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Abstract Polyrotaxane (PRX) is a promising supramolecular carrier for gene delivery. Classic PRX exhibits a linear structure in which the amine-functionalized α-cyclodextrin (CD) is threaded along the entire polyethylene glycol (PEG) backbone. While promising in vitro , the absence of free PEG moieties after CD threading compromised the in vivo implementation, due to the unfavorable pharmacokinetics (PK) and biodistribution profile. Herein, we developed a multi-arm PRX nanocarrier platform, which has been designed for protective nucleic acid encapsulation, augmented biodistribution and PK, and suitable for intravenous (IV) administration. A key design was to introduce cationic CD rings onto a multi-arm PEG backbone in a spatially selective fashion. The optimal structural design was obtained through iterative rounds of experimentation to determine the appropriate type and density of cationic charge on CD ring, the degree of PEGylation, the size and structure of polymer backbone, etc. This allowed us to effectively deliver large size reporter and therapeutic plasmids in cancer mouse models. Post IV injection, we demonstrated that our multi-arm polymer design significantly enhanced circulatory half-life and PK profile compared to the linear PRX. We continued to use the multi-arm PRX to formulate a therapeutic plasmid encoding an immunomodulatory cytokine, IL-12. When tested in a colon cancer syngeneic mouse model with same background, the IL-12 plasmid was protected by the multi-arm PRX and delivered through the tail vein to the tumor site, leading to a significant tumor inhibition effect. Moreover, our delivery system was devoid of major systemic toxicity. [ABSTRACT FROM AUTHOR]

Abstract Mild acidity matrix, rich blood vessels and special biomarkers constitute the primary tumor microenvironment. Nanoparticles could change their physicochemical characteristics by functionalizing a series of moieties which is responsive towards pH or specific markers. So precise regulation of nanocarrier-based drug delivery systems by the tumor microenvironment has showed great potential for theranostics. Herein, we developed a smart nano delivery system STD-NM, showing tumor microenvironment responsive targeting, efficient drug delivery and precise evaluation of therapeutic effect in vivo. STD-NM kept in 'stealth' state in normal environment while 'activated' in the tumor acidic environment, which could show stability in blood circulation while deeply penetrate into tumor tissues. Additionally, STD-NM was designed with aggregation-induced emission (AIE) characteristic, of which the fluorescence 'switch on' when apoptosis taken place. Gene analysis by RNA-seq also confirmed a superior therapeutic effect of drug loaded STD-NM treatment. We envisioned the well-designed smart nano materials for drug delivery could open a new avenue in precisely tumor imaging and specific cancer therapeutics. [ABSTRACT FROM AUTHOR]

Abstract The intrinsic characteristics of the tumor microenvironment (TME), including acidic pH and overexpression of hydrolytic enzymes, offer an exciting opportunity for the rational design of TME-drug delivery systems (DDS). We developed and characterized a pH-responsive biodegradable poly-L-glutamic acid (PGA)-based combination conjugate family with the aim of optimizing anticancer effects. We obtained combination conjugates bearing Doxorubicin (Dox) and aminoglutethimide (AGM) with two Dox loadings and two different hydrazone pH-sensitive linkers that promote the specific release of Dox from the polymeric backbone within the TME. Low Dox loading coupled with a short hydrazone linker yielded optimal effects on primary tumor growth, lung metastasis (∼90% reduction), and toxicological profile in a preclinical metastatic triple-negative breast cancer (TNBC) murine model. The use of transcriptomic analysis helped us to identify the molecular mechanisms responsible for such results including a differential immunomodulation and cell death pathways among the conjugates. This data highlights the advantages of targeting the TME, the therapeutic value of polymer-based combination approaches, and the utility of –omics-based analysis to accelerate anticancer DDS. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Beyond mesoporous silica nanoparticles (MSNs), mesoporous organosilica nanoparticles (MONs) have been becoming an even more attractive alternative to the traditional organic or inorganic nanomaterials in biomedical applications, especially for drug delivery, due to its high surface area, stable physicochemical properties, low toxicity, high biocompatibility, and particularly the devisable features decided by the incorporated organic fragments. However, it is still challenging to fabricate uniform ultrasmall MONs with tunable composition, morphology and fine biodegradability. Herein, we report, on the large-scale fabrication of monodispersed and molecularly organic-inorganic hybrid MONs with framework-incorporated physiologically active thioether bonds, controllable nanostructure, composition and morphology, which provides the material foundation for exploring the versatile biomedical applications of organosilica nanosystems. The hybrid MONs of less than 50 nm in particle size exhibit the unique reduction-responsive biodegradation behavior, and the biodegradation rate is significantly higher than that of traditional mesoporous silica nanoparticles with pure inorganic Si O Si framework. The reductive microenvironment-triggered biodegradation of MONs induces the concurrent reduction-responsive anticancer drug releasing from MONs, enabling tumor-specific drug delivery. Importantly, these biocompatible and biodegradable MONs exhibit significantly improved drug-delivery efficiency and enhanced tumor-suppressing effect for combating cancer. Based on the facile and large-scale fabrication of MONs with controllable key structure/composition/morphology parameters, unique tumor microenvironment-responsive biodegradation behavior and high performance for drug delivery, the MONs therefore show more promising potentials for clinical translation as compared to traditional MSNs. [ABSTRACT FROM AUTHOR]

Despite rapid advancements in the field of nanotechnology, there is mounting frustration in the scientific community regarding the translational impact of nanomedicine. Modest therapeutic performance of FDA-approved nanomedicines combined with multiple disappointing clinical trials (such as phase III HEAT trial) have raised questions about the future of nanomedicine. Encouraging breakthroughs, however, have been made in the last few years towards the development of new classes of nanoparticles that can respond to tumor microenvironmental conditions and successfully deliver therapeutic agents to cancer cells. Concurrently, a great deal of effort has also been devoted to alter various parameters of tumor pathophysiology to pre-treat tumors before nanoparticles are administered. Such ‘priming’ treatments improve access of the systemically administered agents to the tumor and promote drug penetration into the deeper layers of tumor tissue. This review will highlight recent advances in cancer nanomedicine exploiting both nanoparticle design and tumor microenvironment modification; and provide a critical perspective on the future development of nanomedicine delivery in oncology. [ABSTRACT FROM AUTHOR]

Magnetic nanoparticles (MNPs) have been extensively studied for their potential applications to cancer diagnosis and treatment. However, various obstacles limit the use of nanoparticles for delivery in the tumor microenvironment. As a viable solution to such obstacles, advances in nanoparticle surface engineering augmented by a profound understanding of cancer physiology present new opportunities for MNP-based imaging and therapeutic agents. Stimuli-responsive ligands, rationally designed to interact with various physicochemical aspects, can improve the performance of MNPs in cancer-targeted imaging and therapy. In this review, we highlight recent progress in the design of MNP-based stimuli-responsive nanomaterials and their applications to cancer diagnosis and treatment. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME), comprising cancer cells and stroma, plays a significant role in determining clinical outcomes, which makes targeting cancer cells in the TME an important area of research. One way in which cancer cells in the TME can be specifically targeted is by coating drug-encapsulated nanoparticles (NPs) with homotypic cancer cell membranes. However, incomplete targeting is inevitable for biomimetic nanoformulations coated with only cancer cell membranes because of the inherent heterogeneity of the TME. After observing the structural connection between glioma-associated stromal cells (GASCs) and glioma cells from a clinic, we designed a novel drug delivery system that targets the TME by coating polylactic- co -glycolic acid (PLGA) NPs with GASC-glioma cell fusion cell (SG cell) membranes. The resulting SGNPs inherited membrane proteins from both the glioma membrane and GASC membrane, significantly enhancing the tumor targeting efficiency compared to nanoformulations coated with cancer cell membranes alone. We further demonstrated that encapsulation of temozolomide (TMZ) improved the therapeutic efficacy of TMZ in both heterotopic and orthotopic glioma mouse models. Owing to its significant efficacy, our TME-targeting nanoplatform has potential for clinical applications in the treatment of various cancers. [ABSTRACT FROM AUTHOR]

Magnetic hyperthermia as a treatment modality is acquiring increased recognition for loco-regional therapy of primary and metastatic lung malignancies by pulmonary delivery of magnetic nanoparticles (MNP) . The unique characteristic of magnetic nanoparticles to induce localized hyperthermia in the presence of an alternating magnetic field (AMF) allows for preferential killing of cells at the tumor site. In this study we demonstrate the effect of hyperthermia induced by low and high dose of MNP under the influence of an AMF using 3D tumor tissue analogs (TTA) representing the micrometastatic, perfusion independent stage of triple negative breast cancer (TNBC) that infiltrates the lungs. While application of inhalable magnetic nanocomposite microparticles or magnetic nanocomposites (MnMs) to the micrometastatic TNBC model comprised of TTA generated from cancer and stromal cells, showed no measureable adverse effects in the absence of AMF-exposure, magnetic hyperthermia generated under the influence of an AMF in TTA incubated in a high concentration of MNP (1 mg/mL) caused significant increase in cellular death/damage with mechanical disintegration and release of cell debris indicating the potential of these inhalable composites as a promising approach for thermal treatment of diseased lungs. The novelty and significance of this study lies in the development of methods to evaluate in vitro the application of inhalable composites containing MNPs in thermal therapy using a physiologically relevant metastatic TNBC model representative of the microenvironmental characteristics in secondary lung malignancies. [ABSTRACT FROM AUTHOR]

Hypoxia is a common feature within many types of solid tumors, which is closely associated with limited efficacy for tumor therapies. Moreover, the inability to reach hypoxic tumor cells that are distant from blood vessels results in tumor-targeting and penetrating drug delivery systems in urgent need. Here, glucose oxidase (GOX) and hypoxia-activated prodrug tirapazamine (TPZ) are loaded into photothermal conversion agent polydopamine (PDA) as the glucose/oxygen-exhausting nanoreactor named PGT. We further construct a tumor cell membrane-coated nanovesicle for the targeted delivery of PGT. This biomimetic nanovesicle exhibits significantly improved tumor-targeting and tumor-penetrating abilities. After internalization by the tumor cells, the loaded drug is quickly released in response to near-infrared (NIR) laser. The PGT nanoreactor can exhaust glucose and oxygen, and further enhance hypoxia within tumor, which efficiently inhibits hypoxic tumor by combining starvation therapy and hypoxia-activated chemotherapy. Mechanically, it is revealed that the nanoreactor significantly increases hypoxia level and downregulates the expression of hypoxia-inhibitory factor-1α (HIF-1α), thereby promoting T cell activation and macrophage polarization to remodel tumor immunosuppressive microenvironment. Therefore, this tumor microenvironment-regulable nanoreactor with sustainable and cascade targeted starvation-chemotherapy provides a novel insight into the treatment of hypoxic tumor. [ABSTRACT FROM AUTHOR]

To efficiently deliver anti-cancer drug to tumor site and reduce its toxic side effects on normal tissues, a polyethylene glycol (PEG) shielding and tumor microenvironment triggering cascade pH-responsive hollow mesoporous silica nanoparticles (HMSNs) drug delivery system was fabricated. 3-(3, 4-dihydroxyphenyl) propionic acid (DHPA) functionalized beta-cyclodextrin (β-CD) was grafted onto the surfaces of HMSNs via boronic acid-catechol ester bonds. Then, PEG conjugated adamantane (Ada) was anchored on HMSNs-β-CD nanocarrier via host-gust interaction. Various techniques proved the successful fabrication of the system. The in vitro tests confirmed that the system was biocompatible. After the system permeating into tumor via enhanced permeability and retention (EPR) effect, the benzoic-imine bonds between the PEG and Ada were cleaved under weak acid condition in tumor microenvironment (pH 6.8), while the dissociated PEG protective layer facilitating cellular uptake of HMSNs system. Subsequently, the boronic acid-catechol ester bonds linkers further hydrolyzed under even low endosomal pH (4.5–6.5) condition for intracellular drug delivery, leading to efficient cell apoptosis. The in vivo results demonstrated that drug loaded HMSNs significantly inhibited tumor growth while only with minimal toxic side effects. The strategy provides new insight into the development of new generation of drug delivery carriers triggering by tumor microenvironment. [ABSTRACT FROM AUTHOR]

Glioma is still hard to be treated due to their complex microenvironment. In this study, a gold nanoparticle-based delivery system was developed. The system, An-PEG-DOX-AuNPs, was loaded with doxorubicin (DOX) through hydrazone, an acid-responsive linker, and was functionalized with angiopep-2, a specific ligand of low density lipoprotein receptor-related protein-1 (LRP1), which could mediate the system to penetrate blood brain barrier and target to glioma cells. The particle size of An-PEG-DOX-AuNPs was 39.9 nm with a zeta potential of −19.3 mV, while the DOX loading capacity was 9.7%. In vitro, the release of DOX from DOX-AuNPs was pH-dependent. At lower pH values, especially 5.0 and 6.0, release of DOX was much quicker than that at pH 6.8 and 7.4. After coating with PEG, the acid-responsive release of DOX from PEG-DOX-AuNPs was almost the same as that from DOX-AuNPs. Cellular uptake study showed obviously higher intensity of intracellular An-PEG-DOX-AuNPs compared with PEG-DOX-AuNPs. In vivo, An-PEG-DOX-AuNPs could distribute into glioma at a higher intensity than that of PEG-DOX-AuNPs and free DOX. Correspondingly, glioma-bearing mice treated with An-PEG-DOX-AuNPs displayed the longest median survival time, which was 2.89-fold longer than that of saline. In conclusion, An-PEG-DOX-AuNPs could specifically deliver and release DOX in glioma and significantly expand the median survival time of glioma-bearing mice. [ABSTRACT FROM AUTHOR]

Abstract: A tumor targeting nanoparticle system has been successfully developed to response to the lowered tumor extracellular pH (pHe) and upregulated matrix metalloproteinase 2 (MMP2) in the tumor microenvironment. The nanoparticles are modified with activatable cell-penetrating peptide (designated as dtACPP) that's dual-triggered by the lowered pHe and MMP2. In dtACPP, the internalization function of cell-penetrating peptide (CPP) is quenched by a pH-sensitive masking peptide, linking by a MMP2 substrate. The masking peptide is negatively charged to quench the cationic CPP well after systemic administration. Hence, dtACPP-modified nanoparticles possesses passive tumor targetability via the enhanced permeability and retention (EPR) effect. Once reaching the tumor microenvironment, the pre-existing attraction would be eliminated due to the lowered pHe, accompanying the linker cleaved by MMP2, dtACPP would be activated to expose CPP to drive the nanoparticles' internalization into the intratumoral cells. The studies of plasmid DNA loading, toxicity assessment, cellular uptake, tumor targeting delivery, and gene transfection demonstrate that dtACPP-modified nanoparticle system is a potential candidate for tumor targeting gene delivery. [Copyright &y& Elsevier]

Precise targeting and high therapeutic efficiency are the major requisites of personalized cancer treatment. However, some unique features of the tumor microenvironment (TME) such as hypoxia, low pH and elevated interstitial fluid pressure cause cancer cells resistant to most therapies. Bacteria are increasingly being considered for targeted tumor therapy owing to their intrinsic tumor tropism, high motility as well as the ability to rapidly colonize in the favorable TME. Compared to other nano-strategies using peptides, aptamers, and other biomolecules, tumor-targeting bacteria are largely unaffected by the tumor cells and microenvironment. On the contrary, the hypoxic TME is highly conducive to the growth of facultative anaerobes and obligate anaerobes. Live bacteria can be further integrated with anti-cancer drugs and nanomaterials to increase the latter's targeted delivery and accumulation in the tumors. Furthermore, anaerobic and facultatively anaerobic bacteria have also been combined with other anti-cancer therapies to enhance therapeutic effects. In this review, we have summarized the applications and advantages of using bacteria for targeted tumor therapy (Scheme 1) in order to aid in the design of novel intelligent drug delivery systems. The current challenges and future prospects of tumor-targeting bacterial nanocarriers have also been discussed. [ABSTRACT FROM AUTHOR]

Early antitumor therapy is an important determinant of survival in patients with cancer. Utilization of specific pathological states, such as hypoxia, greatly promotes the development of intelligent drug delivery systems (DDSs) for targeted antitumor therapy. However, a slight decrease in oxygen levels in early-stage tumors is not sufficient to trigger hypoxia-responsive drug release. Nitroreductase (NTR) is overexpressed in bioreductive hypoxic cancers, and its expression level has been verified to be directly related to hypoxic status. Herein, using glucose oxidase (GOx) as an O 2 -consuming agent to exacerbate hypoxia, a cascade strategy of GOx-induced overexpression of NTR and amplified NTR-catalyzed release was proposed for early antitumor therapy. Briefly, NTR-sensitive p-nitrobenzyl chloroformate (PNZ-Cl) was adopted to conjugate with the polysaccharide chitosan (CS) and self-assemble into CS-PNZ-Cl micelles. These polymer micelles possess the dual abilities to specifically immobilize GOx and load mitoxantrone (MIT) to form the NTR-responsive nanocascade reactor GOx/MIT@CS-PNZ-Cl. First, as a "key", tumor hypoxia triggers the initial release of GOx, which serves as the O 2 -consuming agent when catalyzing its reaction with glucose, which is accompanied by H 2 O 2 production. Depleted oxygen levels facilitate the expression of NTR, which in turn amplifies the capacity of the nanocascade reactor to decompose into secondary micelles for enhanced intratumoral permeation. GOx-inspired NTR amplification further elicits MIT release, realizing a synergistic "domino effect" cascade. In addition, upregulated H 2 O 2 has been shown to effectively reverse GSH-mediated MIT resistance, reaching the superior tumor inhibition rate of 93.08%. This GOx-based NTR-responsive nanocascade reactor provides amplification of the bioreductive hypoxic tumor microenvironment for early antitumor therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Clinical treatment of malignant glioma remains a major challenge due to high infiltrative growth and chemotherapeutic resistance of tumors and the presence of the blood brain barrier (BBB). Advanced nanoplatforms that can efficiently cross the BBB and target to brain tumor are urgently needed. Encouraged by the intrinsic inflammatory chemotaxis and excellent BBB-crossing capability of neutrophils, a bioinspired neutrophil-exosomes (NEs-Exos) system for delivering loaded doxorubicin (DOX) drug for glioma treatment is proposed and systematically investigated. In vivo zebrafish and C6-Luc glioma-bearing mice models show that NEs-Exos carrying the drug rapidly penetrate the BBB and migrate into the brain. Additionally, a transwell BBB model and mouse brain inflammatory study show that NEs-Exos can respond chemotactically to inflammatory stimuli and target infiltrating tumor cells in inflamed brain tumors. Moreover, intravenous injection of NEs-Exos/DOX efficiently suppress tumor growth and prolong survival time in a glioma mouse model. On the basis of these results, NEs-Exos are confirmed to have neutrophil-like chemotactic function and BBB penetration. This novel NEs-Exos/DOX delivery platform represents a promising chemotherapeutic approach for clinical treatment of glioma and other solid tumor or brain diseases. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is an effective and noninvasive therapeutic strategy employing light-triggered singlet oxygen (SO) and reactive oxygen species (ROS) to kill lesional cells. However, for effective in vivo delivery of PDT agent into the cancer cells, various biological obstacles including blood circulation and condense extracellular matrix (ECM) in the tumor microenvironment (TME) need to be overcome. Furthermore, the enormous challenge in design of smart drug delivery systems is meeting the difference, even contradictory required functions, in different steps of the complicated delivery process. To this end, we present that TME-activatable circular pyrochlorophyll A (PA)-aptamer-PEG (PA-Apt–CHO–PEG) nanostructures, which combine the advantages of PEG and aptamer, would be able to realize efficient in vivo imaging and PDT. Upon intravenous (i.v.) injection, PA-Apt–CHO–PEG shows "stealth-like" long circulation in blood compartments without specific recognition capacity, but once inside solid tumor, PA-Apt–CHO–PEG nanostructures are cleaved and then form PA-Apt Aptamer-drug conjugations (ApDCs) in situ , allowing deep penetration into the solid tumor and specific recognition of cancer cells, both merits, considering anticipated future clinical translation of ApDCs. [ABSTRACT FROM AUTHOR]

Tumor cell populations are highly heterogeneous, which limit the homogeneous distribution and optimal delivery of nanomedicines, thereby inducing insufficient therapeutic benefits. We develop tumor microenvironment activatable and external stimuli-responsive drug delivery system (TAT+AzoNPs), which can improve photodynamic therapy (PDT) induced bioreductive chemotherapy in different tumor cells both proximal and distal to vessels. The TAT peptide on the surface of TAT+AzoNPs can both facilitate the cell uptake and the penetration of TAT+AzoNPs, owing to its responsiveness to tumor stimuli pH. TAT+AzoNPs can keep the cargoes (photosensitizer chlorine e6 (Ce6) and hypoxia activatable prodrug tirapazamine (TPZ)) and highly accumulate within tumor cells proximity and distal to vessels. The Azo -benzene bonds as the linkers between amphiphilic polymers remain stable under normoxia, but quite break at hypoxic conditions. Upon external laser irradiation, the intratumoral fate of TAT+AzoNPs involved two processes: 1) TAT+AzoNPs achieve efficient PDT on tumor cells proximal to vessel, since sufficient O 2 supply; and 2) PDT-induced more hypoxia can trigger TPZ release by breakage of Azo -benzene bond as well as accelerate the activation of TPZ for improvingcombination therapy efficacy in tumor cells distal to vessel. This study gives a direction for the development of stepwise-activatable hypoxia triggered nanosystem for PDT-induced bioreductive chemotherapy for tumor cells in different distances to vessels. [ABSTRACT FROM AUTHOR]

Drug delivery systems (DDSs) have emerged to help delivering the required cargo into the region of the tumor, achieving the objectives of extenuating the potential damage to the body and improving the therapeutic effectiveness. Here, we developed a one-pot process for encapsulating the unstable and hydrophobic d -α-Tocopherol succinate (α-TOS) in zeolitic imidazolate framework-8 (ZIF-8) compounds (defined as α-TOS@ZIF-8) and subsequently coated with a hyaluronic acid (HA) shell to form the HA/α-TOS@ZIF-8 nanoplatform. Of particular note was when the concentration of α-TOS is l mg/mL, the loading rate was high up to 43.03 wt%. The study verified that HA shell, which could act as a smart "switch" and tumor-targeted "guider", had the capacity for extending blood circulation, enhancing the tumor-specific accumulation of DDS via CD44-mediated pathway. HA shell could be disintegrated by hyaluronidase (HAase) in the tumor microenvironment (TME) and the wrapped α-TOS@ZIF-8 exposed, thus leading to the decomposition of ZIF-8 in tumor acidic microenvironment to release the loaded α-TOS. Therefore, the HA/α-TOS@ZIF-8 nanoplatform has been achieved as a tumor-specific and on-demand drug delivery system, which improved the treatment efficiency. Image 1 [ABSTRACT FROM AUTHOR]