Longer Blood Circulation Research Articles

Comparison of novel PSMA-targeting [177Lu]Lu-P17-087 with its albumin binding derivative [177Lu]Lu-P17-088 in metastatic castration-resistant prostate cancer patients: a first-in-human study.

Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and radioligand therapy (RLT) of prostate cancer. Two novel PSMA-targeting radionuclide therapy agents, [177Lu]Lu-P17-087, and its albumin binder modified derivative, [177Lu]Lu-P17-088, were evaluated in metastatic castration-resistant prostate cancer (mCRPC) patients. The primary endpoint was dosimetry evaluation, the second endpoint was radiation toxicity assessment (CTCAE 5.0) and PSA response (PCWG3). Patients with PSMA-positive tumors were enrolled after [68Ga]Ga-PSMA-11 PET/CT scan. Five mCRPC patients received [177Lu]Lu-P17-087 and four other patients received [177Lu]Lu-P17-088 (1.2 GBq/patient). Multiple whole body planar scintigraphy was performed at 1.5, 4, 24, 48, 72, 120 and 168h after injection and one SPECT/CT imaging was performed at 24h post-injection for each patient. Dosimetry evaluation was compared in both patient groups. Patients showed no major clinical side-effects under this low dose treatment. As expected [177Lu]Lu-P17-088 with longer blood circulation (due to its albumin binding) exhibited higher effective doses than [177Lu]Lu-P17-087 (0.151 ± 0.036 vs. 0.056 ± 0.019 mGy/MBq, P = 0.001). Similarly, red marrow received 0.119 ± 0.068 and 0.048 ± 0.020 mGy/MBq, while kidney doses were 0.119 ± 0.068 and 0.046 ± 0.022 mGy/MBq, respectively. [177Lu]Lu-P17-087 demonstrated excellent tumor uptake and faster kinetics; while [177Lu]Lu-P17-088 displayed a slower washout and higher average dose (7.75 ± 4.18 vs. 4.72 ± 2.29 mGy/MBq, P = 0.018). After administration of [177Lu]Lu-P17-087 and [177Lu]Lu-P17-088, 3/5 and 3/4 patients showed reducing PSA values, respectively. [177Lu]Lu-P17-088 and [177Lu]Lu-P17-087 displayed different pharmacokinetics but excellent PSMA-targeting dose delivery in mCRPC patients. These two agents are promising RLT agents for personalized treatment of mCRPC. Further studies with increased dose and frequency of RLT are warranted to evaluate the potential therapeutic efficacy. 177Lu-P17-087/177Lu-P17-088 in Patients with Metastatic Castration-resistant Prostate Cancer (NCT05603559, Registered at 25 October, 2022). URL OF REGISTRY: https://classic. gov/ct2/show/NCT05603559 .

Effect of microbubble as local drug delivery system in endodontic management - An In-Vitro study

Background and ObjectivesMicrobubbles (MBs) are gas or vapor-filled cavities inside liquids with sizes ranging from 2 to 3 µm. Recently, MBs have shown great promise in nanomedicine owing to their high encapsulation efficiency, targeted drug release, improved biocompatibility, and longer blood circulation. Furthermore, they are more suitable for focusing on particular body regions and are safer and non-invasive. MBs generators are used to create bubbles in fluid dynamics, chemistry, medicine, agriculture, and the environment. Drug delivery using MBs increases penetration without causing systemic toxicity.In this study, we examined whether the use of microbubbles as a local drug-delivery mechanism increases tubular penetration of endodontic medications and irrigant. Materials and MethodsAn Enterococcus faecalis culture was added to 38 dentin cylinders of single-rooted teeth. Samples were divided into the experimental and control groups that received a triple antibiotic paste with and without MB infusion (n = 19 in each group), respectively. After 14 days, the number of live bacteria in the samples was determined using confocal laser scanning microscopy. ResultsAfter 14 days of contact with the medication, the percentages of live and dead bacteria were assessed. Results show that Group 2 (Triple antibiotic infused micro bubble) showed significantly (P < 0.05) higher antibacterial efficacy than Group 1 (TAP). ConclusionIn this study, the antibacterial efficacy was significantly higher in the experimental group than in the control group. Therefore, within the limitations of the study it can be said that MB infusion is a viable technique to improve root canal disinfection. Hence, it can be considered as a novel technique for local drug delivery systems in endodontic management.

Photoresponsive Ru Metalloprodrug Assemblies: Red‐Light‐Controlled Self‐Delivery Systems for Enhanced Anticancer Phototherapy

AbstractSmall‐molecule ruthenium (Ru) complexes exhibit limitations in terms of nonspecific delivery, rapid metabolism, and low tumor accumulation. Their delivery can be improved through physical encapsulation into nanocarriers via hydrophobic forces, metallophilic interactions, or π–π stacking interactions. However, delivering Ru complexes for efficient therapy is substantially hindered by potential leakage of drugs, low drug‐loading capacity, or batch‐to‐batch variations. Moreover, current metalloprodrug‐based self‐delivery systems necessitate supramolecular interactions, which are unsuitable for Ru complexes because of their octahedral structures. Herein, two self‐assembled molecular Ru drugs, Ru‐3XOEG and Ru‐PEG, are reported. Ru‐3XOEG involves a three‐arm dendritic oligo(ethylene glycol) (OEG), while Ru‐PEG involves a linear poly(ethylene glycol) (PEG) chain. Furthermore, these drugs contain an anticancer Ru moiety and a planar pyrene moiety to render hydrophobic forces and π–π stacking supramolecular interactions. Ru‐3XOEG self‐assembles into large compound micelles. Ru‐PEG self‐assembles into vesicles. These Ru‐containing self‐delivered systems exhibit well‐defined structures, high Ru loading contents, and long circulation in blood without external nanocarriers. Red light irradiation induces the release of Ru‐H2O anticancer agents and the generation of 1O2 to inhibit tumor growth. The presented design of self‐assembled molecular Ru complexes opens avenues for the concept of self‐delivered metalloprodrugs.

Precisely Amplifying Intracellular Oxidative Storm by Metal-Organic Coordination Polymers to Augment Anticancer Immunity.

Oxidative stress accompanying the reactive oxygen species (ROS) burst governs immunocyte infiltration, activation, and differentiation in tumor microenvironments and thus can elicit robust antitumor immunity. Here, we identify a photoactive metal-organic coordination polymer (MOCP), composed of an organometallic core formed by cytotoxic mitoxantrone (MTX) acylates and photosensitive Ru(BIQ)-HDBB [BIQ = 2,2'-biquinoline, HDBB = 4,4'-di(4-benzoato)-2,2'-bipyridine] linked by Fe(II) ions via coordinate covalent bonds and an amphipathic shell encapsulating cholesterol-modified siRNA against GPX4 (siGPX4) via hydrophobic force, to precisely amplify intracellular oxidative storm. MOCPs simultaneously encapsulated MTX, Ru, and siGPX4 with efficiencies >98% and loaded Fe with efficiencies of ∼0.49%. With longer blood circulation and higher tumor accumulation, MOCPs with a 670 nm LED irradiation generate abundant ROS to induce biomembrane dysfunction and subsequently contribute to ferroptotic and immunogenic cell death, which drive tumor-associated antigen-specific immunity. MTX analogs contributed to Type I immunogenic cell death (ICD), while oxidative storm served as a damager for endo/lysosomal escape, an initiator for ferroptosis, and an inducer for type II ICD. Moreover, the blockade of CD73 that reduces extoATP catabolism unleashes immunosuppression, finally enhancing antitumor immune stimulation of MOCPs to promote orthotopic mammary cancer regression and prevent postoperative advanced cancer from recurrence and metastasis. MOCPs by exposing sufficient antigenicity thus provide a platform to synergize immune checkpoint inhibitors for the treatment of immunologically cold tumors.

Inclusion Complex Formation with Tetra-PEGylated Tetraphenylporphyrin and Face-to-Face Cyclodextrin Dimer through Unprecedented Molecular Threading.

Herein, a host-guest inclusion complex formation between tetra-PEGylated tetraphenylporphyrin with a per-O-methylated cyclodextrin (CD) dimer through the molecular threading process that is physically unexpected to occur is described. Although the molecular size of the PEGylated porphyrin is much greater than that of the CD dimer, the sandwich-type porphyrin/CD dimer 1 : 1 inclusion complex was spontaneously formed in water. The ferrous porphyrin complex binds O2 reversibly in aqueous solution, which functions as an artificial O2 carrier in vivo. Pharmacokinetic study using rats revealed that the inclusion complex showed a long circulation in blood in contrast to the complex without PEG. We further demonstrate the unique host-guest exchange reaction from the PEGylated porphyrin/CD monomer 1/2 inclusion complex to the 1/1 complex with the CD dimer through the complete dissociation process of the CD monomers.

A tumor-associated bacteria-responsive magnetic exosome as a clearable T1 contrast agent for targeted imaging of tumors

Bacteria can colonize and grow in tumors due to the hypoxic and immunosuppressive tumor microenvironment. Indeed, recent studies have revealed that bacteria are intrinsic and integral components of the tumors. Herein, a tumor-associated bacteria-responsive magnetic exosome (Exo@ESIONs) with switchable magnetic resonance imaging (MRI) property is developed for sensitive tumor imaging. The magnetic exosomes loaded with extremely small iron oxide nanoparticles (ESIONs) possess the excellent properties of long circulation in blood, high accumulation in tumor tissues and rapid response in the tumor microenvironment. Stimulated by the pore-forming toxins (PFTs) secreted from the bacteria in the tumors, the Exo@ESIONs can be disintegrated and the ESIONs are rapidly released, enabling dynamic switchable T2/T1 MRI of the tumors. As a result, the T1 contrast effect of the magnetic nanomaterials can be selectively enhanced in the tumor tissues, even the tumor size is as small as 10 mm3. Moreover, the ESIONs can be rapidly elimination from the body via renal clearance after the MRI to avoid the potential toxicity.

Recent advances in self-assembling redox nanoparticles as a radiation protective agent

&lt;abstract&gt; &lt;p&gt;The search for potent radiation-protective drugs for clinical use continues. Studies have, so far, focused on targeting the neutralization of radiation-generated reactive oxygen species (ROS) to protect the cells against the deleterious effects of exposure to ionizing radiation. However, the development of efficacious radioprotective drugs, which are mostly low molecular weight (LMW) compounds, is mainly limited due to their inherent toxicity and rapid excretion from the body. Thus, researchers reformulated these LMW compounds into nano-based formulations. This review discusses recent advances in the use of self-assembling redox nanoparticles as a new group of radioprotective agents. The copolymer micelle (herein referred to as redox nanoparticles; RNP) contains an active part, amino-TEMPO, that effectively scavenges radiation-induced ROS in the body, as demonstrated &lt;italic&gt;in vivo&lt;/italic&gt;. With the use of nanoparticle-based technologies, optimized formulations of these LMW ROS-neutralizers lead to the significant reduction of its toxicity, high bioavailability and longer blood circulation, which consequently resulted in its notable enhanced efficacy (for example, increased survival rate, reduced radiation-induced syndromes and organ damage) against the damaging effects of ionizing radiation. Consistent with the available data on the use of RNP and other nano-based radioprotective agents, it can be concluded that the inherent ROS-targeting activity of a drug intended for radiation protection is as vital as its bioavailability in the specific tissues and organs, where the short-lived ROS are produced during radiation exposure. In this review article, we summarized the current status of the development of radioprotective agents, including our self-assembling radioprotective agents.&lt;/p&gt; &lt;/abstract&gt;

Controlling NIR-II emitting gold organic/inorganic nanohybrids with tunable morphology and surface PEG density for dynamic visualization of vascular dysfunction.

Luminescent Au nanoparticles (AuNPs) and their organic/inorganic nanohybrids are of interest due to their favorable properties and promising biomedical applications. However, most existing AuNP-based hybrid nanostructures cannot satisfy high efficiency in synthesis, deep tissue penetration, and long blood circulation simultaneously, thus cannot be employed in dynamic monitoring of biomedical applications. In this paper, using Pluronic F127 as a template, we report a robust approach for one-pot synthesis of AuNP-based organic/inorganic nanohybrids (AuNHs) with bright luminescence in the second near-infrared (NIR-II) window, tunable shape, and controllable surface polyethylene glycol (PEG) density. The nanohybrids could be controlled from a necklace-like shape with a dense brush PEG configuration to a spherical structure with a brush PEG coating, which greatly impacts the in vivo biological behavior. Compared to spherical AuNHs, the necklace-shaped AuNHs present a higher quantum yield and longer blood circulation, which are superior to most of the individual AuNPs. With these outstanding features, the necklace-shaped AuNHs could achieve real-time, dynamic visualization of vascular dysfunction, capable of directing the precise administration of thrombolytics (a medicine for the breakdown of blood clots). These findings could provide a powerful guide for designing novel NIR-II nanoprobes toward in vivo dynamic information visualization.

Glutathione-responsive PLGA nanocomplex for dual delivery of doxorubicin and curcumin to overcome tumor multidrug resistance.

Aim: This work aims to develop an injectable nano-drug delivery system to overcome tumor multidrug resistance (MDR). Methods: A drug delivery nanoplatform based on PEGylated PLGA with glutathione (GSH) responsivity was constructed for dual delivery of doxorubicin and curcumin (termed DCNP), and its MDR reversal efficiency was studied in vitro and in vivo. Results: The DCNPs exhibited a rapid drug release profile under high GSH concentration and could enhance the cellular uptake and cytotoxicity of doxorubicinto MDR cancer cells. Moreover, the DCNPsshowed better biocompatibility, longer blood circulation and enhanced antitumor efficiency compared withfree drugs. Conclusion: The GSH-responsive nanocarrier is believed to be a promising candidate for overcoming tumor MDR.

A Bacteria-Inspired Morphology Genetic Biomedical Material: Self-Propelled Artificial Microbots for Metastatic Triple Negative Breast Cancer Treatment.

Morphology genetic biomedical materials (MGBMs), referring to fabricating materials by learning from the genetic morphologies and strategies of natural species, hold great potential for biomedical applications. Inspired by the cargo-carrying-bacterial therapy (microbots) for cancer treatment, a MGBM (artificial microbots, AMBs) was constructed. Rather than the inherent bacterial properties (cancerous chemotaxis, tumor invasion, cytotoxicity), AMBs also possessed ingenious nitric oxide (NO) generation strategy. Mimicking the bacterial construction, the hyaluronic acid (HA) polysaccharide was induced as a coating capsule of AMBs to achieve long circulation in blood and specific tissue preference (tumor tropism). Covered under the capsule-like polysaccharide was the combinatorial agent, the self-assembly constructed by the amphiphilic dendrons with abundant l-arginine residues peripherally (as endogenous NO donor) and hydrophobic chemotherapeutic drugs at the core stacking on the surface of SWNTs (the photothermal agent) for a robust chemo-photothermal therapy (chemo-PTT) and the elicited immune therapy. Subsequently, the classic inducible nitric oxide synthase (iNOS) pathway aroused by immune response was revolutionarily utilized to oxidize the l-arginine substrates for NO production, the process for which could also be promoted by the high reactive oxygen species level generated by chemo-PTT. The NO generated by AMBs was intended to regulate vasodilation and cause a dramatic invasion (as the microbots) to disperse the therapeutic agents throughout the solid tumor for a much more enhanced curative effect, which we defined as "self-propulsion". The self-propelled AMBs exhibiting impressive primary tumor ablation, as well as the distant metastasis regression to conquer the metastatic triple negative breast cancer, provided pioneering potential therapeutic opportunities, and enlightened broad prospects in biomedical application.

Infection microenvironment-responsive multifunctional peptide coated gold nanorods for bimodal antibacterial applications

The abuse of antibiotics has led to bacterial drug resistance, which hinders traditional treatments for infection. It is a vitally important task to develop new methods for combating bacterial infection. In this work, we design a multifunctional peptide (BrEK) that consists of three functional building blocks: an antimicrobial sequence (BF2b), a gelatinase B responsive linker, and a zwitterionic antifouling block. The BrEK peptide is conjugated onto gold nanorods (AuNRs) via a cysteine on one end of the peptide sequence, with excellent photothermal conversion ability under near-infrared (NIR) light. The obtained AuNR@BrEK are tested in vitro and in vivo for antibiotic capacity against methicillin-resistant Staphylococcus aureus (MRSA). The multifunctional peptide coating provides the nanocomposite excellent biocompatibility, relative long circulation in blood, infection microenvironment responsive targeting ability, and unique antibacterial performance. Ultimately, we aim to eliminate drug resistance bacteria by (1) integrating infection microenvironment responsiveness for efficient targeting, (2) capitalizing on antibacterial capacity of BF2b peptides, and (3) developing photothermal sterilization. Transmittance electron microscopy, dynamic light scatter, and zeta potential measurements are introduced to characterize the synthesis of AuNR@BrEK. The evaluation of particle stability is conducted by Fourier-transform infrared spectroscopy and UV–vis spectroscopy. Photothermal conversion capacity of AuNR@BrEK is examined via photothermal effect measurement. Cell viability and hemolysis assay are conducted to further assess the biocompatibility of AuNR@BrEK (200 μg/mL). Lastly, results from the in vitro and in vivo experiments indicate the outstanding antibacterial activity of AuNR@BrEK (10 mg/kg). Such multifunctional gold nanorods represent an important step forward in the goal to combat bacterial resistance.

A near-infrared light-responsive extracellular vesicle as a “Trojan horse” for tumor deep penetration and imaging-guided therapy

How to make the nanoparticles evade immune surveillance and deeply penetrate the tumor tissues is of great importance to maximize the therapeutic efficacy of nanomedicines. Here, a near-infrared (NIR) light-responsive extracellular vesicle as a nanoplatform is developed to realize long circulation in blood, deep penetration in tumor tissues and rapid body elimination after the treatment. Like a “Trojan horse”, the nanoplatform is obtained by hiding the anti-tumor soldiers (DOX and 4.2 nm Ag2S quantum dots (QDs)) into the macrophage cell-secreted vesicle through electroporation. The natural composition and tumor targeting activity of the extracellular vesicles enable the nanoplatform to achieve a high accumulation in tumor and the in vivo biodistribution can be monitored by NIR fluorescence imaging of the Ag2S QDs. After the nanomedicines accumulate at the tumor sites, the soldiers will be released from the “Trojan horse” by utilizing the NIR photothermal effect of the Ag2S QDs. The released ultrasmall QDs and DOX can penetrate the whole tumor with a diameter of about 9 mm and effectively kill the tumor cells. Moreover, the inorganic QDs can be rapidly excreted from the body through renal clearance after the treatment to avoid the potential toxicity.

Phosphorylcholine-Grafted Molecular Bottlebrush-Doxorubicin Conjugates: High Structural Stability, Long Circulation in Blood, and Efficient Anticancer Activity.

Controlling the particle structure of tumor-targeting nanomedicines in vivo remains challenging but must be achieved to control their in vivo fate and functions. Molecular bottlebrushes (MBs), where brush side chains are densely grafted from a main chain, have recently received attention as building blocks of polymer-based prodrugs because their rigid structure would be expected to demonstrate high structural stability in vivo. Here, we synthesized a poly(methacryloyloxyethyl phosphorylcholine) (pMPC)-grafted molecular bottlebrush (PCMB) conjugated with a cancer drug, doxorubicin (DOX), via an acid-cleavable hydrazone bond. A pMPC-based linear polymer (LP) conjugated with DOX was also prepared for comparison. We confirmed the lack of structural transition in the PCMB between before and after conjugation with DOX using small-angle light and X-ray scattering techniques, whereas the structure of LP was significantly influenced by DOX conjugation and transformed from a random-coil structure to a large agglomerate via hydrophobic interactions among DOXs. Although PCMB-DOX and LP-DOX showed comparable tissue permeability, pharmacokinetics, and ability to accumulate in tumor tissues, the antitumor efficacy of PCMB-DOX was better than that of LP-DOX. This was presumably due to the formation of LP-DOX agglomerates. The diffusion of cleaved DOX would be restricted in the hydrophobic core of the agglomerate, resulting in the DOX release at the tumor site being compromised. In contrast to LP-DOX, DOX release from PCMB-DOX was not compromised after accumulation in tumor tissues because it did not form such an agglomerate, resulting in the strong antitumor effect. We have demonstrated the potential of MBs as building blocks of drug carriers and believe that these findings can contribute to the design of polymer-based nanomedicines.

Polymeric micelles coated with hybrid nanovesicles enhance the therapeutic potential of the reversible topoisomerase inhibitor camptothecin in a mouse model

Nanoparticles with longer blood circulation, high loading capacity, controlled release at the targeted site, and preservation of camptothecin (CPT) in its lactone form are the key characteristics for the effective delivery of CPT. In this regard, natural membrane-derived nanovesicles, particularly those derived from RBC membrane, are important. RBC membrane can be engineered to form vesicles or can be coated over synthetic nanoparticles, without losing their basic structural features and can have prolonged circulation time. Here, we developed a hybrid system to encapsulate CPT inside the amphiphilic micelle and coat it with RBC membrane. Thus, it uses the dual ability of polymeric micelles to preserve CPT in its active form, while maintaining its “stealth” effect due to conserved RBC membrane coating. The hybrid system stabilized 60% of the drug in its active form even after 30 h of incubation in serum, in contrast to 15% active form present in free drug formulation after 1 h of incubation. It showed strong retention inside the Ehrlich Ascites Carcinoma (EAC) mice models for at least 72 h, suggesting camouflaging ability conferred by RBC membrane. Additionally, the nano formulation retarded the tumor growth rate more efficiently than free drug, with no evident signs of necrotic skin lesions. Histopathological analysis showed a significant reduction in cardiac atrophy, hepato-renal degeneration, and lung metastasis, which resulted in the increased overall survival of mice treated with the nano formulation. Hence, CPT-loaded polymeric micelles when coated with RBC membrane can prove to be a better system for the delivery of poorly soluble drug camptothecin.

Charge Reversion Simultaneously Enhances Tumor Accumulation and Cell Uptake of Layered Double Hydroxide Nanohybrids for Effective Imaging and Therapy

Nanotheranostics have been actively sought in precision nanomedicine in recent years. However, insufficient tumor accumulation and limited cell uptake often impede the nanotheranostic efficacy. Herein, pH-sensitive charge-reversible polymer-coated layered double hydroxide (LDH) nanohybrids are devised to possess long circulation in blood but reserve surface charges in the weakly acidic tumor tissue to re-expose therapeutic LDH nanoparticles for enhanced tumor accumulation and cell uptake. In vitro experimental data demonstrate that charge-reversible nanohybrids mitigate the cell uptake in physiological conditions (pH 7.4), but remarkably facilitate internalization by tumor cells after charge reversion in the weakly acidic environment (pH 6.8). More significantly, about 6.0% of injected charge-reversible nanohybrids accumulate in the tumor tissue at 24 h post injection, far higher than the average accumulation (0.7%) reported elsewhere for nanoparticles. This high tumor accumulation clearly shows the tumor tissues in T1 -weighted magnetic resonance imaging. As a consequence, >95% inhibition of tumor growth in the B16F0-bearing mouse model is achieved via only one treatment combining RNAi and photothermal therapy under very mild irradiation (808 nm laser, 0.3 W cm-2 for 180 s). The current research thus demonstrates a new strategy to functionalize nanoparticles and simultaneously enhance their tumor accumulation and cell internalization for effective cancer theranostics.

Polyphosphoestered Nanomedicines with Tunable Surface Hydrophilicity for Cancer Drug Delivery.

The surface hydrophilicity of nanoparticles has a major impact on their biological fates. Ascertaining the correlation between nanoparticle surface hydrophilicity and their biological behaviors is particularly instructive for future nanomedicine design and their antitumor efficacy optimization. Herein, we designed a series of polymeric nanoparticles based on polyphosphoesters with well-controlled surface hydrophilicity in the molecular level and systemically evaluated their biological behaviors. The results demonstrated that high surface hydrophilicity preferred lower protein absorption, better stability, longer blood circulation, and higher tumor accumulation but lower cellular uptake. Upon encapsulation of drugs, nanoparticles with high hydrophilicity showed an excellent antitumor therapeutic efficacy in both primary and metastatic tumors as compared to the relatively hydrophobic ones. Further analyses revealed that the superior antitumor outcome was attributed to the balance of tumor accumulation and cellular uptake, demonstrating the particular importance of nanoparticle surface hydrophilicity regulation on the antitumor efficacy. Our work provides a potent guideline for a rational designation on the surface hydrophilicity of nanoparticles for cancer treatment optimization.

Hierarchically targetable fiber rods decorated with dual targeting ligands and detachable zwitterionic coronas

The shapes of drug carriers have significant effects on the drug's blood circulation lifetime and tumor accumulation levels. In this study, nonspherical drug carriers of fiber rods are enhanced with hierarchically targeting capabilities to achieve long circulation in blood, on-demand recovery of cell targeting ligands in tumor tissues and dual ligands-mediated cellular uptake. Zwitterionic polymers are conjugated on fiber rods via acid-labile linkers as stealth coronas to reduce the capture by macrophages and shield the targeting ligands. Compared with commonly used poly(ethylene glycol), the zwitterionic grafts show significantly higher inhibition of protein adsorption and lower internalization by macrophages, leading to around 2 folds longer blood circulation and over 2.5 folds higher drug accumulation in tumors than pristine fiber rods. To address the conflicts between blood circulation and cellular uptake, the zwitterionic coronas are efficiently removed in the slightly acidic tumor microenvironment. The exposure of targeting ligands could activate the internalization by tumor cells, resulting in higher cytotoxicity and tumor accumulation than those with stable linkers. Fiber rods are grafted with dual ligands of folate and biotin, and the optimal ligand densities and ratios are determined to maximize the tumor cell uptake. Compared with other treatment, fiber rods with decorated zwitterionic coronas and acid-liable exposure of dual targeting ligands enhance the suppression of tumor growth, prolong animal survival, and cause less lung metastasis. The development of fiber rods with hierarchically targeting capabilities shows great potential in improving the blood circulation, tumor accumulation and cellular uptake, and eventually promoting therapeutic efficacy. Statement of SignificanceThe targeted delivery of chemotherapeutic agents will encounter a series of biological and pathological barriers. In this study, fiber rods were empowered with hierarchically targeting capabilities to resolve the conflict between blood circulation and cellular uptake. This strategy has shown several advantages over the existing methods. Firstly, zwitterionic polymers were used as blood circulation ligands, and concrete evidence was provided via head-to-head comparison with commonly used poly(ethylene glycol) ligands in the macrophage uptake and in vivo tissue distribution. Secondly, the depletion of circulation ligands and on-demand exposure of targeting ligands in tumor tissues showed crucial effects on the uptake by tumor cells. Thirdly, the densities and ratios of the dual targeting ligands were initially determined for a maximal cellular internalization.

Size-dependent tissue-specific biological effects of core\u2013shell structured Fe3O4@SiO2\u2013NH2 nanoparticles

BackgroundUnderstanding the in vivo size-dependent pharmacokinetics and toxicity of nanoparticles is crucial to determine their successful development. Systematic studies on the size-dependent biological effects of nanoparticles not only help to unravel unknown toxicological mechanism but also contribute to the possible biological applications of nanomaterial.MethodsIn this study, the biodistribution and the size-dependent biological effects of Fe3O4@SiO2–NH2 nanoparticles (Fe@Si-NPs) in three diameters (10, 20 and 40 nm) were investigated by ICP-AES, serum biochemistry analysis and NMR-based metabolomic analysis after intravenous administration in a rat model.ResultsOur findings indicated that biodistribution and biological activities of Fe@Si-NPs demonstrated the obvious size-dependent and tissue-specific effects. Spleen and liver are the target tissues of Fe@Si-NPs, and 20 nm of Fe@Si-NPs showed a possible longer blood circulation time. Quantitative biochemical analysis showed that the alterations of lactate dehydrogenase (LDH) and uric acid (UA) were correlated to some extent with the sizes of Fe@Si-NPs. The untargeted metabolomic analyses of tissue metabolomes (kidney, liver, lung, and spleen) indicated that different sizes of Fe@Si-NPs were involved in the different biochemical mechanisms. LDH, formate, uric acid, and GSH related metabolites were suggested as sensitive indicators for the size-dependent toxic effects of Fe@Si-NPs. The findings from serum biochemical analysis and metabolomic analysis corroborate each other. Thus we proposed a toxicity hypothesis that size-dependent NAD depletion may occur in vivo in response to nanoparticle exposure. To our knowledge, this is the first report that links size-dependent biological effects of nanoparticles with in vivo NAD depletion in rats.ConclusionThe integrated metabolomic approach is an effective tool to understand physiological responses to the size-specific properties of nanoparticles. Our results can provide a direction for the future biological applications of Fe@Si-NPs.

&lt;p&gt;Combined administration of PTX and S-HM-3 in TPGS/Solutol micelle system for oncotarget therapy&lt;/p&gt;

BackgroundS-HM-3 is a tumor angiogenesis inhibitor with short half-life (25 min). In this present, TPGS/Solutol polymeric micelles was prepared to load together insoluble paclitaxel (PTX) and soluble S-HM-3, expecting to together deliver them to the tumor site with long-circulating, targeting function and combating multi-drug resistance (MDR).Materials and methodsPTX and S-HM-3 loaded TPGS/Solutol micelles (PHTSm) were prepared by the method of thin-film evaporation, and characterized by dynamic light scattering, transmission electron microscope (TEM), atomic force microscopy (AFM) and releasing properties. The anticancer effect of the polymeric micelles system was evaluated and confirmed by experiments of in vitro cell uptake study, in vivo pharmacokinetics, and pharmacodynamics studies.ResultsMicelles exhibited smooth spherical morphology with 20~30 nm and low critical micelle concentration (CMC) value of 0.000124 mg/mL. Only about 30% of PTX were slowly released from micelles at 48h, which can beneficial to the long circulation in blood. The results of in vitro cell assay proved that S-HM-3 could be easier to get into MDA-MB-231 cell, and its angiogenesis inhibition ability was also enhanced after integrating into micelles. In particular, the results of in vivo studies showed that the half-life of S-HM-3 and PTX was significantly prolonged 25.27 and 5.54 folds, and their AUC0–∞ was enhanced 129.78 and 15.65 times, respectively. Meanwhile 83.05% tumor inhibition rate of PHTSm was achieved compared with 59.99% of PTX.ConclusionsTPGS and Solutol micelles hold promising potential to resolve the conundrum of combined therapy of cytotoxic drug and angiogenesis inhibitor with different physicochemical property and anticancer mechanism in clinical use.

Biodegradable Zwitterionic Nanogels with Long Circulation for Antitumor Drug Delivery.

Zwitterionic nanocarriers have emerged as a new class of biocompatible nanomaterials with outstanding stealth capability in blood circulation. In this work, a novel biodegradable zwitterionic nanogel based on poly(sulfobetaine methacrylate) (PSBMA) was developed for reduction-responsive drug delivery to tumors. PSBMA nanogels were facilely fabricated by one-step reflux precipitation polymerization with the advantage of being surfactant-free and time-saving. The disulfide bond not only endowed the nanogels degradability in a reduction environment but also be modified with a fluorescent group after partial reduction. In vitro release experiments disclosed that doxorubicin (DOX)-loaded PSBMA nanogels could hold the drugs firmly in physiological conditions (only 7% release in 24 h) and release the drugs rapidly and sufficiently in 10 mM glutathione (85% in 8 h). More interestingly, PSBMA nanogels displayed long circulation in blood after intravenous injection, and small change was found in half-life of nanogels between the first (34.1 h) and the second injection (30.5 h), indicating that there was no accelerated blood clearance phenomenon for these nanogels. Meanwhile, no obvious immunogenic response was detected after PSBMA nanogels were injected into BALB/c mice. Furthermore, PSBMA nanogels showed a high accumulation of 9.5 and 10.7% of injected dose per gram of tissue in tumors at 24 and 48 h post intravenous injection, respectively. With outstanding long circulation time, high tumor accumulation, and sufficient drug release in a reduction environment, DOX-loaded PSBMA nanogels demonstrated the strongest tumor growth inhibition effect among all of the treatment groups in human hypopharyngeal carcinoma-bearing mouse models. Therefore, our study provided a facile drug delivery platform based on biodegradable zwitterionic nanogels and may have great potential in tumor drug delivery.