Dual Stimuli-responsive Nanoparticles Research Articles

The Smart Dual-Stimuli Responsive Nanoparticles for Controlled Anti-Tumor Drug Release and Cancer Therapy.

In recent years, the emergence of stimuli-responsive nanoparticles has made drug delivery more efficient. As an intelligent and effective targeted delivery platform, it can reduce the side effects generated during drug transportation while enhancing the treatment efficacy. The stimuli-responsive nanoparticles can respond to different stimuli at corresponding times and locations to deliver and release their drugs and associated therapeutic effects. This review aims to inform researchers on the latest advances in the application of dual-stimuli responsive nanoparticles in precise drug delivery, with special attention to their design, drug release properties, and therapeutic effects. Syntheses of nanoparticles with simultaneous or sequential responses to two or more stimuli (pH-redox, pH-light, redox-light, temperature-magnetic, pH-redox-temperature, redox-enzyme-light, etc.) and the applications of such responsivity properties for drugs control and release have become a hot topic of recent research. A database of relevant information for the production of this review was sourced, screened and analyzed from Pubmed, Web of Science, SciFinder by searching for the following keywords: "dual-stimuli responsive", "controlled release", "cancer therapy", "synergistic treatment". Notably, the nanoparticles with dual-stimuli responsive function have an excellent control effect on drug delivery and release, playing a crucial part in the treatment of tumors. They can improve the encapsulation and delivery efficiency of hydrophobic chemotherapy drugs, combine chemo-photothermal therapies, apply imaging function in the diagnosis of tumors and even conduct multi-drug delivery to overcome Multi-Drug Resistance (MDR). With the development of smart dual-stimuli responsive nanoparticles, cancer treatment methods have become more diverse and effective. All the stimuli-responsive nanoparticles functionalities exhibit their characteristics individually within the single nanosystem.

Tumor microenvironment targeting with dual stimuli-responsive nanoparticles based on small heat shock proteins for antitumor drug delivery

Tumour microenvironment (TME)-targeting nanoparticles (NPs) were developed based on Methanococcus jannaschii small heat shock proteins (Mj-sHSPs). Transactivator of transcription (TAT) were modified on the surface of Mj-sHSPs (T-HSPs) to enhance their cellular internalization ability (CIA), and a pH/enzyme dual sensitive PEG/N-(2-aminoethyl)piperidine-hyaluronic acid (PAHA) coat was combined with T-HSPs (PT-HSPs). PT-HSP NPs exhibited multi-layered morphologies and good stability against plasma protein adsorption. The release of paclitaxel (PTX) from PT-HSP NPs was negligible at physiological pH. Under conditions similar to the TME (acidic pH and overexpressed hyaluronidase (HAase)), the PAHA coat deshielded from PT-HSP NPs because of two factors: charge reversal and HAase degradation. Once the PAHA coat was shed, the size of the NPs decreased; its surface charge became positive; and remarkable drug release was triggered. Cellular experiments indicated that the CIA of PT-HSPs was shielded in the microenvironment of normal cells and recovered in that of tumour cells. In vivo imaging exhibited that the PT-HSP NPs had an impressive tumour targeting ability compared with the uncoated controls. The antitumor efficacy in vivo demonstrated that tumour-bearing mice treated with PTX-loaded PT-HSP NPs achieved better anti-tumour effects and safety than the Taxol formulation. In summary, this study provided Mj-sHSP NPs with coats that could be shed in response to the particular pH and enzymes in the TME, which improved the efficacy of tumour therapy. Statement of significanceThis study reports on tumor microenvironment-targeting protein-based nanoparticles (PT-HSP NPs) for targeted tumor therapy. The NPs had a multilayered structure: a protein cage, a TAT cationic layer, and a dual-sensitive coat. PT-HSP NPs exhibited multilayered morphology, with good stability against plasma protein adsorption, and PTX release negligible at physiological pH. Under the tumor microenvironment (acidic pH and overexpressed HAase), PAHA coat deshielded from PT-HSP NPs due to two factors: the charge reversal induced by protonation of piperidines in PAHA and HAase degradation. The results of cellular uptake, cytotoxicity, in vivo imaging, and tumor inhibition experiments confirmed that PT-HSP NPs exhibited promising tumor targeting efficacy in vitro and in vivo.

PH/redox dual response nanoparticles with poly-γ-glutamic acid for enhanced intracellular drug delivery

Stimuli-responsive nanomaterials drug delivery systems have attracted much attention owing to the ability to deliver drugs to designated locations especially for tumor cells. Here, positively and negatively charged pH/redox dual stimuli-responsive nanoparticles (NPs) were prepared with biocompatible poly-γ-glutamic acid (γ-PGA), cysteine (Cys), and chitosan (CS) through amide bond and electrostatic interactions. These nanocarriers (γ-PGA-S-S-CS NPs) were used to load the anticancer drug doxorubicin (DOX) to reduce toxicity to normal cells and increase uptake by tumor cells. The drug-loaded nanoparticles γ-PGA-S-S-CS-DOX NPs were characterized via DLS, XRD, FT-IR and TEM techniques. The DOX was released from γ-PGA-S-S-CS-DOX NPs under an acidic and redox environment, while the nanoparticles were kept stable under physiological conditions. in vitro cytotoxicity studies showed that the drug carriers do not impair the growth of cells, and cellular uptake experiments indicated that the drug-loaded NPs were taken up easily by tumor cells compared with the free drug. The results suggested that the dual response nanosystem carrier can be applied to the targeted delivery of other drugs in the cancer field.

Dual stimuli-responsive polypyrrole nanoparticles for anticancer therapy

We report the development of dual stimuli-responsive nanoparticles with potential for anticancer therapy. The nanoparticles are composed of a conjugated polymer (polypyrrole, PPY) loaded with an anticancer drug (allicin), and were characterized by a variety of physicochemical techniques. The dual stimuli-responsive nature of the PPY nanoparticles was validated in vitro: the PPY nanoparticles delivered an anticancer drug (allicin) in response to exposure to an electric field in vitro as demonstrated with UV–vis spectroscopy; and the PPY nanoparticles exhibited photothermal activity upon irradiation with near infrared light which resulted in resulted in toxicity towards HEP G2 cells in vitro. We believe that such nanoparticles have long term potential for application in cancer therapy in a variety of tissue niches (e.g. breast cancer, liver cancer, lung cancer, skin cancer).

Dual-stimuli responsive nanoparticles (UCNP-CD@APP) assembled by host-guest interaction for drug delivery

In this paper, dual-sensitive nanoparticles with pH- and photo- responsibility were prepared through host-guest interaction. Self-synthesized copolymer azobenzene -poly-2-(diisopropylamino) ethyl methacrylate – methoxypolyethylene glycols (AZO-PDPAn-PEG45, APP) acted as a guest and inserted into the host cyclodextrins (β-CD) automatically, which had been grafted onto the surface of upconversion nanoparticle (UCNP-CD). The insertion of APP was reversibly due to the alternating cis-trans isomerism of AZO under UV and Vis light, which produced simultaneously by UCNP when irradiated by near-infrared (NIR, 980nm). And, the PDPA block provided a pH sensitive “lock” for releasing cargos. The self-assembled UCNP-CD@APPs were tried to incorporate anti-cancer drug DOX and were proved to release DOX controllably under stimulus of pH and NIR. During the whole process, the reversible isomerism behavior of AZO acted as a ‘perpetual stirrer’ resulting in a quick release. The UCNP-CD@APP nanoparticles displayed good biocompatibility via MTT assay. Meanwhile, the DOX loaded in UCNP-CD@APP exhibited an obvious cytotoxic effect on HeLa cells than free DOX.

Dual Stimuli-Responsive Nanoparticles for Controlled Release of Anticancer and Anti-inflammatory Drugs Combination.

Dual stimuli-responsive nanoparticles capable of fine-tuning drug release to augment therapeutic efficacy have become a promising tool for anticancer drug delivery. However, the rational design of these "smart" nanoparticles for a selective delivery and controlled release of multidrug combinations in cancer cells to achieve synergistic effects remain challenging. Here we report the pH/redox dual responsive nanoparticle FA-DOX-Ind-NP (FA=folic acid, DOX=doxorubicin, Ind=indomethacin, NP=nanoparticle) based on the novel tumor targeting and biodegradable poly(β-amino ester) polymer, and demonstrate its high ability to enter into cancer cells and release a combination of the anticancer drug doxorubicin and the non-steroidal anti-inflammatory drug indomethacin to achieve synergistic chemo-anti-inflammatory effects and overcome multidrug resistance. This study highlights the great potential of tumor targeting and dual stimuli-responsive nanoparticles for an efficient delivery of multidrug combination to improve the cancer therapeutic efficacy.