Matrix metalloproteinase enzyme responsive delivery of 5-Fluorouracil using Collagen-I peptide functionalized Dendrimer-Gold nanocarrier.

OBJECTIVE: The aim was to develop matrix metalloproteinase 1 (MMP1) responsive nanoparticle system for the delivery of 5-fluorouracil (5Fu) anticancer drug. SIGNIFICANCE: The MMP1 in the cancer microenvironment-induced drug release have the advantage of targeted drug release and reduce the distribution of drug to the healthy tissues. METHOD: G5 poly(amidoamine) (PAMAM) dendrimer (G5)-coated gold nanoparticles (G5AuNP) were synthesized and loaded with 5Fu. The drug-loaded nanoparticles were further coated with collagen I (Col-I) peptide, which is a substrate for MMP1 enzyme (Col-I 5Fu@G5AuNP). RESULT: The nanoparticles were highly monodispersed with a particle size of 30 nm and showed high drug encapsulation efficiency. The release of drug from the nanoparticles in HEPES buffer pH 7.4 was faster, higher and better controlled when incubated with MMP1 enzyme. The half-maximum inhibitory concentration for Col-I 5Fu@G5AuNP was eight times lower than the 5Fu against MCF-7, suggesting the improved delivery and anticancer activity of 5Fu after encapsulation in the developed enzyme-responsive nanocarrier system. The computed tomography (CT) X-ray attenuation of Col-I@G5AuNP showed a good contrasting property. CONCLUSION: The formulation Col-I 5Fu@G5AuNP has improved anticancer activity than free drug and the CT imaging results are promising for its theranostic applications for breast cancer treatment.

Self-assembled fluorescent hybrid nanoparticles-mediated collaborative lncRNA CCAT1 silencing and curcumin delivery for synchronous colorectal cancer theranostics.

BACKGROUND: Cancer synergistic therapy strategy in combination with therapeutic gene and small molecule drug offers the possibility to amplify anticancer efficiency. Colon cancer-associated transcript-1 (CCAT1) is a well identified oncogenic long noncoding RNA (lncRNA) exerting tumorigenic effects in a variety of cancers including colorectal cancer (CRC). RESULTS: In the present work, curcumin (Cur) and small interfering RNA targeting lncRNA CCAT1(siCCAT1) were co-incorporated into polymeric hybrid nanoparticles (CSNP), which was constructed by self-assembling method with two amphiphilic copolymers, polyethyleneimine-poly (D, L-lactide) (PEI-PDLLA) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol) (DSPE-mPEG). Owing to the multicolor fluorescence characteristics of PEI-PDLLA, the constructed CSNP could be served as a theranostic nanomedicine for synchronous therapy and imaging both in vitro and in vivo. Resultantly, proliferation and migration of HT-29 cells were efficiently inhibited, and the highest apoptosis ratio was induced by CSNP with coordination patterns. Effective knockdown of lncRNA CCAT1 and concurrent regulation of relevant downstream genes could be observed. Furthermore, CSNP triggered conspicuous anti-tumor efficacy in the HT-29 subcutaneous xenografts model with good biosafety and biocompatibility during the treatment. CONCLUSION: On the whole, our studies demonstrated that the collaborative lncRNA CCAT1 silencing and Cur delivery based on CSNP might emerge as a preferable and promising strategy for synergetic anti-CRC therapy.

From one to all: self-assembled theranostic nanoparticles for tumor-targeted imaging and programmed photoactive therapy.

BACKGROUND: In recent years, multifunctional theranostic nanoparticles have been fabricated by integrating imaging and therapeutic moieties into one single nano-formulations. However, Complexity of production and safety issues limits their further application. RESULTS: Herein, we demonstrated self-assembled nanoparticles with single structure as a "from one to all" theranostic platform for tumor-targeted dual-modal imaging and programmed photoactive therapy (PPAT). The nanoparticles were successfully developed through self-assembling of hyaluronic acid (HA)-cystamine-cholesterol (HSC) conjugate, in which IR780 was simultaneously incorporated (HSCI NPs). Due to the proper hydrodynamic size and intrinsic targeting ability of HA, the HSCI NPs could accumulate at the tumor site effectively after systemic administration. In the presence of incorporated IR780, in vivo biodistribution and accumulation behaviors of HSCI NPs could be monitored by photoacoustic imaging. After cellular uptake, the HSCI NPs would disintegrate resulting from cystamine reacting with over-expressed GSH. The released IR780 would induce fluorescence "turn-on" conversion, which could be used to image tumor sites effectively. Upon treatment with 808 nm laser irradiation, PPAT could be achieved in which generated reactive oxygen species (ROS) would produce photodynamic therapy (PDT), and subsequently the raised temperature would be beneficial to tumor photothermal therapy (PTT). CONCLUSION: The self-assembled HSCI NPs could act as "from one to all" theranostic platform for high treatment efficiency via PPAT pattern, which could also real-time monitor NPs accumulation by targeted and dual-modal imaging in a non-invasive way.

Actively Targeted Deep Tissue Imaging and Photothermal-Chemo Therapy of Breast Cancer by Antibody-Functionalized Drug-Loaded X-Ray-Responsive Bismuth Sulfide@Mesoporous Silica Core-Shell Nanoparticles.

A theranostic platform combining synergistic therapy and real-time imaging attracts enormous attention but still faces great challenges, such as tedious modifications and lack of efficient accumulation in tumor. Here, a novel type of theranostic agent, bismuth sulfide@mesoporous silica (Bi2S3@ mPS) core-shell nanoparticles (NPs), for targeted image-guided therapy of human epidermal growth factor receptor-2 (HER-2) positive breast cancer is developed. To generate such NPs, polyvinylpyrrolidone decorated rod-like Bi2S3 NPs are chemically encapsulated with a mesoporous silica (mPS) layer and loaded with an anticancer drug, doxorubicin. The resultant NPs are then chemically conjugated with trastuzumab (Tam, a monoclonal antibody targeting HER-2 overexpressed breast cancer cells) to form Tam-Bi2S3@mPS NPs. By in vitro and in vivo studies, it is demonstrated that the Tam-Bi2S3@mPS bear multiple desired features for cancer theranostics, including good biocompatibility and drug loading ability as well as precise and active tumor targeting and accumulation (with a bismuth content in tumor being ≈16 times that of nontargeted group). They can simultaneously serve both as an excellent contrast enhancement probe (due to the presence of strong X-ray-attenuating bismuth element) for computed tomography deep tissue tumor imaging and as a therapeutic agent to destruct tumors and prevent metastasis by synergistic photothermalchemo therapy.

Assessing fluorescence detection and effective photothermal therapy of near-infrared polymer nanoparticles using alginate tissue phantoms.

OBJECTIVE: Photothermal therapy (PTT) uses light absorbing materials to generate heat for treatment of diseases, like cancer. The advantages of using PTT components that absorb in the near-infrared (NIR) include reduced tissue auto-fluorescence and higher penetration depths. However, NIR laser light can still be scattered and absorbed by biological tissues, thus decreasing the amount of the energy reaching the PTT agents. We have developed two distinct formulations of NIR-absorbing nanoparticles, one which can be utilized for PTT only, and another for both PTT and fluorescence imaging of colorectal cancer. In this work, the fluorescence detection limit and the PTT heating potential of the two nanoparticle types were determined using alginate tissue phantoms. The objective of this study was to determine the PTT efficiency and theranostic potential of the nanoparticles by irradiating 3D collagen tumor spheroids, containing nanoparticles and CT26 mouse colorectal cancer cells, through increasing tissue phantom thicknesses and then quantifying cell death. Materials and Methods Our lab has previously developed nanoparticles based on the semiconducting, conjugated polymer poly[4,4-bis(2-ethylhexyl)-cyclopenta[2,1-b;3,4-b']dithiophene-2,6-diyl-alt-2,1,3-benzoselenadiazole-4,7-diyl] (PCPDTBSe). We have also made a hybrid nanoparticle that heats and fluoresces by combining PCPDTBSe polymer with the fluorescent poly[(9,9-dihexylfluorene)-co-2,1,3-benzothiadiazole-co-4,7-di(thiophen-2-yl)-2,1,3-benzothiadiazole] (PFBTDBT10) polymer to yield nanoparticles termed Hybrid Donor-Acceptor Polymer Particles (H-DAPPs). H-DAPPs and PCPDTBSe nanoparticles were added to three-dimensional collagen gel tumor spheroids in order to represent nanoparticles in a tumor. Alginate tissue phantoms, comprised of an optical scattering agent (Intralipid) and an optical absorbing material (hemoglobin) in order to mirror biological tissue scattering effects, were used to simulate increasing tissue thickness between the nanoparticles and the PTT energy source. RESULTS: Fluorescence from the H-DAPPs was detectable through 6 mm of tissue phantoms. It was found that less than 10% of the laser energy could penetrate through 9 mm of tissue phantoms and only 60% of the laser energy passed through the 1.5 mm phantoms, regardless of laser power. PTT experiments, using 800 nm light at 2.2 W/cm2 for 60 s through tissue phantoms to stimulate nanoparticle-doped tumor spheroids, showed 55% cell death through 3 mm of tissue phantoms using H-DAPPs. Results from using the PCPDTBSe nanoparticles showed 72% cell death through 3 mm and over 50% cell death through 6 mm of tissue phantoms. CONCLUSION: The results of this work validated the heating potential and fluorescence detection limitations of two theranostic polymer nanoparticles by utilizing alginate tissue phantoms and 3D tumor spheroids. H-DAPPs and PCPDTBSe polymer nanoparticles can be utilized as effective PTT agents by exploiting their absorption of NIR light and H-DAPPs have advantageous fluorescence for imaging colorectal cancer. The data generated from this study design can allow for other NIR absorbing and fluorescing nanoparticle formulations to be evaluated prior to in vivo experimentation. Lasers Surg. Med. 50:1040-1049, 2018. © 2018 Wiley Periodicals, Inc.

Targeted nanomedicine for cancer therapeutics: Towards precision medicine overcoming drug resistance.

Intrinsic anticancer drug resistance appearing prior to chemotherapy as well as acquired resistance due to drug treatment, remain the dominant impediments towards curative cancer therapy. Hence, novel targeted strategies to overcome cancer drug resistance constitute a key aim of cancer research. In this respect, targeted nanomedicine offers innovative therapeutic strategies to overcome the various limitations of conventional chemotherapy, enabling enhanced selectivity, early and more precise cancer diagnosis, individualized treatment as well as overcoming of drug resistance, including multidrug resistance (MDR). Delivery systems based on nanoparticles (NPs) include diverse platforms enabling a plethora of rationally designed therapeutic nanomedicines. Here we review NPs designed to enhance antitumor drug uptake and selective intracellular accumulation using strategies including passive and active targeting, stimuli-responsive drug activation or target-activated release, triggered solely in the cancer cell or in specific organelles, cutting edge theranostic multifunctional NPs delivering drug combinations for synergistic therapy, while facilitating diagnostics, and personalization of therapeutic regimens. In the current paper we review the recent findings of the past four years and discuss the advantages and limitations of the various novel NPs-based drug delivery systems. Special emphasis is put on in vivo study-based evidences supporting significant therapeutic impact in chemoresistant cancers. A future perspective is proposed for further research and development of complex targeted, multi-stage responsive nanomedical drug delivery systems for personalized cancer diagnosis and efficacious therapy.

Nanotechnology for Cancer Therapy Based on Chemotherapy.

Chemotherapy has been widely applied in clinics. However, the therapeutic potential of chemotherapy against cancer is seriously dissatisfactory due to the nonspecific drug distribution, multidrug resistance (MDR) and the heterogeneity of cancer. Therefore, combinational therapy based on chemotherapy mediated by nanotechnology, has been the trend in clinical research at present, which can result in a remarkably increased therapeutic efficiency with few side effects to normal tissues. Moreover, to achieve the accurate pre-diagnosis and real-time monitoring for tumor, the research of nano-theranostics, which integrates diagnosis with treatment process, is a promising field in cancer treatment. In this review, the recent studies on combinational therapy based on chemotherapy will be systematically discussed. Furthermore, as a current trend in cancer treatment, advance in theranostic nanoparticles based on chemotherapy will be exemplified briefly. Finally, the present challenges and improvement tips will be presented in combination therapy and nano-theranostics.

Using Peptide Aptamer Targeted Polymers as a Model Nanomedicine for Investigating Drug Distribution in Cancer Nanotheranostics.

Theranostics is a strategy that combines multiple functions such as targeting, stimulus-responsive drug release, and diagnostic imaging into a single platform, often with the aim of developing personalized medicine.1,2 Based on this concept, several well-established hyperbranched polymeric theranostic nanoparticles were synthesized and characterized as model nanomedicines to investigate how their properties affect the distribution of loaded drugs at both the cell and whole animal levels. An 8-mer peptide aptamer was covalently bound to the periphery of the nanoparticles to achieve both targeting and potential chemosensitization functionality against heat shock protein 70 (Hsp70). Doxorubicin was also bound to the polymeric carrier as a model chemotherapeutic drug through a degradable hydrazone bond, enabling pH-controlled release under the mildly acid conditions that are found in the intracellular compartments of tumor cells. In order to track the nanoparticles, cyanine-5 (Cy5) was incorporated into the polymer as an optical imaging agent. In vitro cellular uptake was assessed for the hyperbranched polymer containing both doxorubicin (DOX) and Hsp70 targeted peptide aptamer in live MDA-MB-468 cells, and was found to be greater than that of either the untargeted, DOX-loaded polymer or polymer alone due to the specific affinity of the peptide aptamer for the breast cancer cells. This was also validated in vivo with the targeted polymers showing much higher accumulation within the tumor 48 h postinjection than the untargeted analogue. More detailed assessment of the nanomedicine distribution was achieved by directly following the polymeric carrier and the doxorubicin at both the in vitro cellular level via compartmental analysis of confocal images of live cells and in whole tumors ex vivo using confocal imaging to visualize the distribution of the drug in tumor tissue as a function of distance from blood vessels. Our results indicate that this polymeric carrier shows promise as a cancer theranostic, demonstrating active targeting to tumor cells with the capability for simultaneous drug release.

Photoluminescence and doping mechanism of theranostic Eu3+/Fe3+ dual-doped hydroxyapatite nanoparticles.

Theranostic nanoparticles currently have been regarded as an emerging concept of 'personalized medicine' with diagnostic and therapeutic dual-functions. Eu3+ doped hydroxyapatite (HAp) has been regarded as a promising fluorescent probe for in vivo imaging applications. Additionally, substitution of Ca2+ with Fe3+ in HAp crystal may endow the capability of producing heat upon exposure to a magnetic field. Here we report a preliminary study of doping mechanism and photoluminescence of Eu3+ and Fe3+ doped HAp nanoparticles (Eu/Fe:HAp). HAp with varied concentration of Eu3+ and Fe3+ doping are presented as Eu(10 mol%):HAp, Eu(7 mol%)-Fe(3 mol%):HAp, Eu(5 mol%)-Fe(5 mol%):HAp, Eu(3 mol%)-Fe(7 mol%):HAp, and Fe(10 mol%):HAp in the study. The results showed that the HAp particles, in nano-size with rod-like morphology, were successfully doped with Eu3+ and Fe3+, and the particles can be well suspended in cell culture medium. Photoluminescence analysis revealed that particles have prominent emissions at 536 nm, 590 nm, 615 nm, 650 nm and 695 nm upon excitation at a wavelength of 397 nm. Moreover, these Eu/Fe:HAp nanoparticles belonged to B-type carbonated HAp, which has been considered an effective biodegradable and biocompatible drug/gene carrier in biological applications.

A versatile theranostic magnetic polydopamine iron oxide NIR laser-responsive nanosystem containing doxorubicin for chemo-photothermal therapy of melanoma.

Theranostics nanoparticles (NPs) have recently received much attention in cancer imaging and treatment. This study aimed to develop a multifunctional nanosystem for the targeted delivery of photothermal and chemotherapy agents. Fe3O4 NPs were modified with polydopamine, bovine serum albumin, and loaded with DOX via a thermal-cleavable Azo linker (Fe3O4@PDA@BSA-DOX). The size of Fe3O4@PDA@BSA NPs was approximately 98 nm under the desired conditions. Because of the ability of Fe3O4 and PDA to convert light into heat, the temperature of Fe3O4@PDA@BSA NPs increased to approximately 47 °C within 10 min when exposed to an 808 nm NIR laser with a power density of 1.5 W/cm2. The heat generated by the NIR laser leads to the breaking of AZO linker and drug release. In vivo and in vitro results demonstrated that prepared NPs under laser irradiation successfully eradicated tumor cells without any significant toxicity effect. Moreover, the Fe3O4@PDA@BSA NPs exhibited the potential to function as a contrasting agent. These NPs could accumulate in tumors with the help of an external magnet, resulting in a significant enhancement in the quality of magnetic resonance imaging (MRI). The prepared novel multifunctional NPs seem to be an efficient system for imaging and combination therapy in melanoma.

Unleashing the Potential of Oral Deliverable Nanomedicine in the Treatment of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), marked by chronic gastrointestinal tract inflammation, poses a significant global medical challenge. Current treatments for IBD, including corticosteroids, immunomodulators, and biologics, often require frequent systemic administration through parenteral delivery, leading to nonspecific drug distribution, suboptimal therapeutic outcomes, and adverse effects. There is a pressing need for a targeted drug delivery system to enhance drug efficacy and minimize its systemic impact. Nanotechnology emerges as a transformative solution, enabling precise oral drug delivery to inflamed intestinal tissues, reducing off-target effects, and enhancing therapeutic efficiency. The advantages include heightened bioavailability, sustained drug release, and improved cellular uptake. Additionally, the nano-based approach allows for the integration of theranostic elements, enabling simultaneous diagnosis and treatment. Recent preclinical advances in oral IBD treatments, particularly with nanoformulations such as functionalized polymeric and lipid nanoparticles, demonstrate remarkable cell-targeting ability and biosafety, promising to overcome the limitations of conventional therapies. These developments signify a paradigm shift toward personalized and effective oral IBD management. This review explores the potential of oral nanomedicine to enhance IBD treatment significantly, focusing specifically on cell-targeting oral drug delivery system for potential use in IBD management. We also examine emerging technologies such as theranostic nanoparticles and artificial intelligence, identifying avenues for the practical translation of nanomedicines into clinical applications.

Novel ligand decorated theranostic zein nanoparticles coloaded with paclitaxel and carbon quantum dots: formulation and optimization.

Aim: The present research focused on development and optimization of ligand decorated theranostic nanocarrier encapsulating paclitaxel and carbon quantum dots (CQDs). Methods: CQDs were prepared by microwave-assisted pyrolysis and were characterized for particle size and fluorescence behavior. Ligand decorated zein nanoparticles, coloaded with paclitaxel and CQDs, were formulated using a one-step nanoprecipitation method and optimized for various process parameters. Results: Particle size for coated and uncoated nanoparticles was 90.16 ± 1.65 and 179.26 ± 3.61 nm, respectively, and entrapment efficiency was >80%. The circular dichroism spectroscopy showed zein retained its secondary structure and release study showed biphasic release behavior. Conclusion: The prepared theranostic nanocarrier showed optimal fluorescence and desired release behavior without altering the secondary structure of zein.

Biomimetic Theranostic Agents with Superior NIR-II Photoacoustic and Magnetic Resonance Imaging Performance for Targeted Photothermal Therapy of Prostate Cancer.

The accurate diagnosis and treatment of prostate cancer at an early stage is crucial to reduce mortality rates. However, the limited availability of theranostic agents with active tumor-targeting abilities hinders imaging sensitivity and therapeutic efficiency. To address this challenge, we have developed biomimetic cell membrane-modified Fe2O3 nanoclusters implanted in polypyrrole (CM-LFPP), achieving photoacoustic/magnetic resonance dual-modal imaging-guided photothermal therapy of prostate cancer. The CM-LFPP exhibits strong absorption in the second near-infrared window (NIR-II, 1000-1700 nm), showing high photothermal conversion efficiency of up to 78.7% under 1064 nm laser irradiation, excellent photoacoustic imaging capabilities, and good magnetic resonance imaging ability with a T2 relaxivity of up to 48.7 s-1 mM-1. Furthermore, the lipid encapsulation and biomimetic cell membrane modification enable CM-LFPP to actively target tumors, leading to a high signal-to-background ratio of ~30.2 for NIR-II photoacoustic imaging. Moreover, the biocompatible CM-LFPP enables low-dose (0.6 W cm-2) photothermal therapy of tumors under 1064 nm laser irradiation. This technology offers a promising theranostic agent with remarkable photothermal conversion efficiency in the NIR-II window, providing highly sensitive photoacoustic/magnetic resonance imaging-guided prostate cancer therapy.

ALA/Ag2S/MnO2 Hybrid Nanoparticles for Near-Infrared Image-Guided Long-Wavelength Phototherapy of Breast Cancer.

The combination of photothermal therapy (PTT) and photodynamic therapy (PDT) based on temperature increase and the formation of reactive oxygen species (ROS), respectively, is an exciting avenue to provide local and improved therapy of tumors with minimal off-site toxicity. 5-Aminolevulinic acid (ALA) is one of the most popular PDT pro-drugs, and its efficiency improves significantly when delivered to tumors with nanoparticles (NPs). But the tumor site's hypoxic environment is a handicap for the oxygen-consuming PDT process. In this work, highly stable, small, theranostic NPs composed of Ag2S quantum dots and MnO2, electrostatically loaded with ALA, were developed for enhanced PDT/PTT combination of tumors. MnO2 catalyzes endogenous H2O2 to O2 conversion and glutathione depletion, enhancing ROS generation and ALA-PDT efficiency. Ag2S quantum dots (AS QDs) conjugated with bovine serum albumin (BSA) support MnO2 formation and stabilization around Ag2S. AS-BSA-MnO2 provided a strong intracellular near-infrared (NIR) signal and increased the solution temperature by 15 °C upon laser irradiation at 808 nm (215 mW, 10 mg/mL), proving the hybrid NP as an optically trackable, long-wavelength PTT agent. In the in vitro studies, no significant cytotoxicity was observed in the absence of laser irradiation in healthy (C2C12) or breast cancer cell lines (SKBR3 and MDA-MB-231). The most effective phototoxicity was observed when AS-BSA-MnO2-ALA-treated cells were co-irradiated for 5 min with 640 nm (300 mW) and 808 nm (700 mW) due to enhanced ALA-PDT combined with PTT. The viability of cancer cells decreased to approximately 5-10% at 50 µg/mL [Ag], corresponding to 1.6 mM [ALA], whereas at the same concentration, individual PTT and PDT treatments decreased the viability to 55-35%, respectively. The late apoptotic death of the treated cells was mostly correlated with high ROS levels and lactate dehydrogenase. Overall, these hybrid NPs overcome tumor hypoxia, deliver ALA to tumor cells, and provide both NIR tracking and enhanced PDT + PTT combination therapy upon short, low-dose co-irradiation at long wavelengths. These agents that may be utilized for treating other cancer types are also highly suitable for in vivo investigations.

Engineering Female Germline Stem Cells with Exocytotic Polymer Dots.

Germline stem cells (GSCs) are the only cell population capable of passing genetic information to offspring, making them attractive targets in reproductive biology and fertility research. However, it is generally more difficult to introduce exogenous biomolecules into GSCs than other cell types, impeding the exploration and manipulation of these cells for biomedical purposes. Herein, semiconductor polymer dots (Pdots)-based nanocomplex Pdot-siRNA is developed and achieves effective knockdown of target genes in female germline stem cells (FGSCs). Advantage of high fluorescence brightness of Pdots is taken for comprehensive investigation of their cellular uptake, intracellular trafficking, and exocytosis in FGSCs. Importantly, Pdots show excellent biocompatibility and minimally disturb the differentiation of FGSCs. Intracellular Pdots escape from the lysosomes and undergo active exocytosis, which makes them ideal nanocarriers for bioactive cargos. Moreover, Pdot-siRNA can penetrate into 3D ovarian organoids derived from FGSCs and down-regulate the expression levels of target genes. This study investigates the interface between a type of theranostic nanoparticles and FGSCs for the first time and sheds light on the manipulation and medical application of FGSCs.

Gadolinium-Bisphosphonate Nanoparticle-Based Low-Dose Radioimmunotherapy for Osteosarcoma.

Osteosarcoma is a malignant osteogenic tumor with a high metastatic rate commonly occurring in adolescents. Although radiotherapy is applied to treat unresectable osteosarcoma with radiation resistance, a high dose of radiotherapy is required, which may weaken the immune microenvironment. Therefore, there is an urgent need to develop novel agents to maximize the radiotherapeutic effects by eliciting immune activation effects. In this study, we synthesized therapeutic gadolinium-based metal-bisphosphonate nanoparticles (NPs) for osteosarcoma treatment that can be combined with radiotherapy. The gadolinium ion (Gd) was chelated with zoledronic acid (Zol), a commonly used drug to prevent/treat osteoporosis or bone metastases from advanced cancers, and stabilized by ovalbumin (OVA) to produce OVA-GdZol NPs. OVA-GdZol NPs were internalized into K7M2 osteosarcoma cells, showing a high sensitization effect under X-ray irradiation. Cell pretreatment of OVA-GdZol NPs significantly enhanced the radiation therapeutic effect in vitro by reducing the cell colonies and increased the signal of γH2AX-positive cells. More importantly, OVA-GdZol NPs promoted the maturation of bone marrow-derived dendritic cells (BMDCs) and M1 polarization of macrophages. The inhibitory effect on K7M2 osteosarcoma of OVA-GdZol NPs and X-ray radiation was evident, indicated by a significantly reduced tumor volume, high survival rate, and decreased lung metastasis. Meanwhile, both innate and adaptive immune systems were activated to exert a strong antitumor effect. The above results highly suggest that OVA-GdZol NPs serve as both radiosensitizers and immune adjuvants, suitable for the sequential combination of vaccination and radiotherapy.

Lanthanide-based ß-Tricalcium Phosphate Upconversion Nanoparticles as an Effective Theranostic Nonviral Vectors for Image-Guided Gene Therapy.

Lanthanide-based beta-tricalcium phosphate (ß-TCP) upconversion nanoparticles are exploited as a non-viral vector for imaging guided-gene therapy by virtue of their unique optical properties and multi-modality imaging ability, high transfection efficiency, high biocompatibility, dispersibility, simplicity of synthesis and surface modification. Ytterbium and thulium-doped ß-TCP nanoparticles (ßTCPYbTm) are synthesized via co-precipitation method, coated with polyethylenimine (PEI) and functionalized with a nuclear-targeting peptide (TAT). Further, in vitro studies revealed that the nanotheranostic carriers are able to transfect cells with the plasmid eGFP at a high efficiency, with approximately 60% of total cells producing the fluorescent green protein. The optimized protocol developed comprises the most efficient ßTCPYbTm/PEI configuration, the amount and the order of assembly of ßTCPYbTm:PEI, TAT, plasmid DNA and the culturing conditions. With having excellent dispersibility and high chemical affinity toward nucleic acid, calcium ions released from ßTCPYbTm:PEI nanoparticles can participate in delivering nucleic acids and other therapeutic molecules, overcoming the nuclear barriers and improving the transfection efficacy. Equally important, the feasibility of the upconversion multifunctional nanovector to serve as an effective contrast agent for imaging modality, capable of converting low-energy light to higher-energy photons via a multi-photons mechanism, endowing greater unique luminescent properties, was successfully demonstrated.

Interfacial engineered iron oxide nanoring for T2-weighted magnetic resonance imaging-guided magnetothermal-chemotherapy.

Due to no penetration depth limitation, low cost, and easy control, magnetic nanoparticles mediated magnetic hyperthermia therapy (MHT) has shown great potential in experimental and clinal treatments of various diseases. However, the low heating conversion efficiencies and short circulation times are major drawback for most existing magnetic-thermal materials. Additionally, single MHT treatment always leads to resistance and recurrence. Herein, a highly efficient magnetic-thermal conversion, ferrimagnetic vortex nanoring Fe3O4 coated with hyaluronic acid (HA) nanoparticles (Fe3O4@HA, FVNH NPs) was firstly constructed. Additionally, the doxorubicin (DOX) was successfully enclosed inside the FVNH and released remotely for synergetic magnetic-thermal/chemo cancer therapy. Due to the ferrimagnetic vortex-domain state, the ring shape Fe3O4 displays a high specific absorption rate (SAR) under an external alternating magnetic field (AMF). Additionally, antitumor drug (DOX) can be encapsulated inside the single large hole of FVNH by the hyaluronic acid (HA) shell and quickly released in response the tumor acidic microenvironments and AMF. What's more, the non-loaded FVNH NPs show good biocompatibility but high cytotoxicity after loading DOX under AMF. Furthermore, the synthesized FVNH can efficiently reduce the transverse relaxation time and enhance negative magnetic resonance imaging (MRI). The impressive in vivo systemic therapeutic efficacy of FVNH was also proved in this work. Taken together, the results of this study demonstrate that the synthesized FVNH NPs offer the promise of serving as multifunctional theranostic nanoplatforms for medical imaging-guided tumor therapies.

Advanced iron oxide nanotheranostics for multimodal and precision treatment of pancreatic ductal adenocarcinoma.

Despite current advances in new approaches for cancer detection and treatment, pancreatic cancer remains one of the most lethal cancer types. Difficult to detect early, aggressive tumor biology, and resistance to chemotherapy, radiotherapy, and immunotherapy result in a poor prognosis of pancreatic cancer patients with a 5-year survival of 10%. With advances in cancer nanotechnology, new imaging and drug delivery approaches that allow the development of multifunctional nanotheranostic agents offer opportunities for improving pancreatic cancer treatment using precision oncology. In this review, we will introduce potential applications of innovative theranostic strategies to address major challenges in the treatment of pancreatic cancer at different disease stages. Several important issues concerning targeted delivery of theranostic nanoparticles and tumor stromal barriers are discussed. We then focus on the development of a magnetic iron oxide nanoparticle platform for multimodal therapy of pancreatic cancer, including MRI monitoring targeted nanoparticle/drug delivery, therapeutic response, and tumor re-staging, activation of tumor immune response by immunoactivating nanoparticle and magnetic hyperthermia therapy, and intraoperative interventions for improving the outcome of targeted therapy. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Novel Strategies for Disrupting Cancer-Cell Functions with Mitochondria-Targeted Antitumor Drug-Loaded Nanoformulations.

Any variation in normal cellular function results in mitochondrial dysregulation that occurs in several diseases, including cancer. Such processes as oxidative stress, metabolism, signaling, and biogenesis play significant roles in cancer initiation and progression. Due to their central role in cellular metabolism, mitochondria are favorable therapeutic targets for the prevention and treatment of conditions like neurodegenerative diseases, diabetes, and cancer. Subcellular mitochondria-specific theranostic nanoformulations for simultaneous targeting, drug delivery, and imaging of these organelles are of immense interest in cancer therapy. It is a challenging task to cross multiple barriers to target mitochondria in diseased cells. To overcome these multiple barriers, several mitochondriotropic nanoformulations have been engineered for the transportation of mitochondria-specific drugs. These nanoformulations include liposomes, dendrimers, carbon nanotubes, polymeric nanoparticles (NPs), and inorganic NPs. These nanoformulations are made mitochondriotropic by conjugating them with moieties like dequalinium, Mito-Porter, triphenylphosphonium, and Mitochondria-penetrating peptides. Most of these nanoformulations are meticulously tailored to control their size, charge, shape, mitochondriotropic drug loading, and specific cell-membrane interactions. Recently, some novel mitochondria-selective antitumor compounds known as mitocans have shown high toxicity against cancer cells. These selective compounds form vicious oxidative stress and reactive oxygen species cycles within cancer cells and ultimately push them to cell death. Nanoformulations approved by the FDA and EMA for clinical applications in cancer patients include Doxil, NK105, and Abraxane. The novel use of these NPs still faces tremendous challenges and an immense amount of research is needed to understand the proper mechanisms of cancer progression and control by these NPs. Here in this review, we summarize current advancements and novel strategies of delivering different anticancer therapeutic agents to mitochondria with the help of various nanoformulations.