Near-infrared Light-triggered Drug Release Research Articles

Gold nanorods-encapsulated thermosensitive drug carriers for NIR light-responsive anticancer therapy

Thermoresponsive polymers incorporated with photo-absorbing agents have been widely utilized for controlled drug delivery using light as an external stimulus. However, previously developed thermoresponsive drug carriers have disadvantages such as low biocompatibility and implantation failure. In the present study, gold nanorods (GNRs)-encapsulated poly(N-vinyl caprolactam) (PVCL) (GNR-PVCL) microparticles were synthesized by the stop-flow lithography (SFL) method. The SFL method enabled the fabrication of near-infrared (NIR) light-responsive GNR-PVCL microparticles of uniform size, which can allow localized injection. Doxorubicin (DOX) was encapsulated into GNR-PVCL microparticles to achieve NIR light-responsive anticancer therapy. DOX-loaded GNR-PVCL (DOX-GNR-PVCL) microparticles exhibited NIR light-triggered drug release due to the photothermal effect of GNRs, which increases the local temperature above the volume phase transition temperature of GNR-PVCL microparticles. In addition, DOX-GNR-PVCL exhibited controlled DOX release in response to the periodic irradiation of NIR light. Moreover, we demonstrated the efficient intracellular release of DOX upon NIR light exposure, and thus, NIR light-responsive anticancer activity. This study demonstrates that DOX-GNR-PVCL microparticles have significant potential as implantable drug carriers enabling NIR light-triggered drug release.

Near-Infrared Light-Triggered Drug Release from Ultraviolet- and Redox-Responsive Polymersome Encapsulated with Core-Shell Upconversion Nanoparticles for Cancer Therapy.

Combining upconversion nanoparticles (UCNPs) and UV-sensitive polymers to form a smart drug delivery system (DDS) is a promising strategy to circumvent drawbacks of direct UV excitation in clinical applications. This study tuned up core-shell UCNPs with a shell thickness of 6 nm and emission wavelength falling in the ultraviolet region at 350 nm under near-infrared (NIR) light irradiation at 980 nm. An amphiphilic block copolymer with UV-responsive o-nitrobenzyl ester (ONB) next to a glutathione (GSH)-responsive disulfide linkage was synthesized and formulated into a polymersome. Core-shell UCNPs and doxorubicin (DOX) were simultaneously encapsulated into the polymersome during double emulsion for DDS. The combination of NIR light-inducing photolysis of the ONB linkage and GSH cleaving the disulfide linkage enhanced DOX release for chemotherapy. From in vitro evaluation, the polymersome alone was nontoxic against three lung cancer cell lines, but the one loaded with core-shell UCNPs and DOX showed severe cell-killing effect under the assistance of a 980 nm diode laser. In vivo study in A549 tumor-bearing mice verified significant inhibition of tumor growth in mice treated with the polymersome containing core-shell UCNPs and DOX under 980 nm diode laser irradiation as compared with those without laser irradiation and those treated with free DOX. This intriguing nanomedicine of well-defined structures responsive to NIR light and reducing agents offers potential for smart DDS applications.

Dynamic-Covalent Hydrogel with NIR-Triggered Drug Delivery for Localized Chemo-Photothermal Combination Therapy.

Near-infrared (NIR) light-responsive, injectable hydrogels are among the most promising drug delivery systems for localized anticancer therapy owing to its minimally invasive administration and remote-controlled manner. However, most currently reported NIR-responsive hydrogels were usually generated through physical mixing of thermosensitive polymers and photothermal conversion agents. In this study, a novel type of dynamic-covalent hydrogel (GelPV-DOX-DBNP) with NIR light-triggered drug release behavior was rationally designed for chemo-photothermal combination treatment of tumors. Concretely, this NIR-responsive hydrogel was formed by specific benzoxaborole-carbohydrate interactions between benzoxaborole (BOB)-modified hyaluronic acid (BOB-HA) and fructose-based glycopolymer (PolyFru), where photosensitizer perylene diimide zwitterionic polymer (PDS), reductant ascorbic acid (Vc), anticancer drug doxorubicin (DOX) as well as photothermal nanoparticles (DB-NPs) were encapsulated, simultaneously. Upon 660 nm light irradiation, both PDS and Vc within the designed hydrogel can convert oxygen into hydrogen peroxide, which could make hydrogel be degraded through the breakage of dynamic covalent bonds based on benzoxaborole-carbohydrate interactions, leading to NIR light-activatable release of DOX and DB-NPs from GelPV-DOX-DBNP. Furthermore, the released DB-NPs can convert 915 nm light irradiation into heat, enabling the application of GelPV-DOX-DBNP as a NIR-responsive drug delivery platform for both chemotherapy and photothermal therapy (PTT). In vivo results prove that GelPV-DOX-DBNP exhibited a markedly enhanced chemo-photothermal synergistic therapy for 4T1 tumor model mice, compared to chemotherapy alone or PTT. This work presents a new strategy to construct NIR light-responsive hydrogel as one alternative drug delivery system for anticancer applications.

Remote Light-Responsive Nanocarriers for Controlled Drug Delivery: Advances and Perspectives.

Engineering of smart photoactivated nanomaterials for targeted drug delivery systems (DDS) has recently attracted considerable research interest as light enables precise and accurate controlled release of drug molecules in specific diseased cells and/or tissues in a highly spatial and temporal manner. In general, the development of appropriate light-triggered DDS relies on processes of photolysis, photoisomerization, photo-cross-linking/un-cross-linking, and photoreduction, which are normally sensitive to ultraviolet (UV) or visible (Vis) light irradiation. Considering the issues of poor tissue penetration and high phototoxicity of these high-energy photons of UV/Vis light, recently nanocarriers have been developed based on light-response to low-energy photon irradiation, in particular for the light wavelengths located in the near infrared (NIR) range. NIR light-triggered drug release systems are normally achieved by using two-photon absorption and photon upconversion processes. Herein, recent advances of light-responsive nanoplatforms for controlled drug release are reviewed, covering the mechanism of light responsive small molecules and polymers, UV and Vis light responsive nanocarriers, and NIR light responsive nanocarriers. NIR-light triggered drug delivery by two-photon excitation and upconversion luminescence strategies is also included. In addition, the challenges and future perspectives for the development of light triggered DDS are highlighted.

Microfluidic fabrication of fatty alcohol-based microparticles for NIR light-triggered drug release

The development of photo-triggered drug delivery system is promising for the temporal and spatial control of drug release. However, most of the progress in photothermal drug delivery has been focused on nanosized particles which can be removed from the injected sites by exocytosis. In this study, injectable and implantable near-infrared (NIR) light-responsive microparticles are fabricated using droplet-based microfluidics. The particles are composed of 1-tetradecanol, as a class of non-toxic phase change material, and IR780, as a NIR-absorbing photothermal agent. Doxorubicin, an anticancer drug, is encapsulated in the particles to obtain NIR light-responsive anticancer drug carriers. The photothermal response of IR780 to NIR irradiation facilitates the release of the encapsulated drug through the melting of 1-tetradecanol and demonstrates the NIR light-responsive drug release. This study shows that IR780-encapsulated 1-tetradecanol microparticles fabricated by droplet-based microfluidics have great potential as injectable and implantable drug carriers featuring NIR light-sensitive drug release.

Multifunctional Thermosensitive Liposomes Based on Natural Phase-Change Material: Near-Infrared Light-Triggered Drug Release and Multimodal Imaging-Guided Cancer Combination Therapy.

Multifunctional theranostic nanoplatforms (NPs) in response to environment stimulations for on-demand drug release are highly desirable. Herein, the near-infrared (NIR)-absorbing dye, indocyanine green (ICG), and the antitumor drug, doxorubicin (DOX), were efficiently coencapsulated into the thermosensitive liposomes based on natural phase-change material. Folate and conjugated gadolinium (Gd) chelate-modified liposome shells enhance active targeting and magnetic resonance performance of the NPs while maintaining the size of the NPs. The ICG/DOX-loaded and gadolinium chelate conjugated temperature-sensitive liposome nanoplatforms (ID@TSL-Gd NPs) exhibited NIR-triggered drug release and prominent chemo-, photothermal, and photodynamic therapy properties. With the coencapsulated ICG, DOX, and the conjugated gadolinium chelates, the ID@TSL-Gd NPs can be used for triple-modal imaging (fluorescence/photoacoustic/magnetic resonance imaging)-guided combination tumor therapy (chemotherapy, photothermotherapy, and photodynamic therapy). After tail vein injection, the ID@TSL-Gd NPs accumulated effectively in subcutaneous HeLa tumor of mice. The tumor was effectively suppressed by accurate imaging-guided NIR-triggered phototherapy and chemotherapy, and no tumor regression and side effects were observed. In summary, the prepared ID@TSL-Gd NPs achieved multimodal imaging-guided cancer combination therapy, providing a promising platform for improving diagnosis and treatment of cancer.

Gold Nanocage-Incorporated Poly(ε-Caprolactone) (PCL) Fibers for Chemophotothermal Synergistic Cancer Therapy.

This paper introduces a new fibrous system for synergistic cancer therapy, which consists of gold nanocage (AuNC)-loaded poly(ε-caprolactone) (PCL) fibers with encapsulation of a chemotherapeutic anticancer drug in their core and loading of a phase-changeable fatty acid in their sheath. Under on–off switching of near-infrared (NIR) light irradiation, the excellent photothermal ability and photostability of AuNCs allows repeated, significant heating of the fibers to a temperature available to hyperthermia. Simultaneously, the NIR light-induced heat generation enables the melting out of the loaded fatty acid, leading to a rapid release of the drug molecules from the fibers. The combination of this NIR light-triggered drug release with the repeated hyperthermia treatment exhibits excellent anticancer efficacy.

Near-infrared light triggered drug release from mesoporous silica nanoparticles.

Stimuli triggered drug delivery systems enable controlled release of drugs at the optimal space and time, thus achieving optimal therapeutic effects. As one of the most important stimuli used in bioapplications, near-infrared (NIR) light possesses unique advantages such as deep tissue penetration with minimum auto-fluorescence & tissue scattering and high biosafety. Mesoporous silica nanoparticles (MSNs) are one of the most studied nanocarriers; apart from having a high surface area and large pore volume for loading of drugs, they can be easily functionalized with inorganic nanomaterials and stimuli responsive polymers or organic switch molecules, creating possibilities for designing complex stimuli triggered drug delivery systems. Considering the high tissue penetration depth of NIR light and the unique mesoporous structure of MSNs, NIR responsive inorganic nanoparticle functionalized MSNs can be further combined with stimuli responsive materials to form smart "nano-devices" for controlled drug delivery toward tumors, and to date much progress has been made. In this article, recent advances in the design of NIR triggered mesoporous silica drug delivery systems are systematically summarized and some outstanding studies are highlighted. We will also discuss the shortcomings, challenges and opportunities in the field.

Near-infrared light-triggered drug release from UV-responsive diblock copolymer-coated upconversion nanoparticles with high monodispersity.

The preparation of a new near-infrared (NIR) light-responsive nanocarrier for controlled drug release is demonstrated. Upconversion nanoparticles (UCNPs) were coated with an amphiphilic diblock copolymer through surface-initiated atom transfer radical polymerization, in which the inner block is hydrophobic, ultraviolet (UV)-sensitive poly(4,5-dimethoxy-2-nitrobenzyl methacrylate) (PNB), and the outer block is hydrophilic poly(methoxy polyethylene glycol monomethacrylate) (POEG). The resulting polymer/UCNP nanocarrier is thermally stable in water over a wide temperature range (5-70 °C) and is uniform in size (120 nm hydrodynamic diameter, polydispersity index <0.1). The diblock copolymer self-assembly on the surface of each UCNP occurs in aqueous solution, which allows encapsulation of antitumor drugs like doxorubicin (DOX) by the hydrophobic "micelle-like" core of PNB surrounding the NIR-sensitive UCNP. Under 980 nm laser exposure, the UV light emitted by the single UCNP is absorbed by the PNB inner layer, which results in cleavage of o-nitrobenzyl groups and formation of carboxylic acid groups. The increasing hydrophilicity of the diblock copolymer resulting from the NIR light-triggered photochemical reaction can thus disrupt the nanocarrier and leads to the release of DOX molecules. This diblock copolymer self-assembly-based approach to constructing NIR light-responsive nanocarriers of well-defined structures is general and offers possibilities for photocontrolled drug delivery.

A novel reactive oxygen species-responsive polymeric micelle for near-infrared light-triggered drug release in cancer cells

A novel reactive oxygen species-responsive polymeric micelle for near-infrared light-triggered drug release in cancer cells

Near-infrared light-triggered drug release from a multiple lipid carrier complex using an all-in-one strategy

The present study reports a drug delivery system comprising nanostructured lipid carrier (NLCs) within liposomes (Lip-NLCs). This multiple lipid carrier complex features laser-triggered responsive drug release. Both hydrophobic and hydrophilic drugs can be loaded into the same formulation by applying an all-in-one strategy. We hypothesized that if we loaded the hydrophobic near-infrared (NIR) dye IR780 into the liposome phospholipid bilayer, the bilayer would be disrupted by laser irradiation so that drug release would be triggered remotely at the tumor site. We used in vitro and in vivo methods to verify that laser irradiation facilitated controlled release of both hydrophobic and hydrophilic drugs. The degree of drug release triggered by NIR laser light could be adjusted by varying the laser intensity and irradiation time. Following laser treatment, hydrophilic AMD3100 was released from the aqueous liposome chamber and then bound with CXCR4 receptors on the tumor cell surface to inhibit metastasis. NLCs carrying lipophilic IR780 were also released from the aqueous chamber of liposomes and taken up into tumor cells to enhance the photothermal therapeutic effect of IR780. More importantly, Lip-NLCs loaded with IR780 and AMD3100 (IR780-AMD-Lip-NLCs) exhibited enhanced anti-tumor and anti-metastasis effects. These results suggest that Lip-NLCs are a safe and simply prepared all-in-one platform for delivery of drugs with different solubilities. This system facilitates easily controlled release of cargoes to achieve multi-functional combined therapy.

Near-infrared light-activatable polymeric nanoformulations for combined therapy and imaging of cancer

Near infrared (NIR) light allows deep tissue penetration and high spatial resolution due to the reduced scattering of long-wavelength photons. NIR light-activatable polymer nanoparticles are widely exploited for enhanced cancer imaging (diagnosis) and therapy owing to their superior photostability, photothermal conversion efficiency (or high emission rate), and minimal toxicity to cells and tissues. This review surveys the most recent advances in the synthesis of different NIR-absorbing and emissive polymer nanoformulations, and their applications for cancer imaging, photothermal therapy, theranostics and combination therapy by delivering multiple small molecule chemotherapeutics. Photo-responsive drug delivery systems for NIR light-triggered drug release are also discussed with particular emphasis on their molecular designs and formulations as well as photo-reaction mechanisms. Finally, outlook and challenges are presented regarding potential clinical applications of NIR light-activatable nanoformulations.

Remotely controlled red blood cell carriers for cancer targeting and near-infrared light-triggered drug release in combined photothermal chemotherapy

Red blood cells (RBCs), the “innate carriers” in blood vessels, are gifted with many unique advantages in drug transportation over synthetic drug delivery systems (DDSs). Herein, a tumor angiogenesis targeting, light stimulus-responsive, RBC-based DDS is developed by incorporating various functional components within the RBC platform. An albumin bound near-infrared (NIR) dye, together with a chemotherapy drug doxorubicin, is encapsulated inside RBCs, the surfaces of which are modified with a targeting peptide to allow cancer targeting. Under stimulation by an external NIR laser, the membrane of the RBCs would be destroyed by the light-induced photothermal heating, resulting in effective drug release. As a proof of principle, RBC-based cancer cell targeted drug delivery and light-controlled drug release is demonstrated in vitro, achieving a marked synergistic therapeutic effect through the combined photothermal–chemotherapy. This work presents a novel design of smart RBC carriers, which are inherently biocompatible, promising for targeted combination therapy of cancer.

Sphingomyelin Liposomes Containing Porphyrin-phospholipid for Irinotecan Chemophototherapy.

Porphyrin-phospholipid (PoP) liposomes can entrap anti-cancer agents and release them in response to near infrared (NIR) light. Doxorubicin, when remotely loaded via an ammonium sulfate gradient at a high drug-to-lipid ratio, formed elongated crystals that altered liposome morphology and could not be loaded into liposomes with higher PoP content. On the other hand, irinotecan could also be remotely loaded but did not form large crystals and did not induce liposome elongation. The loading, stability, and NIR light-triggered release of irinotecan in PoP liposomes was altered by the types of lipids used and the presence of PEGylation. Sphingomyelin, which has been explored previously for liposomal irinotecan, was found to produce liposomes with relatively improved serum stability and rapid NIR light-triggered drug release. PoP liposomes composed from sphingomyelin, cholesterol and 2 molar percent PoP rapidly released irinotecan in vivo in response to NIR irradiation as monitored by intravital microscopy and also induced effective tumor eradication in mice bearing MIA Paca-2 subcutaneous tumor xenografts.

Near-infrared light-triggered drug release nanogels for combined photothermal-chemotherapy of cancer.

Near-infrared (NIR) light-triggered drug release systems are promising for drug delivery applications in view of the advantages of NIR light, which include high tissue penetration and low damage. In this report, we developed nanogels (NGs) by supramolecular self-assembly from adamantine (AD)-conjugated copolymer, poly[poly(ethylene glycol)monomethyl ether metharcylate]-co-poly(N-(2-hydroxypropyl)methacrylamide)-co-poly(N-adamantan-1-yl-2-methacrylamide) (PPEGMA-co-PHPMA-co-PADMA), and β-cyclodextrin (β-CD)-functionalized poly(amidoamine) (PAMAM) dendrimer based on the host-guest interaction of the AD and β-CD moieties, and they were used to encapsulate indocyanine green (ICG) and doxorubicin (DOX) for combined photothermal-chemotherapy. NGs simultaneously loading ICG and DOX (DINGs) showed significant photothermal effects and stimuli-triggered drug release under NIR laser irradiation by the photothermal-induced relaxation or dissociation of the NGs. In vitro cytotoxicity evaluation of DINGs under NIR irradiation demonstrated the synergistic effects of hyperthermia, photothermal-triggered drug release, and chemotherapy. In vivo investigation revealed their high accumulation in tumor tissue and significant tumor growth suppression under NIR irradiation. These NIR light-triggered drug release NGs represent efficient and promising anticancer drug vectors for the combined photothermal-chemotherapy of cancer to maximize therapeutic efficacy and minimize side effects.

Biointerfacing polymeric microcapsules for in vivo near-infrared light-triggered drug release.

Seeking safe and effective water-soluble drug carriers is of great significance in nanomedicine. To achieve this goal, we present a novel drug delivery system based on biointerfacing hollow polymeric microcapsules for effectively encapsulating water-soluble antitumor drug and gold nanorod (GNR) functionalization for triggered release of therapeutic drugs on-demand using low power near-infrared (NIR) radiation. The surface of polymeric microcapsules is covered with fluidic lipid bilayers to decrease the permeability of the wall of polymeric capsules. The temperature increase upon NIR illumination deconstructs the structure of the lipid membrane and polyelectrolyte multilayers, which in turn results in the rapid release of encapsulated water-soluble drug. In vivo antitumor tests demonstrate that this microcapsule has the effective ability of inhibiting tumor growth and preventing metastases. Real time in vivo fluorescence imaging results confirm that capsules can be excreted gradually from the animal body which in turn demonstrates the biocompatibility and biodegradation of these biointerfacing GNR-microcapsules. This intelligent system provides a novel anticancer platform with the advantages of controlled release, biological friendliness and credible biosafety.

Fabrication of Upconverting Hybrid Nanoparticles for Near-Infrared Light Triggered Drug Release

Low tissue penetration and harmful effects of (ultraviolet) UV or visible light on normal tissue limit exploiting nanocarriers for the application of light-controlled drug release. Two strategies may solve the problem: one is to improve the sensitivity of the nanocarriers to light to decrease the radiation time; the other one is using more friendly light as the trigger. In this work, we fabricated a core-shell hybrid nanoparticle with an upconverting nanoparticle (UCNP) as the core and thermo- and light-responsive block copolymers as the shell to combine the two strategies together. The results indicated that the sensitivity of the block copolymer to light could be enhanced by decreasing the photolabile moieties in the polymer, and the UCNP could transfer near-infrared (NIR) light, which is more friendly to tissue and cell, to UV light to trigger the phase conversion of the block polymersin situ. Using Nile Red (NR) as the model drug, the hybrid nanoparticles were further proved to be able to act as carriers with the character of NIR triggered drug release.

Targeting Chemophotothermal Therapy of Hepatoma by Gold Nanorods/Graphene Oxide Core/Shell Nanocomposites

Nanographene oxide (NGO) are highly suitable to be the shells of inorganic nanomaterials to enhance their biocompatibility and hydrophilicity for biomedical applications while retaining their useful photonic, magnetic, or radiological functions. In this study, a novel nanostructure with gold nanorods (AuNRs) encapsulated in NGO shells is developed to be an ultraefficient chemophotothermal cancer therapy agent. The NGO shells decrease the toxicity of surfactant-coated AuNRs and provide anchor points for the conjugation of hyaluronic acid (HA). The HA-conjugated NGO-enwrapped AuNR nanocomposites (NGOHA-AuNRs) perform higher photothermal efficiency than AuNRs and have the capability of targeting hepatoma Huh-7 cells. NGOHA-AuNR is applied to load doxorubicin (DOX), and it exhibits pH-responsive and near-infrared light-triggered drug-release properties. Chemophotothermal combined therapy by NGOHA-AuNRs-DOX performs 1.5-fold and 4-fold higher targeting cell death rates than single chemotherapy and photothermal therapy, respectively, with biosafety to nontargeting cells simultaneously. Furthermore, our strategy could be extended to constructing other NGO-encapsulated functional nanomaterial-based carrier systems.

Upconversion Nanoparticles for Photodynamic Therapy and Other Cancer Therapeutics

Photodynamic therapy (PDT) is a non-invasive treatment modality for a variety of diseases including cancer. PDT based on upconversion nanoparticles (UCNPs) has received much attention in recent years. Under near-infrared (NIR) light excitation, UCNPs are able to emit high-energy visible light, which can activate surrounding photosensitizer (PS) molecules to produce singlet oxygen and kill cancer cells. Owing to the high tissue penetration ability of NIR light, NIR-excited UCNPs can be used to activate PS molecules in much deeper tissues compared to traditional PDT induced by visible or ultraviolet (UV) light. In addition to the application of UCNPs as an energy donor in PDT, via similar mechanisms, they could also be used for the NIR light-triggered drug release or activation of 'caged' imaging or therapeutic molecules. In this review, we will summarize the latest progresses regarding the applications of UCNPs for photodynamic therapy, NIR triggered drug and gene delivery, as well as several other UCNP-based cancer therapeutic approaches. The future prospects and challenges in this emerging field will be also discussed.

Exceptionally High Payload of Doxorubicin in Hollow Gold Nanospheres for Near-Infrared Light-Triggered Drug Release

We report dual-functional hollow gold nanospheres (HAuNS, approximately 40-nm diameter) capable of mediating both photothermal ablation of cancer cells and drug release upon near-infrared (NIR) light irradiation. As high as 63% DOX by weight ( approximately 1.7 microg DOX/microg Au) could be loaded to polyethylene glycol (PEG)-coated HAuNS since DOX was coated to both the outer and the inner surfaces of HAuNS. Irradiation with NIR laser induced photothermal conversion, which triggered rapid DOX release from DOX-loaded HAuNS. The release of DOX was also pH-dependent, with more DOX released in aqueous solution at lower pH. Significantly greater cell killing was observed when MDA-MB-231 cells incubated with DOX-loaded HAuNS were irradiated with NIR light, attributable to both HAuNS-mediated photothermal ablation and cytotoxicity of released free DOX.