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Implantable nanogenerator (i-NG) has shown great promises for enabling self-powered implantable medical devices (IMDs). One essential requirement for practical i-NG applications is its long-term bio-compatibility and bio-safety. This paper presents a systematic study of polydimethylsiloxane (PDMS) and PDMS/Parylene-C packaged polyvinylidene fluoride (PVDF) NGs implanted inside female ICR (Institute of Cancer Research) mice for up to six months. The PVDF NG had a stable in vitro output of 0.3 V when bended for 7200 cycles and an in vivo output of 0.1 V under stretching. Multiple advanced imaging techniques, including computed tomography (CT), ultrasound, and photoacoustic were used to characterize the embedded i-NGs in vivo . The i-NGs kept excellent adhesion to the adjacent muscle surface, and exhibited stable electrical output during the entire examine period. No signs of toxicity or incompatibility were observed from the surrounding tissues, as well as from the whole body functions by pathological analyses and blood and serum test. The PDMS package was also able to effectively insulate the i-NG in biological environment with negligible stray currents at a pA scale. This series of in-vivo and in-vitro studies confirmed the biological feasibility of using i-NG in vivo for biomechanical energy harvesting. [ABSTRACT FROM AUTHOR]

The rapid developments of implantable biomedical electronics give rise to the motivation of exploring efficient and durable self-powered charging system. In this paper, we report a mesoporous polyvinylidene fluoride (PVDF)-based implantable piezoelectric nanogenerator (NG) for in vivo biomechanical energy harvesting. The NG was built with a sponge-like mesoporous PVDF film and encapsulated by polydimethylsiloxane (PDMS). After embedding this NG into rodents, a V oc of ~200 mV was produced from the gentle movement of rodent muscle. Meanwhile, no toxicity or incompatibility sign was found in the host after carrying the packaged NG for 6 weeks. Moreover, the electric output of this NG was extremely stable and exhibited no deterioration after 5 days of in vivo operation or 1.512×10 8 times mechanical deformation. This NG device could practically output a constant voltage of 52 mV via a 1 μF capacitor under living circumstance. The outstanding efficiency, magnificent durability and exceptional biocompatibility promise this mesoporous PVDF-based NG in accomplishing self-powered bioelectronics with potentially lifespan operation period. [ABSTRACT FROM AUTHOR]

Implantable nanogenerators (i-NG) provide power to cardiovascular implantable electronic devices (CIEDs) by harvesting biomechanical energy locally eliminating the need for batteries. However, its long-term operation and biological influences on the heart have not been tested. Here, we evaluate a soft and flexible i-NG system engineered for long-term in vivo cardiac implantation. It consisted of i-NG, leads, and receivers, and was implanted on the epicardium of swine hearts for 2 months. The i-NG system generated electric current throughout the testing period. Biocompatibility and biosafety were established based on normal blood and serum test results and no tissue reactions. Heart function was unchanged over the testing period as validated by normal electrocardiogram (ECG), transthoracic ultrasound, and invasive cardiac functional measures. This research demonstrates the safety, long term operation and therefore the feasibility of using i-NGs to power the next generation CIEDs. A soft and flexible implantable nanogenerator (i-NG) system engineered for long-term in vivo cardiac implantation was evaluated. The system, which exhibited great potential of real-time detecting ischemic heart attack and powering small electronics, was implanted on the epicardium of swine hearts for 2 months. Blood chemistry and tissue pathology analysis demonstrated good biocompatibility. Heart function was unchanged over the course of study, as evidenced by electrocardiogram (ECG), transthoracic ultrasound and cardiac pressure–volume loop analysis. This work provides a critical step for the potential translation of i-NG system toward clinical applications. [Display omitted] • A soft and flexible NG was implanted on the epicardium of swine hearts and operated consistently for 2 months. • The in vivo performance of the implantable NG (i-NG) was monitored over time enabled by leads and under-skin receivers. • Heart functions and chemistry analyses demonstrated long-term biosafety and biocompatibility of the cardiac NG implants. • The i-NG system and exhibited great potential of real-time detecting ischemic heart attack and powering electronics. [ABSTRACT FROM AUTHOR]

Summary: This review summarizes the current state-of-the-art of radiolabeled nanoparticles for molecular imaging and internal radiotherapy applications targeting cancer. With the capacity to provide enormous flexibility, radiolabeled nanoparticles have the potential to profoundly impact disease diagnosis and patient management in the near future. Currently, the major challenges facing the research on radiolabeled nanoparticles are desirable (tumor) targeting efficacy, robust chemistry for both radionuclide encapsulation/incorporation and targeting ligand conjugation, favorable safety profile, as well as certain commercial and regulatory hurdles. [Copyright &y& Elsevier]

Summary: Nanoparticle-based molecular imaging has emerged as an interdisciplinary field which involves physics, chemistry, engineering, biology, and medicine. Single-walled carbon nanotubes (SWCNTs) have unique properties which make them suitable for applications in a variety of imaging modalities, such as magnetic resonance, near-infrared fluorescence, Raman spectroscopy, photoacoustic tomography, and radionuclide-based imaging. In this review, we will summarize the current state-of-the-art of SWCNTs in molecular imaging applications. Multifunctionality is the key advantage of nanoparticles over traditional approaches. Targeting ligands, imaging labels, therapeutic drugs, and many other agents can all be integrated into the nanoparticle to allow for targeted molecular imaging and molecular therapy by encompassing many biological and biophysical barriers. A multifunctional, SWCNT-based nanoplatform holds great potential for clinical applications in the future. [Copyright &y& Elsevier]

Abstract: Cancer, with more than 10 million new cases a year worldwide, is the third leading cause of death in developed countries. One critical requirement during cancer progression is angiogenesis, the formation of new blood vessels. Structural and functional imaging of tumor vasculature has been studied using various imaging modalities such as magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound. Molecular imaging, a key component of the 21st‐century cancer‐patient management strategy, takes advantage of these traditional imaging techniques and introduces molecular probes to determine the expression of indicative molecular markers at different stages of cancer development. In this chapter, we will focus on two tumor vasculature–related targets: integrin αvβ3 and vascular endothelial growth factor receptor (VEGFR). For imaging of integrin αvβ3 on the tumor vasculature, only nanoparticle‐based probes will be discussed. VEGFR imaging will be discussed in depth, and we will give a detailed example of positron emission tomography (PET) imaging of VEGFR expression using radio‐labeled VEGF121 protein. Future clinical translation will be critical for maximum patient benefit from these agents. To achieve this goal, multidisciplinary approaches and cooperative efforts from many individuals, institutions, industries, and organizations are needed to quickly translate multimodality tumor vasculature imaging into multiple facets of cancer patient management. [Copyright &y& Elsevier]

Catalytic radiosensitization opens up a new promising direction of radiotherapy enhancement from the perspective of catalytic chemistry, and also provides more opportunities for the design and application of biomedical catalytic materials. This review summarizes the ingenious design and application of catalytic nanomaterials in tumor catalytic radiosensitization from the aspects of electron modulation and energy conversion, respectively, and proposes the strategies, challenges and guidelines for the further development of the catalytic radiosensitization. [Display omitted] Radiotherapy is indispensable in clinical cancer treatment, but because both tumor and normal tissues have similar sensitivity to X-rays, their clinical curative effect is intrinsically limited. Advanced nanomaterials and nanotechnologies have been developed for radiotherapy sensitization, typically employing high atomic number (high-Z) materials to enhance the energy deposition of X-rays in tumor tissues, but the efficiency is largely limited by the toxicity of heavy metals. A new and promising approach for radiosensitization is catalytic radiosensitization, which takes advantage of the catalytic activity of nanomaterials triggered by radiation. The efficiency of catalytic radiosensitization can be greatly enhanced by electron modulation and energy conversion of nanocatalysts upon X-ray irradiation, further enhancing the clinical curative effect. In this review, we highlight the challenges and opportunities in cancer radiosensitization, discuss novel approaches to catalytic radiosensitization, and finally describe the development of catalytic radiosensitization based on an in-depth understanding of radio-nano interactions and catalysis–biological interactions. [ABSTRACT FROM AUTHOR]

Abstract: Nitric oxide (NO) and NO synthases (NOSs) are crucial factors in many pathophysiological processes such as inflammation, vascular/neurological function, and many types of cancer. Noninvasive imaging of NO or NOS can provide new insights in understanding these diseases and facilitate the development of novel therapeutic strategies. In this review, we will summarize the current state-of-the-art multimodality imaging in detecting NO and NOSs, including optical (fluorescence, chemiluminescence, and bioluminescence), electron paramagnetic resonance (EPR), magnetic resonance (MR), and positron emission tomography (PET). With continued effort over the last several years, these noninvasive imaging techniques can now reveal the biodistribution of NO or NOS in living subjects with high fidelity which will greatly facilitate scientists/clinicians in the development of new drugs and/or patient management. Lastly, we will also discuss future directions/applications of NO/NOS imaging. Successful development of novel NO/NOS imaging agents with optimal in vivo stability and desirable pharmacokinetics for clinical translation will enable the maximum benefit in patient management. [Copyright &y& Elsevier]

Since diabetes is becoming a global epidemic, there is a great need to develop early β-cell specific diagnostic techniques for this disorder. There are two types of diabetes (i.e. , type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM)). In T1DM, the destruction of pancreatic β-cells leads to reduced insulin production or even absolute insulin deficiency, which consequently results in hyperglycemia. Actually, a central issue in the pathophysiology of all types of diabetes is the relative reduction of β-cell mass (BCM) and/or impairment of the function of individual β-cells. In the past two decades, scientists have been trying to develop imaging techniques for noninvasive measurement of the viability and mass of pancreatic β-cells. Despite intense scientific efforts, only two tracers for positron emission tomography (PET) and one contrast agent for magnetic resonance (MR) imaging are currently under clinical evaluation. β-cell specific imaging probes may also allow us to precisely and specifically visualize transplanted β-cells and to improve transplantation outcomes, as transplantation of pancreatic islets has shown promise in treating T1DM. In addition, some of these probes can be applied to the preoperative detection of hidden insulinomas as well. In the present review, we primarily summarize potential tracers under development for imaging β-cells with a focus on tracers for PET, SPECT, MRI, and optical imaging. We will discuss the advantages and limitations of the various imaging probes and extend an outlook on future developments in the field. Unlabelled Image [ABSTRACT FROM AUTHOR]

Radiolabeled nanoprobes for positron emission tomography (PET) imaging has received special attention over the past decade, allowing for sensitive, non-invasive, and quantitative detection of different diseases. The rapidly renal clearable nanomaterials normally suffer from a low accumulation in the tumor through the enhanced permeability and retention (EPR) effect due to the rapidly reduced concentration in the blood circulation after renal clearance. It is highly important to design radiolabeled nanomaterials which can meet the balance between the rapid renal clearance and strong EPR effect within a suitable timescale. Herein, renal clearable polyoxometalate (POM) clusters of ultra-small size (∼1 nm in diameter) were readily radiolabeled with the oxophilic 89 Zr to obtain 89 Zr-POM clusters, which may allow for efficient staging of kidney dysfunction in a murine model of unilateral ureteral obstruction (UUO). Furthermore, the as-synthesized clusters can accumulate in the tumor through EPR effect and self-assemble into larger nanostructures in the acidic tumor microenvironment for enhanced tumor accumulation, offering an excellent balance between renal clearance and EPR effect. [ABSTRACT FROM AUTHOR]

Mesoporous silica nanoshell (MSN) coating has been demonstrated as a versatile surface modification strategy for various kinds of inorganic functional nanoparticles, such as gold nanorods (GNRs), to achieve not only improved nanoparticle stability but also concomitant drug loading capability. However, limited drug loading capacity and low tumor accumulation rate in vivo are two major challenges for the biomedical applications of MSN-coated GNRs (GNR@MSN). In this study, by coating uniformly sized GNRs with MSN in an oil-water biphase reaction system, we have successfully synthesized a new bacteria-like GNR@MSN (i.e., bGNR@MSN) with a significantly enlarged pore size (4–8 nm) and surface area (470 m 2 /g). After PEGylation and highly efficient loading of doxorubicin (DOX, 40.9%, w/w), bGNR@MSN were used for positron emission tomography (PET, via facile and chelator-free 89 Zr-labeling) and photoacoustic imaging-guided chemo-photothermal cancer therapy in vivo . PET imaging showed that 89 Zr-labeled bGNR@MSN(DOX)-PEG can passively target to the 4T1 murine breast cancer-bearing mice with high efficiency (∼10 %ID/g), based on enhanced permeability and retention effect. Significantly enhanced chemo-photothermal combination therapy was also achieved due to excellent photothermal effect and near-infrared-light-triggered drug release by bGNR@MSN(DOX)-PEG at the tumor site. The promising results indicate great potential of bGNR@MSN-PEG nanoplatforms for future cancer diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Development of novel imaging probes for cancer diagnosis is critical for early disease detection and management. The past two decades have witnessed a surge in the development and evolution of radiolabeled nanoparticles as a new frontier in personalized cancer nanomedicine. The dynamic synergism of positron emission tomography (PET) and nanotechnology combines the sensitivity and quantitative nature of PET with the multifunctionality and tunability of nanomaterials, which can help overcome certain key challenges in the field. In this review, we discuss the recent advances in radionanomedicine, exemplifying the ability to tailor the physicochemical properties of nanomaterials to achieve optimal in vivo pharmacokinetics and targeted molecular imaging in living subjects. Innovations in development of facile and robust radiolabeling strategies and biomedical applications of such radionanoprobes in cancer theranostics are highlighted. Imminent issues in clinical translation of radiolabeled nanomaterials are also discussed, with emphasis on multidisciplinary efforts needed to quickly move these promising agents from bench to bedside. [ABSTRACT FROM AUTHOR]

As peripheral arterial disease (PAD) results in muscle ischemia and neovascularization, it has been claimed that nanoparticles can passively accumulate in ischemic tissues through the enhanced permeability and retention (EPR) effect. At this time, a quantitative evaluation of the passive targeting capabilities of nanoparticles has not been reported in PAD. Using a murine model of hindlimb ischemia, we quantitatively assessed the passive targeting capabilities of 64 Cu-labeled PEGylated reduced graphene oxide – iron oxide nanoparticles ( 64 Cu-RGO-IONP-PEG) through the EPR effect using positron emission tomography (PET) imaging. Serial laser Doppler imaging was performed to monitor changes in blood perfusion upon surgical induction of ischemia. Nanoparticle accumulation was assessed at 3, 10, and 17 days post-surgery and found to be highest at 3 days post-surgery, with the ischemic hindlimb displaying an accumulation of 14.7 ± 0.5% injected dose per gram (%ID/g). Accumulation of 64 Cu-RGO-IONP-PEG was lowest at 17 days post-surgery, with the ischemic hindlimb displaying only 5.1 ± 0.5%ID/g. Furthermore, nanoparticle accumulation was confirmed by photoacoustic imaging (PA). The combination of PET and serial Doppler imaging showed that nanoparticle accumulation in the ischemic hindlimb negatively correlated with blood perfusion. Thus, we quantitatively confirmed that 64 Cu-RGO-IONP-PEG passively accumulated in ischemic tissue via the EPR effect, which is reduced as the perfusion normalizes. As 64 Cu-RGO-IONP-PEG displayed substantial accumulation in the ischemic tissue, this nanoparticle platform may function as a future theranostic agent, providing both imaging and therapeutic applications. [ABSTRACT FROM AUTHOR]

[Display omitted] Recently, spectral computed tomography (CT) technology has received great interest in the field of radiology. Spectral CT imaging utilizes the distinct, energy-dependent X-ray absorption properties of substances in order to provide additional imaging information. Dual-energy CT and multi-energy CT (Spectral CT) are capable of constructing monochromatic energy images, material separation images, energy spectrum curves, constructing effective atomic number maps, and more. However, poor contrast, due to neighboring X-ray attenuation of organs and tissues, is still a challenge to spectral CT. Hence, contrast agents (CAs) are applied for better differentiation of a given region of interest (ROI). Currently, many different kinds of inorganic nanoparticulate CAs for spectral CT have been developed due to the limitations of clinical iodine (I)-based contrast media, leading to the conclusion that inorganic nanomedicine applied to spectral CT will be a powerful collaboration both in basic research and in clinics. In this review, the underlying principles and types of spectral CT techniques are discussed, and some evolving clinical diagnosis applications of spectral CT techniques are introduced. In particular, recent developments in inorganic CAs used for spectral CT are summarized. Finally, the challenges and future developments of inorganic nanomedicine in spectral CT are briefly discussed. [ABSTRACT FROM AUTHOR]

Tetracarboxylic porphyrins and polyethylene glycol (PEG) diamines were crosslinked in conditions that gave rise to a water-soluble porphyrin polyamide. Using PEG linkers 2 kDa or larger prevented fluorescence self-quenching. This networked porphyrin mesh was retained during dialysis with membranes with a 100 kDa pore size, yet passed through the membrane when centrifugal filtration was applied. Following intravenous administration, the porphyrin mesh, but not the free porphyrin, was rapidly cleared via renal excretion. The process could be monitored by fluorescence analysis of collected urine, with minimal background due to the large Stokes shift of the porphyrin (230 nm separating excitation and emission peaks). In a rhabdomyolysis mouse model of renal failure, porphyrin mesh urinary clearance was significantly impaired. This led to slower accumulation in the bladder, which could be visualized non-invasively via fluorescence imaging. Without further modification, the porphyrin mesh was chelated with 64 Cu for dynamic whole body positron emission tomography imaging of renal clearance. Together, these data show that small porphyrin-PEG polymers can serve as effective multimodal markers of renal function. [ABSTRACT FROM AUTHOR]

Although graphene oxide (GO) has recently been considered as a highly attractive nanomaterial for future cancer imaging and therapy, it is still a major challenge to improve its in vivo tumor active targeting efficiency. Here in this full article, we demonstrated the successful and significantly enhanced in vivo tumor vasculature targeting efficacy of well-functionalized GO nanoconjugates by using vascular endothelial growth factor 121 (VEGF121) as the targeting ligand. As-developed GO nanoconjugate exhibits excellent in vivo stability, specific in vitro and in vivo vascular endothelial growth factor receptor (VEGFR) targeting, significantly enhanced tumor accumulation (>8 %ID/g) as well as high tumor-to-muscle contrast, showing great potential for future tumor targeted imaging and therapy. [ABSTRACT FROM AUTHOR]

Summary: Coactivator-associated arginine methyltransferase 1 (CARM1), a coactivator for various cancer-relevant transcription factors, is overexpressed in breast cancer. To elucidate the functions of CARM1 in tumorigenesis, we knocked out CARM1 from several breast cancer cell lines using Zinc-Finger Nuclease technology, which resulted in drastic phenotypic and biochemical changes. The CARM1 KO cell lines enabled identification of CARM1 substrates, notably the SWI/SNF core subunit BAF155. Methylation of BAF155 at R1064 was found to be an independent prognostic biomarker for cancer recurrence and to regulate breast cancer cell migration and metastasis. Furthermore, CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation. [Copyright &y& Elsevier]

Abstract: Unimolecular micelles formed by dendritic amphiphilic block copolymers poly(amidoamine)–poly(l-lactide)-b-poly(ethylene glycol) conjugated with anti-CD105 monoclonal antibody (TRC105) and 1,4,7-triazacyclononane-N, N′, N-triacetic acid (NOTA, a macrocyclic chelator for 64Cu) (abbreviated as PAMAM–PLA-b-PEG–TRC105) were synthesized and characterized. Doxorubicin (DOX), a model anti-cancer drug, was loaded into the hydrophobic core of the unimolecular micelles formed by PAMAM and PLA via physical encapsulation. The unimolecular micelles exhibited a uniform size distribution and pH-sensitive drug release behavior. TRC105-conjugated unimolecular micelles showed a CD105-associated cellular uptake in human umbilical vein endothelial cells (HUVEC) compared with non-targeted unimolecular micelles, which was further validated by cellular uptake in CD105-negative MCF-7 cells. In 4T1 murine breast tumor-bearing mice, 64Cu-labeled targeted micelles exhibited a much higher level of tumor accumulation than 64Cu-labeled non-targeted micelles, measured by serial non-invasive positron emission tomography (PET) imaging and confirmed by biodistribution studies. These unimolecular micelles formed by dendritic amphiphilic block copolymers that synergistically integrate passive and active tumor-targeting abilities with pH-controlled drug release and PET imaging capabilities provide the basis for future cancer theranostics. [Copyright &y& Elsevier]

Abstract: Graphene-based nanomaterials have attracted tremendous attention in the field of biomedicine due to their intriguing properties. Herein, we report tumor vasculature targeting and imaging in living mice using reduced graphene oxide (RGO), which was conjugated to the anti-CD105 antibody TRC105. The RGO conjugate, 64Cu–NOTA–RGO–TRC105, exhibited excellent stability in vitro and in vivo. Serial positron emission tomography (PET) imaging studies non-invasively assessed the pharmacokinetics and demonstrated specific targeting of 64Cu–NOTA–RGO–TRC105 to 4T1 murine breast tumors in vivo, compared to non-targeted RGO conjugate (64Cu–NOTA–RGO). In vivo (e.g., blocking 4T1 tumor uptake with excess TRC105), in vitro (e.g., flow cytometry), and ex vivo (e.g., histology) experiments confirmed the specificity of 64Cu–NOTA–RGO–TRC105 for tumor vascular CD105. Since RGO exhibits desirable properties for photothermal therapy, the tumor-specific RGO conjugate developed in this work may serve as a promising theranostic agent that integrates imaging and therapeutic components. [Copyright &y& Elsevier]

Abstract: The goal of this study was to employ nano-graphene for tumor targeting in an animal tumor model, and quantitatively evaluate the pharmacokinetics and tumor targeting efficacy through positron emission tomography (PET) imaging using 66Ga as the radiolabel. Nano-graphene oxide (GO) sheets with covalently linked, amino group-terminated six-arm branched polyethylene glycol (PEG; 10 kDa) chains were conjugated to NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid, for 66Ga-labeling) and TRC105 (an antibody that binds to CD105). Flow cytometry analyses, size measurements, and serum stability studies were performed to characterize the GO conjugates before in vivo investigations in 4T1 murine breast tumor-bearing mice, which were further validated by histology. TRC105-conjugated GO was specific for CD105 in cell culture. 66Ga-NOTA-GO-TRC105 and 66Ga-NOTA-GO exhibited excellent stability in complete mouse serum. In 4T1 tumor-bearing mice, these GO conjugates were primarily cleared through the hepatobiliary pathway. 66Ga-NOTA-GO-TRC105 accumulated quickly in the 4T1 tumors and tumor uptake remained stable over time (3.8 ± 0.4, 4.5 ± 0.4, 5.8 ± 0.3, and 4.5 ± 0.4 %ID/g at 0.5, 3, 7, and 24 h post-injection respectively; n = 4). Blocking studies with unconjugated TRC105 confirmed CD105 specificity of 66Ga-NOTA-GO-TRC105, which was corroborated by biodistribution and histology studies. Furthermore, histological examination revealed that targeting of NOTA-GO-TRC105 is tumor vasculature CD105 specific with little extravasation. Successful demonstration of in vivo tumor targeting with GO, along with the versatile chemistry of graphene-based nanomaterials, makes them suitable nanoplatforms for future biomedical research such as cancer theranostics. [Copyright &y& Elsevier]

Abstract: A multifunctional unimolecular micelle made of a hyperbranched amphiphilic block copolymer was designed, synthesized, and characterized for cancer-targeted drug delivery and non-invasive positron emission tomography (PET) imaging in tumor-bearing mice. The hyperbranched amphiphilic block copolymer, Boltorn® H40-poly(L-glutamate-hydrazone-doxorubicin)-b-poly(ethylene glycol) (i.e., H40-P(LG-Hyd-DOX)-b-PEG), was conjugated with cyclo(Arg-Gly-Asp-D-Phe-Cys) peptides (cRGD, for integrin αvβ3 targeting) and macrocyclic chelators (1,4,7-triazacyclononane-N, N’, N’’-triacetic acid [NOTA], for 64Cu-labeling and PET imaging) (i.e., H40-P(LG-Hyd-DOX)-b-PEG-OCH3/cRGD/NOTA, also referred to as H40-DOX-cRGD). The anti-cancer drug, doxorubicin (DOX) was covalently conjugated onto the hydrophobic segments of the amphiphilic block copolymer arms (i.e., PLG) via a pH-labile hydrazone linkage to enable pH-controlled drug release. The unimolecular micelles exhibited a uniform size distribution and pH-sensitive drug release behavior. cRGD-conjugated unimolecular micelles (i.e., H40-DOX-cRGD) exhibited a much higher cellular uptake in U87MG human glioblastoma cells due to integrin αvβ3-mediated endocytosis than non-targeted unimolecular micelles (i.e., H40-DOX), thereby leading to a significantly higher cytotoxicity. In U87MG tumor-bearing mice, H40-DOX-cRGD-64Cu also exhibited a much higher level of tumor accumulation than H40-DOX-64Cu, measured by non-invasive PET imaging and confirmed by biodistribution studies and ex vivo fluorescence imaging. We believe that unimolecular micelles formed by hyperbranched amphiphilic block copolymers that synergistically integrate passive and active tumor-targeting abilities with pH-controlled drug release and PET imaging capabilities provide the basis for future cancer theranostics. [Copyright &y& Elsevier]

Abstract: Multifunctional and water-soluble superparamagnetic iron oxide (SPIO) nanocarriers were developed for targeted drug delivery and positron emission tomography/magnetic resonance imaging (PET/MRI) dual-modality imaging of tumors with integrin αvβ3 expression. An anticancer drug was conjugated onto the PEGylated SPIO nanocarriers via pH-sensitive bonds. Tumor-targeting ligands, cyclo(Arg-Gly-Asp-d-Phe-Cys) (c(RGDfC)) peptides, and PET 64Cu chelators, macrocyclic 1,4,7-triazacyclononane-N, N′, N″-triacetic acid (NOTA), were conjugated onto the distal ends of the PEG arms. The effectiveness of the SPIO nanocarriers as an MRI contrast agent was evaluated via an in vitro r2 MRI relaxivity measurement. cRGD-conjugated SPIO nanocarriers exhibited a higher level of cellular uptake than cRGD-free ones in vitro. Moreover, cRGD-conjugated SPIO nanocarriers showed a much higher level of tumor accumulation than cRGD-free ones according to non-invasive and quantitative PET imaging, and ex vivo biodistribution studies. Thus, these SPIO nanocarriers demonstrated promising properties for combined targeted anticancer drug delivery and PET/MRI dual-modality imaging of tumors. [Copyright &y& Elsevier]

Design, controlled synthesis, physico-chemical and biological characteristics of novel well-defined biodegradable star-shaped copolymers intended for advanced drug delivery is described. These new biocompatible star copolymers were synthesised by grafting monodispersed semitelechelic linear (sL) N -(2-hydroxypropyl)methacrylamide copolymers onto a 2,2-bis(hydroxymethyl)propionic acid (bisMPA)-based polyester dendritic core of various structures. The hydrodynamic diameter of the star copolymer biomaterials can be tuned from 13 to 31 nm and could be adjusted to a given purpose by proper selection of the bisMPA dendritic core type and generation and by considering the sL copolymer molecular weight and polymer-to-core molar ratio. The hydrolytic degradation was proved for both the star copolymers containing either dendron or dendrimer core, showing the spontaneous hydrolysis in duration of few weeks. Finally, it was shown that the therapy with the biodegradable star conjugate with attached doxorubicin strongly suppresses the tumour growth in mice and is fully curative in most of the treated animals at dose corresponding approximately to one fourth of maximum tolerated dose (MTD) value. Both new biodegradable systems show superior efficacy and tumour accumulation over the first generation of star copolymers containing non-degradable PAMAM core. [ABSTRACT FROM AUTHOR]