Biomedical nanoparticle carriers with combined thermal and magnetic responses

Several biocompatible polymers are capable of large responses to small temperature changes around 37ºC. In water, their responses include shrinkage and swelling as well as transitions in wettability. These properties have been harnessed for biomedical applications such as tissue engineering scaffolds and drug delivery carriers. A soft material/hard material hybrid in which a magnetic metal or oxide is embedded in a temperature-responsive polymer matrix can combine the thermal sensitivity with magnetic signatures. Importantly, nanosizing such construct brings about new desirable features of extremely fast thermal response time, small magnetic hysteresis and enhanced magnetic susceptibility. Remote magnetic maneuvering and heating of the hybrid nanocolloids makes possible such applications as high-throughput enzyme separation and cell screening. Robust drug release on demand may also be obtained using these colloids and nanoparticle-derived thin film devices of combined thermal magnetic sensitivity

Functional Nanoparticles for Tumor Penetration of Therapeutics

Theranostic nanoparticles recently received great interest for uniting unique functions to amplify therapeutic efficacy and reduce side effects. Despite the enhanced permeability and retention (EPR) effect, which amplifies the accumulation of nanoparticles at the site of a tumor, tumor heterogeneity caused by the dense extracellular matrix of growing cancer cells and the interstitial fluid pressure from abnormal angiogenesis in the tumor inhibit drug/particle penetration, leading to inhomogeneous and limited treatments. Therefore, nanoparticles for penetrated delivery should be designed with different strategies to enhance efficacy. Many strategies were developed to overcome the obstacles in cancer therapy, and they can be divided into three main parts: size changeability, ligand functionalization, and modulation of the tumor microenvironment. This review summarizes the results of ameliorated tumor penetration approaches and amplified therapeutic efficacy in nanomedicines. As the references reveal, further study needs to be conducted with comprehensive strategies with broad applicability and potential translational development

Hybrid polymeric nanoparticles with high zoledronic acid payload and proton sponge-triggered rapid drug release for anticancer applications

Zoledronic acid (ZA), a third-generation nitrogen-heterocycle-containing bisphosphonate, has been frequently used as an anti-resorptive agent to treat cancer-involved hypercalcemia and painful bone metastases. In order to expand the clinical applications of ZA toward the extraskeletal tumor treatment, it is essential to develop the functionalized nanocarriers capable of carrying high ZA payload and achieving intracellular triggered ZA release. In this end, the ZA-encapsulated hybrid polymeric nanoparticles were fabricated in this work by co-association of the amphiphilic diblock copolymer poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG), tocopheryl polyethylene glycol succinate (TPGS) segments and ionic complexes composed of ZA molecules and branched poly(ethylenimine) (PEI) segments. Notably, the ionic pairings of PEI segments with ZA molecules not only assisted encapsulation of ZA into the PLGA-rich core of hybrid nanoparticles but also reduced adhesion of ZA on the surfaces of hydrophobic cores, thus largely increasing ZA loading capacity. The dynamic light scattering (DLS) and transmission electron microscopy (TEM) characterization revealed that the ZA/PEI-loaded nanoparticles had a well-dispersed spherical shape. Moreover, compared to short PEI1.8k (1.8 kDa) segments, the longer PEI10k (10 kDa) segments formed more robust complexes with ZA molecules, thus prominently promoting ZA loading content of hybrid nanoparticles and their colloidal stability. Interestingly, with the suspension pH being reduced from 7.4 to 5.0, the considerable disruption of ZA/PEI ionic complexes owing to the acid-activated protonation of ZA molecules and the developed proton sponge-like effect inside the nanoparticle matrix upon the protonated PEI segments facilitated the rapid release of ZA molecules from drug-loaded hybrid nanoparticles. The results of in vitro cellular uptake and cytotoxicity studies showed that the ZA/PEI-loaded hybrid nanoparticles were internalized by MCF-7 cells upon energy-dependent endocytosis and displayed a superior cytotoxic effect to free ZA. This work demonstrates that the unique ZA/PEI-loaded hybrid polymeric nanoparticles display great promise for anticancer applications

Programmed Catalytic Therapy-Mediated ROS Generation and T-Cell Infiltration in Lung Metastasis by a Dual Metal-Organic Framework (MOF) Nanoagent

Nano-catalytic agents actuating Fenton-like reaction in cancer cells cause intratumoral generation of reactive oxygen species (ROS), allowing the potential for immune therapy of tumor metastasis via the recognition of tumor-associated antigens. However, the self-defense mechanism of cancer cells, known as autophagy, and unsustained ROS generation often restricts efficiency, lowering the immune attack, especially in invading metastatic clusters. Here, a functional core-shell metal-organic framework nanocube (dual MOF) doubling as a catalytic agent and T cell infiltration inducer that programs ROS and inhibits autophagy is reported. The dual MOF integrated a Prussian blue (PB)-coated iron (Fe2+)-containing metal-organic framework (MOF, MIL88) as a programmed peroxide mimic in the cancer cells, facilitating the sustained ROS generation. With the assistance of Chloroquine (CQ), the inhibition of autophagy through lysosomal deacidification breaks off the self-defense mechanism and further improves the cytotoxicity. The purpose of this material design was to inhibit autophagy and ROS efficacy of the tumor, and eventually improve T cell recruitment for immune therapy of lung metastasis. The margination and internalization-mediated cancer cell uptake improve the accumulation of dual MOF of metastatic tumors in vivo. The effective catalytic dual MOF integrated dysfunctional autophagy at the metastasis elicits the ~3-fold recruitment of T lymphocytes. Such synergy of T cell recruitment and ROS generation transported by dual MOF during the metastases successfully suppresses more than 90% of tumor foci in the lung

Injectable DNA-architected nanoraspberry depot-mediated on-demand programmable refilling and release drug delivery

Drug delivery depots boosting a local concentration of therapeutic agents have received great attention in clinical applications due to their low occurrence of side effects and high therapeutic efficacy. However, once the payload is exhausted, the local drug concentration will be lower than the therapeutic window. To address this issue, an injectable double-strand deoxyribonucleic acid (DNA)-architected nanoraspberry depot (DNR-depot) was developed that can refill doxorubicin (Dox, an anticancer drug) from the blood and remotely control drug release on demand. The large porous surface on a uniform nanoraspberry (NR) filled covalently with DNA serves as a Dox sponge-like refilling reservoir, and the NR serves as a magnetic electrical absorber. Via the strong affinity between Dox and DNA molecules, the refilling process of Dox can be achieved on DNR-depot both in vitro and in vivo. Upon high-frequency magnetic field (HFMF) treatment, the remotely triggered release of Dox is actuated by the dissociation of Dox and DNA molecules, facilitating an approximately 800% improvement in drug concentration at the tumor site compared to free Dox injection alone. Furthermore, the cycles of refilling and release can be carried out more than 3 times in vivo within 21 days. The combination of refilling and HFMF-programmable Dox release in tumors via DNR-depot can effectively inhibit tumor growth for 30 days

A Novel Oral Astaxanthin Nanoemulsion from Haematococcus pluvialis Induces Apoptosis in Lung Metastatic Melanoma

Astaxanthin (AST) is a naturally occurring xanthophyll carotenoid having the potential to be used as an anticancer agent; however, the human body has a low bioavailability of AST due to its poor solubility in the water phase. Therefore, we applied D-α-tocopheryl polyethylene glycol succinate (TPGS) as an emulsifier and natural edible peanut oil to form a steady oil-in-water (O/W) nanoemulsion loaded with AST (denoted as TAP-nanoemulsion). TAP-nanoemulsions were stable without the droplet coalescence against thermal treatments (30-90°C), pH value changes (over a range of 2.0-8.0), and ionic strength adjustments (at NaCl concentrations of 100-500 mM) measured by dynamic light scattering (DLS). AST within TAP-nanoemulsion was released up to 80% in a simulated intestinal enzymatic fluid in vitro, and the overall recovery rate was fairly consistent in the Caco-2 cellular model. In order to further evaluate in vivo melanoma inhibitory experiments, we injected the fluorescent-stained B16F10 cells into female C57BL/6 mouse tail veins and treated TAP-nanoemulsion in an oral gavage. qRT-PCR and Western blot demonstrated that TAP-nanoemulsion triggered effectively the apoptosis pathway, including enhancements of cleaved caspase-3 and caspase-9, ataxia-telangiectasia mutated kinase (ATM), and p21WAF1/CIP1 (p21) and decreases of B-cell lymphoma 2 (Bcl-2); cyclins D, D1, and E; mitogen-activated protein kinase (MEK); extracellular signal-regulated kinases (ERK); nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB); and matrix metallopeptidase-1 and metallopeptidase-9 (MMP-1 and MMP-9) in both gene and protein expressions. In conclusion, this study suggests that TAP-nanoemulsion with the oral treatment has a positive chemotherapy effect in melanoma with lung metastases in vivo. As far as we know, this is the first time to demonstrate that an antioxidant in nanoparticle administration cures lung metastatic melanoma

A Novel Oral Astaxanthin Nanoemulsion fromHaematococcus pluvialisInduces Apoptosis in Lung Metastatic Melanoma

Astaxanthin (AST) is a naturally occurring xanthophyll carotenoid having the potential to be used as an anticancer agent; however, the human body has a low bioavailability of AST due to its poor solubility in the water phase. Therefore, we applied D-α-tocopheryl polyethylene glycol succinate (TPGS) as an emulsifier and natural edible peanut oil to form a steady oil-in-water (O/W) nanoemulsion loaded with AST (denoted as TAP-nanoemulsion). TAP-nanoemulsions were stable without the droplet coalescence against thermal treatments (30-90°C), pH value changes (over a range of 2.0-8.0), and ionic strength adjustments (at NaCl concentrations of 100-500 mM) measured by dynamic light scattering (DLS). AST within TAP-nanoemulsion was released up to 80% in a simulated intestinal enzymatic fluid in vitro, and the overall recovery rate was fairly consistent in the Caco-2 cellular model. In order to further evaluate in vivo melanoma inhibitory experiments, we injected the fluorescent-stained B16F10 cells into female C57BL/6 mouse tail veins and treated TAP-nanoemulsion in an oral gavage. qRT-PCR and Western blot demonstrated that TAP-nanoemulsion triggered effectively the apoptosis pathway, including enhancements of cleaved caspase-3 and caspase-9, ataxia-telangiectasia mutated kinase (ATM), and p21WAF1/CIP1 (p21) and decreases of B-cell lymphoma 2 (Bcl-2); cyclins D, D1, and E; mitogen-activated protein kinase (MEK); extracellular signal-regulated kinases (ERK); nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB); and matrix metallopeptidase-1 and metallopeptidase-9 (MMP-1 and MMP-9) in both gene and protein expressions. In conclusion, this study suggests that TAP-nanoemulsion with the oral treatment has a positive chemotherapy effect in melanoma with lung metastases in vivo. As far as we know, this is the first time to demonstrate that an antioxidant in nanoparticle administration cures lung metastatic melanoma

Transdermal Composite Microneedle Composed of Mesoporous Iron Oxide Nanoraspberry and PVA for Androgenetic Alopecia Treatment

The transdermal delivery of therapeutic agents amplifying a local concentration of active molecules have received considerable attention in wide biomedical applications, especially in vaccine development and medical beauty. Unlike oral or subcutaneous injections, this approach can not only avoid the loss of efficacy of oral drugs due to the liver's first-pass effect but also reduce the risk of infection by subcutaneous injection. In this study, a magneto-responsive transdermal composite microneedle (MNs) with a mesoporous iron oxide nanoraspberry (MIO), that can improve the drug delivery efficiency, was fabricated by using a 3D printing-molding method. With loading of Minoxidil (Mx, a medication commonly used to slow the progression of hair loss and speed the process of hair regrowth), MNs can break the barrier of the stratum corneum through the puncture ability, and control the delivery dose for treating androgenetic alopecia (AGA). By 3D printing process, the sizes and morphologies of MNs is able to be, easily, architected. The MIOs were embedded into the tip of MNs which can deliver Mx as well as generate mild heating for hair growth, which is potentially attributed by the expansion of hair follicle and drug penetration. Compared to the mice without any treatments, the hair density of mice exhibited an 800% improvement after being treated by MNs with MF at 10-days post-treatment