membrane camouflage enables their targeting to both metastatic tumor cells and osteoclasts in bone metastasis through homologous targeting mechanism, thus achieving an enhanced nanoparticle accumulation in tumors. The semiconducting polymer mediates near-infrared (NIR) fluorescence imaging and sonodynamic therapy (SDT), and Fe3 O4 nanoparticles are used for magnetic resonance (MR) imaging and chemodynamic therapy (CDT). Because both cancer cells and osteoclasts are killed synchronously via the combinational action of SDT and CDT, the vicious cycle in bone metastasis is broken to realize high antitumor efficacy. Therefore, 4T1 breast cancer-based bone metastasis can be effectively detected and cured by using SPFeNOC as dual-targeting theranostic nanoagents. This study provides an unusual biomimetic nanoplatform that simultaneously targets osteoclasts and cancer cells for amplified theranostics of bone metastasis.

Dual‐Targeting Biomimetic Semiconducting Polymer Nanocomposites for Amplified Theranostics of Bone Metastasis

AbstractBone metastasis is a type of metastatic tumors that involves the spreads of malignant tumor cells into skeleton, and its diagnosis and treatment remain a big challenge due to the unique tumor microenvironment. We herein develop osteoclast and tumor cell dual‐targeting biomimetic semiconducting polymer nanocomposites (SPFeNOC) for amplified theranostics of bone metastasis. SPFeNOC contain semiconducting polymer and iron oxide (Fe3O4) nanoparticles inside core and surface camouflaged hybrid membrane of cancer cells and osteoclasts. The hybrid membrane camouflage enables their targeting to both metastatic tumor cells and osteoclasts in bone metastasis through homologous targeting mechanism, thus achieving an enhanced nanoparticle accumulation in tumors. The semiconducting polymer mediates near‐infrared (NIR) fluorescence imaging and sonodynamic therapy (SDT), and Fe3O4 nanoparticles are used for magnetic resonance (MR) imaging and chemodynamic therapy (CDT). Because both cancer cells and osteoclasts are killed synchronously via the combinational action of SDT and CDT, the vicious cycle in bone metastasis is broken to realize high antitumor efficacy. Therefore, 4T1 breast cancer‐based bone metastasis can be effectively detected and cured by using SPFeNOC as dual‐targeting theranostic nanoagents. This study provides an unusual biomimetic nanoplatform that simultaneously targets osteoclasts and cancer cells for amplified theranostics of bone metastasis.

Calcium carbonate nanoparticles tumor delivery for combined chemo-photodynamic therapy: Comparison of local and systemic administration.

The use of nanoparticles (NPs) as delivery vehicles for multiple drugs is an intensively developing area. However, the success of NPs' accumulation in the tumor area for efficient tumor treatment has been recently questioned. Distribution of NPs in a laboratory animal is mainly related to the administration route of NPs and their physicochemical parameters, which significantly affect the delivery efficiency. In this work, we aim to compare the therapeutic efficiency and side effects of the delivery of multiple therapeutic agents with NPs by both intravenous and intratumoral injections. For this, we systematically developed universal nanosized carriers based on calcium carbonate (CaCO3) NPs (< 100nm) that were co-loaded with a photosensitizer (Chlorin e6, Ce6) and chemotherapeutic agent (doxorubicin, Dox) for combined chemo- and photodynamic therapy (PDT) of B16-F10 melanoma tumors. By performing intratumoral or intravenous injections of NPs, we observed different biodistribution profiles and tumor accumulation efficiencies. In particular, after intratumoral administration of NPs, they mostly remained in the tumors (> 97%); while for intravenous injection, the tumor accumulation of NPs was determined to be 8.67-12.4 ID/g%. Although the delivery efficiency of NPs (presented in ID/g%) in the tumor differs, we have developed an effective strategy for tumor inhibition based on combined chemo- and PDT by both intratumoral and intravenous injections of NPs. Notably, after the combined chemo- and PDT treatment with Ce6/Dox@CaCO3 NPs, all B16-F10 melanoma tumors in mice shrank substantially, by approximately 94% for intratumoral injection and 71% for intravenous injection, which are higher values compared to mono-therapy. In addition, the CaCO3 NPs showed negligible in vivo toxicity towards major organs such as the heart, lungs, liver, kidneys, and spleen. Thus, this work demonstrates a successful approach for the enhancement of NPs' efficiency in combined anti-tumor therapy.

Delivery of Theranostic Nanoparticles to Various Cancers by Means of Integrin-Binding Peptides.

Active targeting of tumors is believed to be the key to efficient cancer therapy and accurate, early-stage diagnostics. Active targeting implies minimized off-targeting and associated cytotoxicity towards healthy tissue. One way to acquire active targeting is to employ conjugates of therapeutic agents with ligands known to bind receptors overexpressed onto cancer cells. The integrin receptor family has been studied as a target for cancer treatment for almost fifty years. However, systematic knowledge on their effects on cancer cells, is yet lacking, especially when utilized as an active targeting ligand for particulate formulations. Decoration with various integrin-targeting peptides has been reported to increase nanoparticle accumulation in tumors ≥ 3-fold when compared to passively targeted delivery. In recent years, many newly discovered or rationally designed integrin-binding peptides with excellent specificity towards a single integrin receptor have emerged. Here, we show a comprehensive analysis of previously unreviewed integrin-binding peptides, provide diverse modification routes for nanoparticle conjugation, and showcase the most notable examples of their use for tumor and metastases visualization and eradication to date, as well as possibilities for combined cancer therapies for a synergetic effect. This review aims to highlight the latest advancements in integrin-binding peptide development and is directed to aid transition to the development of novel nanoparticle-based theranostic agents for cancer therapy.

A pH-Responsive Cluster Metal-Organic Framework Nanoparticle for Enhanced Tumor Accumulation and Antitumor Effect.

As a result of the deficient tumor-specific antigens, potential off-target effect, and influence of protein corona, metal-organic framework nanoparticles have inadequate accumulation in tumor tissues, limiting their therapeutic effects. In this work, a pH-responsive linker (L) is prepared by covalently modifying oleylamine (OA) with 3-(bromomethyl)-4-methyl-2,5-furandione (MMfu) and poly(ethylene glycol) (PEG). Then, the L is embedded into a solid lipid nanoshell to coat apilimod (Ap)-loaded zeolitic imidazolate framework (Ap-ZIF) to form Ap-ZIF@SLN#L. Under the tumor microenvironment, the hydrophilic PEG and MMfu are removed, exposing the hydrophobic OA on Ap-ZIF@SLN#L, increasing their uptake in cancer cells and accumulation in the tumor. The ZIF@SLN#L nanoparticle induces reactive oxygen species (ROS). Ap released from Ap-ZIF@SLN#L significantly promotes intracellular ROS and lactate dehydrogenase generation. Ap-ZIF@SLN#L inhibits tumor growth, increases the survival rate in mice, activates the tumor microenvironment, and improves the infiltration of macrophages and T cells in the tumor, as demonstrated in two different tumor-bearing mice after injections with Ap-ZIF@SLN#TL. Furthermore, mice show normal tissue structureof the main organs and the normal serum level in alanine aminotransferase and aspartate aminotransferase after treatment with the nanoparticles. Overall, this pH-responsive targeting strategy improves nanoparticle accumulation in tumors with enhanced therapeutic effects.

Tumor-Associated Enzyme-Activatable Spherical Nucleic Acids.

Maximizing the tissue-targeting efficiency of nanomaterials while also protecting them from rapid clearance from the bloodstream and limiting their immunogenicity remains a central problem in the field of systemic-administered nanomedicine. Herein, we introduce a generalizable strategy to simultaneously increase tumor accumulation, prolong blood circulation, and limit nonspecific immune activation of nanomaterials via peptide-based, tumor-responsive, "sheddable" coatings. Spherical nucleic acids (SNAs) were designed and synthesized to contain an exterior coating composed of zwitterionic polypeptides with recognition sequences for tumor-associated proteases. In the presence of matrix metalloproteinases (MMPs), the polypetide coating is rapidly cleaved, leading to increased cellular uptake of these SNAs, relative to SNAs containing nonsheddable shells. Moreover, the zwitterionic nature of the polypeptide shell shields the SNAs from immune system recognition, which extends their blood circulation time and improves tumor accumulation and in vivo cellular uptake relative to control SNAs with no protective coating. Taken together, these results indicate that this strategy is a viable method for increasing nanoparticle tumor accumulation and can have utility for the systemic delivery of oligonucleotides and nanomaterials to target cells in vivo with low immunogenicity.

PET-CT Imaging of Polymeric Nanoparticle Tumor Accumulation in Patients.

Several FDA/EMA-approved nanomedicines have demonstrated improved pharmacokinetics and toxicity profiles compared to their conventional chemotherapeutic counterparts. The next step to increase therapeutic efficacy depends on tumor accumulation, which can be highly heterogeneous. A clinical tool for patient stratification is urgently awaited. Therefore, a docetaxel-entrapping polymeric nanoparticle (89 Zr-CPC634) is radiolabeled, and positron emission tomography/computed tomography (PET/CT) imaging is performed in seven patients with solid tumors with two different doses of CPC634: an on-treatment (containing 60 mg m-2 docetaxel) and a diagnostic (1-2 mg docetaxel) dose (NCT03712423). Pharmacokinetic half-life for 89 Zr-CPC634 is mean 97.0 ± 14.4 h on-treatment, and 62.4 ± 12.9 h for the diagnostic dose (p= 0.003). At these doses accumulation is observed in 46% and 41% of tumor lesions with a median accumulation in positive lesions 96 h post-injection of 4.94 and 4.45%IA kg-1 (p= 0.91), respectively. In conclusion, PET/CT imaging with a diagnostic dose of 89 Zr-CPC634 accurately reflects on-treatment tumor accumulation and thus opens the possibility for patient stratification in cancer nanomedicine with polymeric nanoparticles.

NIR-II Fluorescent Activatable Drug Delivery Nanoplatform for Cancer-Targeted Combined Photodynamic and Chemotherapy.

Nanotheranostics with integrated imaging functions can help monitor nanoparticle accumulation in tumors, thus achieving synergism and higher therapeutic accuracy in cancer therapy. However, it remains challenging to monitor the release of therapeutic drugs in real time from a nanoparticulate drug delivery system (nano-DDS) in the body. Herein, we developed a nano-DDS for fluorescence imaging in the second near-infrared window (NIR-II) region, which can be used for monitoring the responsive release of drugs and cancer-targeted combined photodynamic and chemotherapy. There is a linear correlation between the cumulative release of the drug and the NIR-II fluorescence intensity. Moreover, hyaluronidase/glutathione dual-response RGD-SS-DOX/Ce6@HA-IR-1061 (RSSDCHI) exhibited a higher tumor-to-normal-tissue ratio in NIR-II fluorescence imaging and enhanced antitumor efficacy in vivo. This makes it possible to visualize drug release at the cellular level by the nanocomposites and to predict the treatment effect according to the NIR-II fluorescence intensity in the tumor site, serving as a promising nanoplatform for precision nanomedicine.

Biomimetic nanoparticles directly remodel immunosuppressive microenvironment for boosting glioblastoma immunotherapy

Glioblastoma (GBM), as a very aggressive cancer of central nervous system, is very challenging to completely cure by the conventional combination of surgical resection with radiotherapy and chemotherapy. The success of emerging immunotherapy in hot tumors has attracted considerable interest for the treatment of GBM, but the unique tumor immunosuppressive microenvironment (TIME) of GBM leads to the failure of immunotherapy. Here, we show the significant improvement of the immunotherapy efficacy of GBM by modulating the TIME through novel all-in-one biomimetic nanoparticles (i.e. CS-I/J@CM NPs). The nanoparticles consist of utrasmall Cu2-xSe nanoparticles (NPs) with outstanding intrinsic properties (e.g., photo-responsive Fenton-like catalytic property for inducing immunogenic cell death (ICD) and alleviating the hypoxia of tumor), indoximod (IND, an inhibitor of indoleamine-2,3-dioxygenease in tumor), JQ1 (an inhibitor for reducing the expression of PD-L1 by tumor cells), and tumor cell membrane for improving the targeting capability and accumulation of nanoparticles in tumor. We reveal that these smart CS-I/J@CM NPs could drastically activate the immune responses through remodeling TIME of GBM by multiple functions. They could (1) increase M1-phenotype macrophages at tumor site by promoting the polarization of tumor-associated macrophages through the reactive oxygen species (ROS) and oxygen generated from the Fenton-like reaction between nanoparticles and H2O2 within tumor under NIR II irradiation; (2) decrease the infiltration of Tregs cells at tumor site through the release of IND; (3) decrease the expression of PD-L1 on tumor cells through JQ1. The notable increments of anti-tumor CD8+T cells in the tumor and memory T cells (TEM) in the spleen show excellent therapy efficacy and effectively prevent the recurrence of GBM after modulation of the TIME. This work demonstrates the modulation of TIME could be a significant strategy to improve the immunotherapy of GBM and other cold tumors.

Systematic Review of Cancer Targeting by Nanoparticles Revealed a Global Association between Accumulation in Tumors and Spleen.

Active targeting of nanoparticles toward tumors is one of the most rapidly developing topics in nanomedicine. Typically, this strategy involves the addition of cancer-targeting biomolecules to nanoparticles, and studies on this topic have mainly focused on the localization of such formulations in tumors. Here, the analysis of the factors determining efficient nanoparticle targeting and therapy, various parameters such as types of targeting molecules, nanoparticle type, size, zeta potential, dose, and the circulation time are given. In addition, the important aspects such as how active targeting of nanoparticles alters biodistribution and how non-specific organ uptake influences tumor accumulation of the targeted nanoformulations are discussed. The analysis reveals that an increase in tumor accumulation of targeted nanoparticles is accompanied by a decrease in their uptake by the spleen. There is no association between targeting-induced changes of nanoparticle concentrations in tumors and other organs. The correlation between uptake in tumors and depletion in the spleen is significant for mice with intact immune systems in contrast to nude mice. Noticeably, modulation of splenic and tumor accumulation depends on the targeting molecules and nanoparticle type. The median survival increases with the targeting-induced nanoparticle accumulation in tumors; moreover, combinatorial targeting of nanoparticle drugs demonstrates higher treatment efficiencies. Results of the comprehensive analysis show optimal strategies to enhance the efficiency of actively targeted nanoparticle-based medicines.

Noninvasive and Highly Multiplexed Five-Color Tumor Imaging of Multicore Near-Infrared Resonant Surface-Enhanced Raman Nanoparticles In Vivo

In vivo multiplexed imaging aims for noninvasive monitoring of tumors with multiple channels without excision of the tissue. While most of the preclinical imaging has provided a number of multiplexing channels up to three, Raman imaging with surface-enhanced Raman scattering (SERS) nanoparticles was suggested to offer higher multiplexing capability originating from their narrow spectral width. However, in vivo multiplexed SERS imaging is still in its infancy for multichannel visualization of tumors, which require both sufficient multiplicity and high sensitivity concurrently. Here we create multispectral palettes of gold multicore-near-infrared (NIR) resonant Raman dyes-silica shell SERS (NIR-SERRS) nanoparticle oligomers and demonstrate noninvasive and five-plex SERS imaging of the nanoparticle accumulation in tumors of living mice. We perform the five-plex ratiometric imaging of tumors by varying the administered ratio of the nanoparticles, which simulates the detection of multiple biomarkers with different expression levels in the tumor environment. Furthermore, since this method does not require the excision of tumor tissues at the imaging condition, we perform noninvasive and longitudinal imaging of the five-color nanoparticles in the tumors, which is not feasible with current ex vivo multiplexed tissue analysis platforms. Our work surpasses the multiplicity limit of previous preclinical tumor imaging methods while keeping enough sensitivity for tumor-targeted in vivo imaging and could enable the noninvasive assessment of multiple biological targets within the tumor microenvironment in living subjects.

Enzyme-induced morphological transformation of drug carriers: Implications for cytotoxicity and the retention time of antitumor agents

Nanocarriers have been widely employed to deliver chemotherapeutic drugs for cancer treatment. However, the insufficient accumulation of nanoparticles in tumors is an important reason for the poor efficacy of nanodrugs. In this study, a novel drug delivery system with a self-assembled amphiphilic peptide was designed to respond specifically to alkaline phosphatase (ALP), a protease overexpressed in cancer cells. The amphiphilic peptide self-assembled into spherical and fibrous nanostructures, and it easily assembled into spherical drug-loaded peptide nanoparticles after loading of a hydrophobic chemotherapeutic drug. The cytotoxicity of the drug carriers was enhanced against tumor cells over time. These spherical nanoparticles transformed into nanofibers under the induction of ALP, leading to efficient release of the encapsulated drug. This drug delivery strategy relying on responsiveness to an enzyme present in the tumor microenvironment can enhance local drug accumulation at the tumor site. The results of live animal imaging showed that the residence time of the morphologically transformable drug-loaded peptide nanoparticles at the tumor site was prolonged in vivo, confirming their potential use in antitumor therapy. These findings can contribute to a better understanding of the influence of drug carrier morphology on intracellular retention.

Construction of a pH/TGase "Dual Key"-Responsive Gold Nano-radiosensitizer with Liver Tumor-Targeting Ability.

The method of tumor microenvironment (TME)-responsive aggregation has become a promising approach to enhance treatment effect by improving the accumulation of nanoparticles in tumors. The enzymatic cross-linking strategy has widely attracted attention owing to its good aggregation stability and biocompatibility. However, the enzymes in nontumor tissue can also catalyze the cross-linking reaction and reduce accumulation of nanoparticles in tumor. In this work, a "dual key"-responsive strategy is utilized to construct a transglutaminase (TGase)/pH-responsive radiosensitizer (Au@TAcoGal) with specific aggregation behavior in hepatic tumor cells. Au@TAcoGal can retain its stability in blood circulation (pH 7.4) even in the presence of TGase in plasma. On reaching tumor sites, it can be endocytosed by hepatoma cells by the active targeting of phenylboronic acid (PBA) and aggregated under acidity and overexpression of TGase in cells. Due to its specific accumulation in hepatoma cells, radiotherapy can be operated under a lower dose of X-ray. The results show that the cellular accumulation of Au@TAcoGal increases by 30-70%, and the cell survival rate is less than 25% under X-ray irradiation. The antineoplastic results show that Au@TAcoGal exhibits a higher therapeutic effect, and the tumor inhibition rate can reach 84.21%.

Low-dose X-ray enhanced tumor accumulation of theranostic nanoparticles for high-performance bimodal imaging-guided photothermal therapy

BackgroundTheranostic nanoparticles (NPs) have achieved rapid development owing to their capacity for personalized multimodal diagnostic imaging and antitumor therapy. However, the efficient delivery and bulk accumulation of NPs in tumors are still the decisive factors in improving therapeutic effect. It is urgent to seek other methods to alters tumor microenvironment (like vascular permeability and density) for enhancing the efficiency of nanoparticles delivery and accumulation at the tumor site.MethodsHerein, we developed a Raman-tagged hollow gold nanoparticle (termed as HAuNP@DTTC) with surface-enhanced Raman scattering (SERS) property, which could be accumulated efficiently in tumor site with the pre-irradiation of low-dose (3 Gy) X-ray and then exerted highly antitumor effect in breast cancer model.ResultsThe tumor growth inhibition (TGI) of HAuNP@DTTC-induced photothermal therapy (PTT) was increased from 60% for PTT only to 97%, and the lethal distant metastasis of 4T1 breast cancer (such as lung and liver) were effectively inhibited under the X-ray-assisted PTT treatment. Moreover, with the strong absorbance induced by localized surface plasmon resonance in near-infrared (NIR) region, the signals of Raman/photoacoustic (PA) imaging in tumor was also significantly enhanced after the administration of HAuNP@DTTC, indicating it could be used as the Raman/PA imaging and photothermal agent simultaneously under 808 nm laser irradiation.ConclusionsOur studied of the as-prepared HAuNP@DTTC integrated the Raman/PA imaging and PTT functions into the single platform, and showed the good prospects for clinical applications especially with the low-dose X-ray irradiation as an adjuvant, which will be a productive strategy for enhancing drug delivery and accumulation in tumor theranostics.Graphic

Theoretical evaluation of enhanced gold nanoparticle delivery to PC3 tumors due to increased hydraulic conductivity or recovered lymphatic function after mild whole body hyperthermia.

The objective of this study is to investigate the effect of hyperthermia-induced improvement of hydraulic conductivity and lymphatic function on both tumoral IFP reduction and nanoparticle delivery to PC3 tumors. We developed a theoretical model for nanoparticle transport in a tumor incorporating Starling's law, Darcy's law, transient convection, and diffusion of chemical species in porous media, and nanoparticle accumulation in tumors. Results have shown that both mechanisms were effective to decrease the IFP at the tumor center from 1600 Pa in the control without heating to 800 Pa in tumors with whole body heating. IFP reductions not only elevate the nanoparticle concentration in the tumor, but also result in a more uniform nanoparticle concentration in the tumor than that in the control without heating. Due to the IFP reductions at the tumor center and/or local blood perfusion increases, the final amount of accumulated nanoparticles in the tumor increased by more than 35-95% when compared to the control without heating. We conclude that increases in the hydraulic conductivity and recovery of lymphatic functions are possible mechanisms that lead to IFP reductions and enhancement in nanoparticle deposition in PC3 tumors observed in our in vivo experimental studies.

Use of macrophage as a Trojan horse for cancer nanotheranostics

Nano-based cancer theranostics are often not as effective as expected due to the low accumulation of nanoparticles in tumors, and cell-aided strategies may represent a rescue to improve the efficacy of nanomedicines. Among the strategies, macrophages appear to be an outstanding candidate due to their wide-spread tissue presence and natural ability to take up nanoparticles carrying cargoes, and also the remarkable capability to modulate tumor microenvironment for enhanced therapeutic efficacy and anti-tumor immunotherapy. However, there are limitations, inconsistencies, and knowledge gaps in the current stage in developing macrophage-mediated nanotherapeutics to realize its fullest potential. Thus, it demands more efforts on understanding the interplays between macrophage and nanomedicine as well as nanomedicines and tumor cells in modulating anti-cancer immunity in the tumor microenvironment. Here, we recapitulate the current progress and knowledge gaps in the macrophage-mediated nano-drug delivery system, and we also shed light on future research directions towards clinical translation.