Manipulating the Crosstalk between Cancer and Immunosuppressive Cells with Phototherapeutic Gold-Nanohut for Reprogramming Tumor Microenvironment.

Photoimmunotherapy faces challenges due to insufficient intratumoral accumulation of photothermal agents and the reversion of the cancer-immunity cycle during treatment. In this study, an anti-PD-L1-immobilized magnetic gold nanohut, AuNH-2-Ab, with photoresponsive, thermosensitive, and immunomodulatory properties to effectively suppress the growth of primary tumors, elevate immunogenic cell death (ICD) levels, reverse the tumor immune microenvironment (TIME), and consequently inhibit metastases are developed. AuNH-2-Ab achieves high tumor accumulation (9.54% injected dose) following systemic administration, allowing the modulation of hyperthermia dose of over 50 °C in the tumor. By optimizing the hyperthermia dose, AuNH-2-Ab simultaneously target and eliminate cancer cells and tumor-associated macrophages, thereby activating potent antitumor immunity without being compromised by immunosuppressive elements. Hyperthermia/pH induced morphological transformation of AuNH-2-Ab involving the detachment of the surface antibody for in situ PD-L1 inhibition, and exposure of the inner fucoidan layer for natural killer (NK) cell activation. This precision photoimmunotherapy approach reprograms the TIME, significantly prolongs survival in a murine hepatocellular carcinoma model (Hep55.1c), and harnesses the synergistic effects of ICD production and checkpoint inhibitors by utilizing a single nanoplatform.

Stem cell-nanomedicine system as a theranostic bio-gadolinium agent for targeted neutron capture cancer therapy.

The potential clinical application of gadolinium-neutron capture therapy (Gd-NCT) for glioblastoma multiforme (GBM) treatment has been compromised by the fast clearance and nonspecific biodistribution of gadolinium-based agents. We have developed a stem cell-nanoparticle system (SNS) to actively target GBM for advanced Gd-NCT by magnetizing umbilical cord mesenchymal stem cells (UMSCs) using gadodiamide-concealed magnetic nanoparticles (Gd-FPFNP). Nanoformulated gadodiamide shielded by a dense surface composed of fucoidan and polyvinyl alcohol demonstrates enhanced cellular association and biocompatibility in UMSCs. The SNS preserves the ability of UMSCs to actively penetrate the blood brain barrier and home to GBM and, when magnetically navigates by an external magnetic field, an 8-fold increase in tumor-to-blood ratio is achieved compared with clinical data. In an orthotopic GBM-bearing rat model, using a single dose of irradiation and an ultra-low gadolinium dose (200 µg kg-1), SNS significantly attenuates GBM progression without inducing safety issues, prolonging median survival 2.5-fold compared to free gadodiamide. The SNS is a cell-based delivery system that integrates the strengths of cell therapy and nanotechnology, which provides an alternative strategy for the treatment of brain diseases.

Fucoidan-Based Nanoparticles with Inherently Therapeutic Efficacy for Cancer Treatment.

The anticancer properties of fucoidan have been widely studied in cancer research. However, the lack of safety information on the parenteral administration of fucoidan and its rapid clearance from the system have limited its application. Herein, we assessed the therapeutic efficacy and safety of fucoidan and developed fucoidan nanoparticles (FuNPs) to enhance their therapeutic effect in the mouse model of breast cancer. FuNPs were synthesized through the emulsion method, and the stable colloid has an average size of 216.3 nm. FuNPs were efficiently internalized into breast cancer cells in vitro, demonstrating an enhanced antitumor activity in comparison with free form fucoidan. After the treatment of FuNPs, the tumor progression was significantly inhibited in viv. The tumor volume was reduced by 2.49-fold compared with the control group. Moreover, the inhibition of the invasion of tumor cells into the lungs revealed the antimetastatic properties of the FuNPs. FuNPs, as naturally marine polysaccharide-based nanoparticles, have shown their broader therapeutic window and enhanced antimetastatic ability, opening an avenue to the development of the inherently therapeutic nanomedicines.

Tumor cell-targeting radiotherapy in the treatment of glioblastoma multiforme using linear accelerators.

Although boron neuron capture therapy (BNCT) has enabled the delivery of stronger radiation dose to glioblastoma multiforme (GBM) cells for precision radiotherapy (RT), patients in need are almost unable to access the treatment due to insufficient operating devices. Therefore, we developed targeted sensitization-enhanced radiotherapy (TSER), a strategy that could achieve precision cell-targeted RT using common linear accelerators. TSER, which involves the combination of GoldenDisk (GD; a spherical radioenhancer), 5-aminolevulinic acid (5-ALA), low-intensity ultrasound (US), and low-dose RT, exhibited synergized radiosensitization effects. Both 5-ALA and hyaluronic-acid-immobilized GD can selectively accumulate in GBM to induce chemical and biological enhancement of radiosensitization, resulting in DNA damage, escalation of reactive oxygen species levels, and cell cycle redistribution, in turn sensitizing GBM cells to radiation under US. TSER showed an enhanced therapeutic effect and survival in the treatment of an orthotropic GBM model with only 20% of the radiation dose compared to that of a 10-Gy RT. The strategy with the potential to inhibit GBM progress and rescue the organ at risk using low-dose RT, thereby improving the quality of life of GBM patients, shedding light on achieving cell-targeted RT using universally available linear accelerators. STATEMENT OF SIGNIFICANCE: We invented GoldenDisk (GD), a radioenhancer with hyaluronic-acid (HAc)-coated gold nanoparticle (AuNP)-core/silica shell nanoparticle, to make radiotherapy (RT) safer and smarter. The surface modification of HAc and silica allows GD to target CD44-overexpressed glioblastoma multiforme (GBM) cells and stay structurally stable in cytoplasm throughout the course of RT. By combining GD with low-energy ultrasound and an FDA-approved imaging agent, 5-aminolevulinic acid (5-ALA), GBM cells were sensitized to RT leaving healthy tissues in the vicinity unaffected. The ionized radiation can further be transferred to photoelectronic products with higher cytotoxicity by GD upon collision, achieving higher therapeutic efficacy. With the newly-developed strategy, we are able to achieve low-dose precision RT with the use of only 20% radiation dose.

Advances in Magnetic Nanoparticle-Mediated Cancer Immune-Theranostics.

Cancer immunotherapy is a cutting-edge strategy that eliminates cancer cells by amplifying the host's immune system. However, the low response rate and risks of inducing systemic toxicity have raised uncertainty in the treatment. Magnetic nanoparticles (MNPs) as a versatile theranostic tool can be used to target delivery of multiple immunotherapeutics and monitor cell/tissue responses. These capabilities enable the real-time characterization of the factors that contribute to immunoactivity so that future treatments can be optimized. The magnetic properties of MNPs further allow the implementation of magnetic navigation and magnetic hyperthermia for boosting the efficacy of immunotherapy. The multimodal approach opens an avenue to induce robust immune responses, minimize safety issues, and monitor immune activities simultaneously. Thus, the object of this review is to provide an overview of the burgeoning fields and to highlight novel technologies for next-generation immunotherapy. The review further correlates the properties of MNPs with the latest treatment strategies to explore the crosstalk between magnetic nanomaterials and the immune system. This comprehensive review of MNP-derived immunotherapy covers the obstacles and opportunities for future development and clinical translation.

Dextran-modified Quercetin-Cu(II)/hyaluronic acid nanomedicine with natural poly(ADP-ribose) polymerase inhibitor and dual targeting for programmed synthetic lethal therapy in triple-negative breast cancer.

Serious side effects from chemotherapies are the main problem with cancer treatments. To solve these issues, precision cancer nanomedicine based on natural therapeutic materials is developed, which enables specifically apoptosis by interacting with genetic mutation in cancer cells, while leaving normal cells unaffected. Here, we report a novel nanomedicine (CuQDA/IO@HA) composed of hyaluronic acid (HA) / copper ion (Cu(II))-chelated dextran-aldehyde (DA)-quercetin (Q) with dual targeting for synthetic lethal therapy. The CuQDA/IO@HA prepared using a ratio of metal/Q at 0.5:1 resulted in a stable particle structure with uniform particle distribution. The CuQDA/IO@HA can specifically target and induce specific cytotoxicity in BRCA-mutant cancer cells in vitro. Combination treatment with CuQDA/IO@HA and magnetic navigation can induce poly (ADP-ribose) polymerase (PARP) inhibition and DNA damage in BRCA-mutant triple-negative breast cancer (TNBC) via CD44 targeting. The dual-targeting CuQDA/IO@HA can extend the median survival of the BRCA-mutant xenograft mice from 34 to 61 days in comparison to Q treatment alone in vivo, which is attributed to the significant increase in γH2AX, leading to significant apoptosis. More importantly, the CuQDA/IO@HA displayed biocompatibility and no obvious side-effect in normal organs. These results demonstrate the promising potential of integrating natural and metal ions into a nanomedicine that can provide precision medicine through synthetic lethality.

Development and Characterization of a Fucoidan-Based Drug Delivery System by Using Hydrophilic Anticancer Polysaccharides to Simultaneously Deliver Hydrophobic Anticancer Drugs.

Fucoidan, a natural sulfated polysaccharide, which can activate the immune response and lessen adverse effects, is expected to be an adjuvant agent in combination with chemotherapy. Using natural hydrophilic anticancer polysaccharides to simultaneously encapsulate hydrophobic anticancer drugs is feasible, and a reduced side effect can be achieved to amplify the therapeutic efficacy. In this study, a novel type of fucoidan-PLGA nanocarrier (FPN-DTX) was developed for the encapsulation of the hydrophobic anticancer drug, docetaxel (DTX), as a drug delivery system. From the comparison between FPN-DTX and the PLGA particles without fucoidan (PLGA-DTX), FPNs-DTX with fucoidan were highly stable with smaller sizes and dispersed well without aggregations in an aqueous environment. The drug loading and release can be further modified by modulating relative ratios of Fucoidan (Fu) to PLGA. The (FPN 3-DTX) nanoparticles with a 10:3 ratio of Fu:PLGA displayed uniform particle size with higher encapsulation efficiency than PLGA NPs and sustained drug release ability. The biocompatible fucoidan-PLGA nanoparticles displayed low cytotoxicity without drug loading after incubation with MDA-MB-231 triple-negative breast cancer cells. Despite lower cellular uptake than that of PLGA-DTX due to a higher degree of negative zeta potential and hydrophilicity, FPN 3-DTX effectively exerted better anticancer ability, so FPN 3-DTX can serve as a competent drug delivery system.

Circulating tumor-cell-targeting Au-nanocage-mediated bimodal phototherapeutic properties enriched by magnetic nanocores.

Metastasis resulting from circulating tumor cells (CTCs) is associated with 90% of all cancer mortality. To disrupt cancer dissemination, therapeutic targeting of CTCs by extracorporeal photodynamic therapy (PDT) has emerged; however, it still remains impractical due to its limited therapeutic window. Herein, we developed a photosensitive and magnetic targeted core-satellite nanomedicine (TCSN) to augment the light-induced damage to the targeted cells. The magnetic nanocore (MNC) with multiple iron oxide nanoparticles stabilized using thiolated polyvinyl alcohol can magnetize the CTCs to achieve magnetic enrichment under a magnetic field. Multiple gold nanocage (AuNC) satellites were conjugated on the MNC to facilitate bimodal photothermal therapy and PDT. Adjusting the thiol content in the MNC allows manipulating the AuNC density on TCSNs, which has been found to demonstrate a density-dependent bimodal phototherapeutic effect under laser irradiation at 808 and 940 nm. Moreover, with the immobilization of anti-epithelial cell adhesion molecule (anti-EpCAM), TCSN exhibited an enhanced affinity toward EpCAM-expressing 4T1 cells. We demonstrate that TCSN-labeled 4T1 cells can be isolated and photo-eradicated in a microfluidic channel with a dynamic flow. Our studies showed that TCSN with the complementary properties of MNC and AuNCs can largely augment the therapeutic window by magnetic enrichment and bimodal phototherapy, serving as an advanced extracorporeal strategy to remove CTCs.

One-stop radiotherapeutic targeting of primary and distant osteosarcoma to inhibit cancer progression and metastasis using 2DG-grafted graphene quantum dots.

The application of radiotherapy (RT) to treat osteosarcoma (OS) has been limited, but this is starting to change as the ability to target radiation energy to niches improves. Furthermore, lung cancer from highly metastatic OS is a major cause of death, so it is critical to explore new strategies to tackle metastasis. In this study, we designed a nanoscale radiosensitizer by grafting 2-deoxy-d-glucose (2DG) onto graphene quantum dots (GQD) to achieve OS targeting and boost RT efficacy. Combining the use of 2DG-grafted GQDs (2DG-g-GQD) with RT produced a significant increase in oxidative stress response and DNA damage in the 143B OS cell line compared with RT alone. Moreover, 2DG-g-GQDs selectively associated with 143B cells, and demonstrated the inhibition of migration in a scratch assay. We also demonstrated remarkable improvement in their ability to inhibit tumour progression and lung metastasis in an OS xenograft mouse model. Our results show that the use of 2DG-g-GQDs as OS-targeting radiosensitizers improves their therapeutic outcome and exhibits potential for use in low-dose precision RT for OS.

Dual-drug nanomedicine with hydrophilic F127-modified magnetic nanocarriers assembled in amphiphilic gelatin for enhanced penetration and drug delivery in deep tumor tissue.

INTRODUCTION: Deep penetration of large-sized drug nanocarriers into tumors is important to improve the efficacy of tumor therapy. METHODS: In this study, we developed a size-changeable "Trojan Horse" nanocarrier (THNC) composed of paclitaxel (PTX)-loaded Greek soldiers (GSs; ~20 nm) assembled in an amphiphilic gelatin matrix with hydrophilic losartan (LST) added. RESULTS: With amphiphilic gelatin matrix cleavage by matrix metalloproteinase-2, LST showed fast release of up to 60% accumulated drug at 6 h, but a slow release kinetic (~20%) was detected in the PTX from the GSs, indicating that THNCs enable controllable release of LST and PTX drugs for penetration into the tumor tissue. The in vitro cell viability in a 3D tumor spheroid model indicated that the PTX-loaded GSs liberated from THNCs showed deeper penetration as well as higher cytotoxicity, reducing a tumor spheroid to half its original size and collapsing the structure of the tumor microenvironment. CONCLUSION: The results demonstrate that the THNCs with controlled drug release and deep penetration of magnetic GSs show great potential for cancer therapy.

Using the interplay of magnetic guidance and controlled TGF-ß release from protein-based nanocapsules to stimulate chondrogenesis.

INTRODUCTION: Stimulating the proliferation and differentiation of chondrocytes for the regeneration of articular cartilage is a promising strategy, but it is currently ineffective. Although both physical stimulation and growth factors play important roles in cartilage repair, their interplay remains unclear and requires further investigation. In this study, we aimed to clarify their contribution using a magnetic drug carrier that not only can deliver growth factors but also provide an external stimulation to cells in the two-dimensional environment. MATERIALS AND METHODS: We developed a nanocapsule (transforming growth factor-ß1 [TGF-ß1]-loaded magnetic amphiphilic gelatin nanocapsules [MAGNCs]; TGF-ß1@MAGNCs) composed of hexanoic-anhydride-grafted gelatin and iron oxide nanoparticles to provide a combination treatment of TGF-ß1 and magnetically induced physical stimuli. With the expression of Arg-Gly-Asp peptide in the gelatin, the TGF-ß1@MAGNCs have an inherent affinity for chondrogenic ATDC5 cells. RESULTS: In the absence of TGF-ß1, ATDC5 cells treated with a magnetic field show significantly upregulated Col2a1 expression. Moreover, TGF-ß1 slowly released from biodegradable TGF-ß1@ MAGNCs further improves the differentiation with increased expression of Col2a1 and Aggrecan. CONCLUSION: Our study shows the time-dependent interplay of physical stimuli and growth factors on chondrogenic regeneration, and demonstrates the promising use of TGF-ß1@MAGNCs for articular cartilage repair.

Combination of fucoidan-based magnetic nanoparticles and immunomodulators enhances tumour-localized immunotherapy.

Checkpoint immunotherapy that inhibits tumour immune evasion has demonstrated significant clinical success. However, the therapeutic response is limited to certain patient populations, and immunotoxicity as well as autoimmunity have compromised the therapeutic benefits. Here, we report on an inherently therapeutic fucoidan-dextran-based magnetic nanomedicine (IO@FuDex3) conjugated with a checkpoint inhibitor (anti-PD-L1) and T-cell activators (anti-CD3 and anti-CD28). IO@FuDex3 can repair the immunosuppressive tumour microenvironment by reinvigorating tumour-infiltrating lymphocytes, while targeting the nanomedicine via magnetic navigation to the tumour to minimize off-target effects. Treatment that combines IO@FuDex3 and magnetic navigation reduces the occurrence of adverse events and extends the median survival from 32 to 63 days with less than 1 per cent dose compared with soluble anti-PD-L1. Thus, we demonstrate the potential of integrating anti-PD-L1 and T-cell activators as a form of inherently therapeutic nanomedicine to augment the therapeutic index of combination checkpoint immunotherapy.

Multistage Continuous Targeting with Quantitatively Controlled Peptides on Chitosan-Lipid Nanoparticles with Multicore-Shell Nanoarchitecture for Enhanced Orally Administrated Anticancer In Vitro and In Vivo.

A DOX-loaded polysaccharide-lecithin reverse micelles triglyceride-based oral delivery nanocarrier (D-PL/TG NPs) conjugated with (i) RGD peptide for targeting to ß1 integrin of M cells and (ii) Lyp-1 peptide for targeting to the p32 receptor of MDA-MB-231 cells is used to investigate the multistage continuous targeting capabilities of these peptide-conjugated nanocarriers (GLD-PL/TG NPs) for tumor therapy. Variations in the targeting efficacy and pharmacokinetic properties are investigated by quantitatively controlling the surface density of different peptides on the nanoparticles. In vitro permeability in a human follicle-associated epithelium model and cytotoxicity against MDA-MB-231 cells indicate that the nanocarriers conjugated with high RGD peptide concentrations display a higher permeability due to the existence of M cells with higher transcytosis activity, but a higher concentration of conjugated Lyp-1 peptide exhibits the lowest cell viability. Being benefited from specific targeting of peptide conjugation, improved bioavailability and enhanced tumor accumulation are achieved by the GLD-PL/TG NPs, leading to better antitumor efficacy. The results of in vivo biodistribution and antitumor studies reveal that the effect of LyP-1 peptide is more predominant than that of RGD peptide. This proof of multistage continuous targeting may open the door to a new generation of oral drug delivery systems in targeted cancer therapy.

Synergistic Combination of Multistage Magnetic Guidance and Optimized Ligand Density in Targeting a Nanoplatform for Enhanced Cancer Therapy.

A new therapeutic strategy of combining multistage short-term magnetic guidance with optimized ligand-mediated targeting in a newly developed nanodelivery system is investigated to promote accumulation and modulate intratumoral distribution behavior of the nanocarriers for enhanced tumor therapy. The multifunctional magnetic nanocarriers (MNCs) composed of single-component thiol-functionalized PVA/PMASH copolymer and superparamagnetic nanoparticles are developed for providing tunable dual-targeting ability and simultaneously modulating pH-responsive on/off drug release. Results show that plasma doxorubicin (Dox) concentration of the mice treated with Trastuzumab (Tra)-targeted Dox-MNCs can be rapidly decreased by applying dual-targeting treatment. More importantly, cooperative modulation of magnetic targeting and Tra density on the nanocarrier significantly optimize intratumoral distribution and enhance the utilization rate of nanomedicines within tumor to inhibit tumor growth. The mice treated with 2T-Dox-MNCs + multistage magnetic targeting (MT) (2 h d(-1) ) show 7.63-fold, 3.25-fold, and 2.7-fold reduction in HER2-positive tumor volume compared to Dox-MNCs, 2T-Dox-MNCs, and 2T-Dox-MNCs + single MT (12 h). The synergistic dual-targeting approach represents a major paradigm advance in tumor treatment and nanocarrier design in preclinical application.

Amifostine-conjugated pH-sensitive calcium phosphate-covered magnetic-amphiphilic gelatin nanoparticles for controlled intracellular dual drug release for dual-targeting in HER-2-overexpressing breast cancer.

We developed a surfactant-free method utilizing amifostine to stably link a targeting ligand (Herceptin) to amphiphilic gelatin (AG)-iron oxide@calcium phosphate (CaP) nanoparticles with hydrophobic curcumin (CUR) and hydrophilic doxorubicin (DOX) encapsulated in the AG core and CaP shell (AGIO@CaP-CD), respectively. This multi-functional nanoparticle system has a pH-sensitive CaP shell and degradable amphiphilic gelatin (AG) core, which enables controllable sequential release of the two drugs. The dual-targeting system of AGIO@CaP-CD (HER-AGIO@CaP-CD) with a bioligand and magnetic targeting resulted in significantly elevated cellular uptake in HER2-overexpressing SKBr3 cells and more efficacious therapy than delivery of targeting ligand alone due to the synergistic cell multi-drug resistance/apoptosis-inducing effect of the CUR and DOX combination. This nanoparticle combined with Herceptin and iron oxide nanoparticles not only provided a dual-targeting functionality, but also encapsulated CUR and DOX as a dual-drug delivery system for the combination therapy. This study further demonstrated that the therapeutic efficacy of this dual-targeting co-delivery system can be improved by modifying the application duration of magnetic targeting, which makes this combination therapy system a powerful new tool for in vitro/in vivo cancer therapy, especially for HER2-positive cancers.

Magnetically Targeted Nanocapsules for PAA-Cisplatin-Conjugated Cores in PVA/SPIO Shells via Surfactant-Free Emulsion for Reduced Nephrotoxicity and Enhanced Lung Cancer Therapy.

Cis-diamminedichloroplatinum (II) (cisplatin, CDDP) is one of the most potent chemotherapy agents, but its side effects toward normal tissues, particularly toxicity in the kidney and nonspecific biodistribution, limit its ability to have significant clinical activity against a variety of solid tumors. A magnetic CDDP-encapsulated nanocapsule (CDDP-PAA-NC) with CDDP-polyacrylic acid (PAA) core in amphiphilic polyvinyl alcohol/superparamagnetic iron oxide nanoparticles shell is synthesized through a double emulsion to provide both high loading efficiency and controlled drug release. The CDDP-PAA-NCs significantly increase the blood circulation time of CDDP in vivo, with nearly 100-fold higher concentration, and drastically reduce side effects, including nephrotoxicity and hepatotoxicity, compared with the delivery of free CDDP. Furthermore, with a magnetic targeting effect, the CDDP-PAA-NCs show ninefold higher level accumulation in tumor tissue than the free CDDP treatment when administered at the equivalent dose, and mice treated with the CDDP-PAA-NCs display approximately 3.5-fold lower tumor volume than those of the control group on day 24. This result demonstrates that the magnetic CDDP-PAA-NCs, which are synthesized using a facile emulsion process, can significantly reduce toxicity and exhibit anticancer activity in A549-tumor bearing mice with negligible side effects.

A multitheragnostic nanobubble system to induce blood-brain barrier disruption with magnetically guided focused ultrasound.

A novel magnetically guidable nanobubble is designed for disrupting the blood-brain barrier (BBB) by combining magnetic guidance with focused ultrasound in vivo. The magnetic-nanobubble platform also demonstrates the potential to serve as a unique theranostic tool via performing focused ultrasound (FUS)-induced BBB disruption and magnetic resonance imaging (MRI)/ultrasound dual-modality contrast-agent imaging to improve the drug delivery of therapeutic substances or gene therapy into the central nervous system.

Multifunctional nanocarriers for simultaneous encapsulation of hydrophobic and hydrophilic drugs in cancer treatment.

Combination therapy for cancer patients is an important standard of care protocol because it can elicit synergistic therapeutic effects and reduce systemic toxicity by simultaneously modulating multiple cell-signaling pathways and overcoming multidrug resistance. Nanocarriers are expected to play a major role in delivering multiple drugs to tumor tissues by overcoming biological barriers. However, especially considering the different physical chemistry of chemotherapeutic drugs, it is highly desirable to develop a codelivery nanocarrier for controlled and targeted delivery of both hydrophobic and hydrophilic drugs. This review reports the recent developments in various combinational drug delivery systems and the simultaneous use of combinational drug delivery systems with functional agents.

Enhancement of cancer therapy efficacy by trastuzumab-conjugated and pH-sensitive nanocapsules with the simultaneous encapsulation of hydrophilic and hydrophobic compounds.

Trastuzumab-conjugated pH-sensitive double emulsion nanocapsules (DENCs) stabilized by a single-component Poly (vinyl alcohol) (PVA) with magnetic nanoparticles can be fabricated through a two-step double emulsion process; these nanocapsules can be used to encapsulate hydrophilic doxorubicin (Dox) and hydrophobic paclitaxel (PTX) simultaneously. When PMASH was attached to the shell of the DENCs, enhanced dual drug release of PTX/Dox was detected, specifically in intracellular acidic pH environments. The targeting ability of these Trastuzumab-conjugated DENCs was demonstrated with confocal images, which revealed a significantly elevated cellular uptake in HER-2 overexpressing SkBr3 cells. More importantly, an intravenous injection of this co-delivery system followed by magnetic targeting (MT) chemotherapy suppressed cancer growth in vivo more efficiently than the delivery of either PTX or Dox alone. The integration of the functionalities makes this combination therapy system a powerfully new tool for in vitro/in vivo cancer therapy, especially for in HER-2 positive cancers. FROM THE CLINICAL EDITOR: Trastuzumab-conjugated pH-sensitive nanocapsules were used in this study for simultaneous targeted delivery of hydrophobic (PTX) and hydrophilic (Dox) anti-cancer agents to HER-2 positive cancer cells. Additional use of magnetic targeting demonstrated superior efficacy of this delivery system compared to PTX or Dox alone.

SPIO nanoparticle-stabilized PAA-F127 thermosensitive nanobubbles with MR/US dual-modality imaging and HIFU-triggered drug release for magnetically guided in vivo tumor therapy.

Nanobubbles can serve as promising, next-generation theranostic platforms for ultrasound (US) and magnetic resonance (MR) imaging, and combined magnetic targeting (MT) and high-intensity focused ultrasound (HIFU)-triggered drug release for tumor therapy. Nanobubble-based dual contrast enhancement agents encapsulated with perfluoropentane and stabilized with superparamagnetic iron oxide (SPIO) nanoparticles have been synthesized through a single-step emulsion process from thermosensitive F127 and polyacrylic acid (PAA). Both US and MR imaging contrast can be optimized by varying the shell thickness and SPIO-embedded concentration. The US contrast can be enhanced from a mean gray value of 62 to 115, and the MR r2 value can be enhanced from 164 to 208 (s(-1)mM (-1)Fe) by increasing the SPIO concentration from 14.1 to 28.2mg/mL, respectively. In vivo investigations of SPIO-embedded nanobubbles in excised tumors under external MT revealed that the US and MR signals change quantitatively compared to the same site without MT. This combined strategy enables the nanobubbles to enhance both passive targeting (increasing the permeability by HIFU) and physical MT of chemotherapeutic drugs to tumors. The integration of functionalities makes this nanobubble system a powerful and viable new tool to achieve simultaneous in vivo tumor imaging and efficacious cancer therapy.