Multifunctional Nanomedicine Research Articles

Bifunctional Elastin-like Polypeptide Nanoparticles Bind Rapamycin and Integrins and Suppress Tumor Growth in Vivo.

Recombinant protein-polymer scaffolds such as elastin-like polypeptides (ELPs) offer drug-delivery opportunities including biocompatibility, monodispersity, and multifunctionality. We recently reported that the fusion of FK-506 binding protein 12 (FKBP) to an ELP nanoparticle (FSI) increases rapamycin (Rapa) solubility, suppresses tumor growth in breast cancer xenografts, and reduces side effects observed with free-drug controls. This new report significantly advances this carrier strategy by demonstrating the coassembly of two different ELP diblock copolymers containing drug-loading and tumor-targeting domains. A new ELP nanoparticle (ISR) was synthesized that includes the canonical integrin-targeting ligand (Arg-Gly-Asp, RGD). FSI and ISR mixed in a 1:1 molar ratio coassemble into bifunctional nanoparticles containing both the FKBP domain for Rapa loading and the RGD ligand for integrin binding. Coassembled nanoparticles were evaluated for bifunctionality by performing in vitro cell-binding and drug-retention assays and in vivo MDA-MB-468 breast tumor regression and tumor-accumulation studies. The bifunctional nanoparticle demonstrated superior cell target binding and similar drug retention to FSI; however, it enhanced the formulation potency, such that tumor growth was suppressed at a 3-fold lower dose compared to an untargeted FSI-Rapa control. This data suggests that ELP-mediated scaffolds are useful tools for generating multifunctional nanomedicines with potential activity in cancer.

Bioreducible Hydrophobin-Stabilized Supraparticles for Selective Intracellular Release.

One of the main hurdles in nanomedicine is the low stability of drug–nanocarrier complexes as well as the drug delivery efficiency in the region-of-interest. Here, we describe the use of the film-forming protein hydrophobin HFBII to organize dodecanethiol-protected gold nanoparticles (NPs) into well-defined supraparticles (SPs). The obtained SPs are exceptionally stable in vivo and efficiently encapsulate hydrophobic drug molecules. The HFBII film prevents massive release of the encapsulated drug, which, instead, is activated by selective SP disassembly triggered intracellularly by glutathione reduction of the protein film. As a consequence, the therapeutic efficiency of an encapsulated anticancer drug is highly enhanced (2 orders of magnitude decrease in IC50). Biodistribution and pharmacokinetics studies demonstrate the high stability of the loaded SPs in the bloodstream and the selective release of the payloads once taken up in the tissues. Overall, our results provide a rationale for the development of bioreducible and multifunctional nanomedicines.

Stable and Multifunctional Dye-Modified Black Phosphorus Nanosheets for Near-Infrared Imaging-Guided Photothermal Therapy

Nanomedicines intergrating both therapy and diagnosis functions provide promising strategy for anticancer treatment. As novel 2D materials, black phosphorus nanosheets (BPs) possess unique properties for biomedical applications, partically for photothermal therapy (PTT) of cancer, but its lack of air- and water-stability may hinder its application. Herein, a covalent functionalization strategy based on Nile Blue (NB) dye via diazonium chemistry is established to modify BPs, not only enhancing the stability of BPs, but also rendering BPs near-infrared (NIR) fluorescence, forming a novel multifunctional nanomedicine with both PTT and NIR-imaging capabilities. In vitro tests demonstrate that the dye-modified BPs (named NB@BPs) have good biocompatibility, and exhibit strong PTT and NIR-imaging efficiency. In vivo experiments show that the NB@BPs can mark the tumor site with red fluorescence, and lead efficient tumor ablation under NIR-irradiation. These results reveal a potential BPs-based nanomedicine with m...

Dacarbazine-Loaded Hollow Mesoporous Silica Nanoparticles Grafted with Folic Acid for Enhancing Antimetastatic Melanoma Response.

Dacarbazine (DTIC) is one of the most important chemotherapeutic agents for the treatment of melanoma; however, its poor solubility, photosensitivity, instability, and serious toxicity to normal cells limit its clinical applications. In this article, we present a rationally designed nanocarrier based on hollow mesoporous silica nanoparticles (HMSNs) for the encapsulation and targeted release of DTIC for eradicating melanoma. The nanocarrier (DTIC@HMLBFs) is prepared by modifying HMSNs with carboxyl groups to enhance the loading of DTIC, followed by further enveloping of folic acid-grafted liposomes, which act as a melanoma active target for controlled and targeted drug release. In vitro, DTIC@HMLBFs exhibited the strongest cytotoxicity to melanoma cells compared with DTIC@HMSNs and free DTIC. The in vivo investigations demonstrate that the rationally designed nanocarrier loaded with DTIC achieves significant improvement against lung metastasis of melanoma via targeting melanoma cells and tumor-associated macrophages. This study provides a promising platform for the design and fabrication of multifunctional nanomedicines, which are potentially useful for the treatment of melanoma.

A multifunctional lipid nanoparticle for co-delivery of paclitaxel and curcumin for targeted delivery and enhanced cytotoxicity in multidrug resistant breast cancer cells.

The objective of the work was to develop a multifunctional nanomedicine based on a folate-conjugated lipid nanoparticles loaded with paclitaxel and curcumin. The novel system combines therapeutic advantageous of efficient targeted delivery via folate and timed-release of curcumin and paclitaxel via 2-hydroxypropyl-ß-cyclodextrin, thereby overcoming multidrug resistance in breast cancer cells (MCF-7/ADR). The faster release of curcumin from the folate-conjugated curcumin and paclitaxel-loaded lipid nanoparticles enables sufficient p-glycoprotein inhibition, which allows increased cellular uptake and cytotoxicity of paclitaxel. In western blot assay, curcumin can efficiently inhibit the expression of p-glycoprotein, conformed the enhancement of cytotoxicity by paclitaxel. Furthermore, folate-conjugated curcumin and paclitaxel-loaded lipid nanoparticles exhibited increased uptake of paclitaxel and curcumin into MCF-7/ADR cells through the folate receptor-mediated internalization. Taken together, these results indicate that folate-conjugated curcumin and paclitaxel-loaded lipid nanoparticles enables the enhanced, folate-targeted delivery of multiple anticancer drugs by inhibiting the multi-drug resistance efficiently, which may also serve as a useful nano-system for co-delivery of other anticancer drugs.

Redox-responsive theranostic nanoplatforms based on inorganic nanomaterials

Spurred on by advances in materials chemistry and nanotechnology, scientists have developed many novel nanopreparations for cancer diagnosis and therapy. To treat complex malignant tumors effectively, multifunctional nanomedicines with targeting ability, imaging properties and controlled drug release behavior should be designed and exploited. The therapeutic efficiency of loaded drugs can be dramatically improved using redox-responsive nanoplatforms which can sense the differences in the redox status of tumor tissues and healthy ones. Redox-sensitive nanocarriers can be constructed from both organic and inorganic nanomaterials; however, at present, drug delivery nanovectors progressively lean towards inorganic nanomaterials because of their facile synthesis/modification and their unique physicochemical properties. In this review, we focus specifically on the preparation and application of redox-sensitive nanosystems based on mesoporous silica nanoparticles (MSNs), carbon nanomaterials, magnetic nanoparticles, gold nanomaterials and other inorganic nanomaterials. We discuss relevant examples of redox-sensitive nanosystems in each category. Finally, we discuss current challenges and future strategies from the aspect of material design and practical application.

Multifunctional nanospheres for co-delivery of methotrexate and mild hyperthermia to colon cancer cells

A multifunctional nanomedicine platform was designed and evaluated for efficient colon cancer therapy by a combinatorial therapeutic approach based on a chemotherapeutic drug and mild hyperthermia. Advantage was taken from the dual role of methotrexate (MTX), as folate receptor-targeting, overexpressed in tumor cells, and as anticancer drug. Incorporation of superparamagnetic iron oxide nanoparticles (SPIONs) allows to heat cancer cells externally through an alternating magnetic field. The developed nanocarrier was based on polyethylene glycol–polylactic acid (PEG-PLA) nanospheres to improve biocompatibility, enhancing their targeting by prolonging blood circulation time. By an emulsion-evaporation method the nanospheres were produced and then characterized for size distribution, zeta-potential, in vitro drug release profile and cellular studies. The co-delivery of MTX and SPIONs on PEG-PLA nanospheres resulted in nanocarriers with a size of 160nm in diameter, a polydispersity index below 0.2 and a zeta potential of ca. −18mV. Multifunctional nanospheres were monodisperse and stable up to 3months. MTX was released preferentially under mild hyperthermia conditions. The multifunctional nanospheres were able to increase the cytotoxicity of MTX towards Caco-2 and SW-480 colon cancer cells, in comparison to free drug. Also, the nanospheres allowed the incorporated MTX to induce greater cell cycle arrest and apoptotic effects than the free MTX. This study provides evidences that MTX-SPIONs-PEG-PLA nanospheres are a promising solution to address colorectal cancer over-expressing folate receptors, by a combinatory approach.

Engineered Multifunctional Nanomedicine for Simultaneous Stereotactic Chemotherapy and Inhibited Osteolysis in an Orthotopic Model of Bone Metastasis.

A novel multifunctional Ag2 S quantum dot (QD)-based nanomedicine of alendronate (Ald)/doxorubicin (DOX)@Ag2 S is developed for highly effective bone tumor therapy in an orthotopic model. The bone-targeting and osteolysis inhibition of Ald and the chemotherapeutic effect of DOX on the bone tumor are in situ visualized by Ag2 S QDs with emission in the second near-infrared window.

Robust, Responsive, and Targeted PLGA Anticancer Nanomedicines by Combination of Reductively Cleavable Surfactant and Covalent Hyaluronic Acid Coating.

PLGA-based nanomedicines have enormous potential for targeted cancer therapy. To boost their stability, targetability, and intracellular drug release, here we developed novel multifunctional PLGA anticancer nanomedicines by combining a reductively cleavable surfactant (RCS), vitamin E-SS-oligo(methyl diglycol l-glutamate), with covalent hyaluronic acid (HA) coating. Reduction-sensitive HA-coated PLGA nanoparticles (rHPNPs) were obtained with small sizes of 55-61 nm and ζ potentials of -26.7 to -28.8 mV at 18.4-40.3 wt % RSC. rHPNPs were stable against dilution and 10% FBS while destabilized under reductive condition. The release studies revealed significantly accelerated docetaxel (DTX) release in the presence of 10 mM glutathione. DTX-rHPNPs exhibited potent and specific antitumor effect to CD44 + A549 lung cancer cells (IC50 = 0.52 μg DTX equiv/mL). The in vivo studies demonstrated that DTX-rHPNPs had an extended circulation time and greatly enhanced tolerance in mice. Strikingly, DTX-rHPNPs completely inhibited growth of orthotopic human A549-Luc lung tumor in mice, leading to a significantly improved survival rate and reduced adverse effect as compared to free DTX. This study highlights that advanced nanomedicines can be rationally designed by combining functional surfactants and surface coating.

Preparation and Characterization of Folate-Targeted Fe3O4 Nanoparticle Codelivering Cisplatin and TFPI-2 Plasmid DNA for Nasopharyngeal Carcinoma Therapy

A novel folate (FA) receptor-targeted superparamagnetic Fe3O4 nanoparticles (SPIONs) codelivering cisplatin (CDDP) and tissue factor pathway inhibitor-2 (TFPI-2) plasmid DNA (pDNA) was constructed. The core shell nanocomposites (FA-PEG-PEI@SPION-CDDP-TFPI-2) were composed of superparamagnetic Fe3O4 core that binds CDDP and TFPI-2 shell that combines with folate-polyethylene glycol-polyethyleneimine (FA-PEG-PEI) via electrostatic interaction. The shell containing FA-PEG-PEI and TFPI-2 plasmid was synthesized through amidation reaction and electrostatic adsorption and the core containing SPION-CDDP was modified by aldehyde sodium alginate. Proton nuclear magnetic resonance and Fourier transform infrared spectra on FA-PEG-PEI polymers showed characteristic peaks of various metabolites in corresponding frequency. Transmission electron microscopy image of FA-PEG-PEI@SPION-CDDP-TFPI-2 nanoparticles demonstrated a near-monodisperse spherical morphology, while dynamic light scattering studies indicated an intensity-average diameter of 149.5 nm. Zeta potential was 14.89 ± 1.83 mv and the final concentration of loaded CDDP was 100 ug/ml. Gel electrophoresis data showed that the nanocomposite would protect TFPI-2 pDNA from being digested by DNases. Compared with CNE-2 cells, the good targetability and better gene transfection efficiency (57.9%) were detected by Prussian blue iron stain and fluorescence analysis in HNE-1 cells in vitro. The results suggested the potential application of FA-PEG-PEI@SPION-CDDP-TFPI-2 as a multifunctional anticancer nanomedicine on targeting therapy for FR positive NPC.

Lessons Learned from Gemcitabine: Impact of Therapeutic Carrier Systems and Gemcitabine's Drug Conjugates on Cancer Therapy.

Currently, drug delivery systems have a high impact in cancer therapy and are receiving more attention than conventional cancer treatment modalities. Compared with current cancer therapies, gemcitabine (2', 2'-difluoro-2'-deoxycytidine) has been proven to be an effective chemotherapeutic agent against pancreatic, colon, bladder, breast, ovarian, non-small-cell lung, and head and neck cancers in combination with other anticancer agents. To improve the safety and efficacy of cytotoxic drugs, several drug delivery systems have been explored. This review outlines the recent work directed toward gemcitabine delivery systems for cancer therapy, including aerosols, polymeric nanoparticles, liposomes, microparticles, carbon nanotubes, and multifunctional theranostic nanomedicines. It also provides insight into the design and development of gemcitabine conjugation for safe and effective cancer therapy. Despite the clinical promises of gemcitabine, many therapeutic challenges remain. Specifically, its therapeutic use in cancer chemotherapy is impeded by a short biological half-life, caused by its rapid metabolism, and resistance due to increased expression of ribonucleotide reductase. In our opinion, many research investigations have contributed to improve the selectivity and efficacy of gemcitabine. This combined approach of drug delivery systems and gemcitabine conjugates has shown promising efficacy in preclinical models and significant potential for future clinical cancer-therapeutic applications. Also, these strategies overcome most of the aforementioned limits of gemcitabine.

Black Phosphorus Nanosheet-Based Drug Delivery System for Synergistic Photodynamic/Photothermal/Chemotherapy of Cancer.

A black phosphorus (BP)-based drug delivery system for synergistic photodynamic/photothermal/chemotherapy of cancer is constructed. As a 2D nanosheet, BP shows super high drug loading capacity and pH-/photoresponsive drug release. The intrinsic photothermal and photodynamic effects of BP enhance the antitumor activities. The synergistic photodynamic/photothermal/chemotherapy makes BP-based drug delivery system a multifunctional nanomedicine platform.

Nanoparticles for Effective Combination Therapy of Cancer

Cancer continues to remains a major healthcare problem across the world despite strong translational research efforts towards tackling the disease. Surgery, when possible, along with radiation and chemotherapy continue to remain the mainstay of cancer treatment. Novel targeted therapies or biologics and immunotherapies have recently been approved to improve treatment efficacies while reducing collateral damage to normal, non-cancerous tissues. Combination therapies have shown better results than individual monotherapies in the clinic but often the improvements in therapeutic indices remain marginal, at best. Several combinations treatments have been clinically approved for different types of cancer. Nanomedicine, the application of nanotechnology for medicine, has already made some positive impacts on the clinical care in this fight against cancer. Several nano-sized formulations of conventional chemotherapies have been clinically approved. Nanotechnology provides a novel way to deliver combination therapies with spatiotemporal control over drug release. This review explores the recent advances in nanotechnology-mediated combination treatments against cancer. Multifunctional nanomedicines for mechanism-based combination therapies are likely to deliver the right drugs to the right place at the right time for optimal treatment responses with reduced morbidity. No nanomedicine that combines two or more drugs in a single platform has been approved for clinical use yet. This is because several challenges still remain in the development of nano-combinations including but not limited to - the optimal drug ratios in these nanomedicines, control over these drug ratios over multiple batches, large scale, reproducible manufacturing of these nanomedicines and cost of these nano-combinations among others. These challenges need to be addressed soon using a multidisciplinary approach with collaborations between academia, the pharmaceutical industry and the regulatory bodies involved to ensure that nano-combination therapy delivers on its promise of better treatment outcomes while severely reducing morbidity thus improving the quality of life in cancer patients.

Versatile Nanodelivery Platform to Maximize siRNA Combination Therapy.

The unsatisfactory outcomes of typical multiple cytotoxic chemotherapeutic combination therapies used to treat patients have fostered a need for new unconventional combinations of therapeutic agents. Among the candidates, siRNA has been widely discussed and tested. However, the right time right place codelivery of siRNA with other types of active ingredients is challenging because of the possible differences among their physiochemical and pharmacodynamics properties. To accomplish a synergistic cytotoxic effect, a nanoassembly is thus designed to codeliver siRNA with other therapeutic agents. A siRNA, targeting prosurvival gene for the p75 neurotrophin receptor, and an organelle-fusing peptide, targeting mitochondria, are layered onto a nanotemplate by charge-charge interaction, followed by a layer of CD44 targeting ligand. The formulated triple-functional nanomedicine is efficiently internalized by the CD44 expressing triple-negative breast cancer cells. The encapsulated siRNA and the pro-apoptotic peptide are released inside cells, silencing the intended prosurvival gene, and inducing apoptosis by fusing the mitochondrial membrane, respectively. A synergistic effect is achieved by this three-agent combination. The design of the developed multifunctional nanomedicine can be generalized to deliver other siRNA and drugs for a maximum therapeutic combination with minimal off-targeting effects.

Near-Infrared Polymeric Nanoparticles with High Content of Cyanine for Bimodal Imaging and Photothermal Therapy.

The discovery and synthesis of theranostic nanomedicines with high loading of imaging and therapeutic agents is challenging. In this work, a polymer assembling strategy was used to make nanoparticles with exceptionally high loading of theranostic agent. As an example, poly(heptamethine) was synthesized via multicomponent Passerini reaction, and then assembled into nanoparticles in the presence of poly(ethylene glycol)2k-block-poly(d,l-lactide)2k (PEG-PLA) with high heptamethine loading (>50%). The formed nanoparticles could be used for bimodal bioimaging and photothermal therapy. The bimodal bioimaging provided complementary message about biodistribution, and photothermal treatment inhibited the growth of cervical carcinoma upon laser irradiation. This assembly of polymers formed by imaging and therapeutic agents opens new possibilities for the construction of multifunctional nanomedicines.

One-Pot To Synthesize Multifunctional Carbon Dots for Near Infrared Fluorescence Imaging and Photothermal Cancer Therapy.

It is an emerging focus to develop a simple and straightforward strategy to synthesize multifunctional nanomedicines for cancer imaging and treatment. In this work, a new carbon dot (named CyCD) with intrinsic theranostic properties was prepared from a hydrophobic cyanine dye [2-((E)-2-((E)-2-chloro-3-((E)-2-(1-(2-hydroxyethyl)-3,3-dimethylindolin-2-ylidene) ethylidene)cyclohex-1-en-1-yl)vinyl)-1-(2-hydroxyethyl)-3,3-dimethyl-3H-indol-1-ium iodide, CyOH] and poly(ethylene glycol) (PEG800) via a simple solvothermal process. The as-prepared CyCD is well dispersed in water media with an average diameter of 2.9 ± 0.5 nm; it possesses favorable hydrophilicity and excellent photostability. More importantly, the strong absorption and near-IR (NIR) emission within the range from 600 to 900 nm, along with preferential uptake at tumors and high photothermal conversion efficiency (η = 38.7%), facilitate CyCD to act as an ideal theranostic agent for NIR fluorescent imaging and photothermal therapy in vitro and in vivo. This work highlights theranostic CDs as an excellent candidate for efficient cancer imaging and therapy.

Robust, active tumor-targeting and fast bioresponsive anticancer nanotherapeutics based on natural endogenous materials.

We demonstrate that with rational design, simple and multifunctional anticancer nanotherapeutics can be developed to achieve highly efficient and targeted cancer chemotherapy. Doxorubicin-loaded multifunctional nanoparticles based on hyaluronic acid-g-poly(γ-benzyl-l-glutamate)-lipoic acid conjugates exhibit a high drug loading, superior stability, fast bioresponsivity, high tolerability, and obvious selectivity toward CD44-overexpressing tumors in vivo. These nanotherapeutics achieve effective tumor suppression, drastically improved survival rate and reduced side effects as compared to clinically used pegylated liposomal doxorubicin in MCF-7 human breast tumor-bearing nude mice. Unlike previously reported multifunctional nanomedicines, the present nanotherapeutics primarily based on natural endogenous materials are simple and straightforward to fabricate, which makes them potentially interesting for clinical translation.

Gadolinium polytungstate nanoclusters: a new theranostic with ultrasmall size and versatile properties for dual-modal MR/CT imaging and photothermal therapy/radiotherapy of cancer

The development of a new generation of nanoscaled theranostics with simple compositions and versatile properties to realize enhanced diagnoses and treatment outcomes and to avoid side effects is highly desirable but remains a great challenge. Here we report a new ultrasmall theranostic based on bovine serum albumin-coated GdW10O36 nanoclusters (GdW10 NCs) as multifunctional theranostics for multifunctional bio-imaging, highly effective in vitro photothermal ablation of cancer cells and in vivo radiotherapy of tumors. The as-synthesized GdW10 NCs afford significantly enhanced computed tomography/magnetic resonance imaging signals and remarkable photothermal therapy (PTT)/radiotherapy therapy (RT) therapeutic effects for tumor treatment. Moreover, toxicity studies confirmed their low toxicity and efficient renal clearance, suggesting their potential for practical applications. These results indicated that the as-prepared GdW10 nanoclusters are promising as multifunctional nanotheranostics for multimodal imaging-guided PTT/RT of tumors. These results also encourage the further exploration of other polyoxometalate-based multifunctional nanotheranostics for cancer diagnoses and therapy. Nanostructures that can diagnose tumours and treat them with laser light and radiotherapy have been developed by researchers in China. ‘Theranostic’ nanoparticles that combine bioimaging with targeted action against cancer cells are often too large to pass safely through the kidney, leading to cytotoxicity issues. To overcome such problems, Zhanjun Gu from the Chinese Academy of Sciences and co-workers synthesized polytungstates nanoclusters containing rare-earth gadolinium ions and coated them with a biocompatible protein film. These water-soluble, sub-5-nanometre particles enhanced magnetic resonance and computed tomography imaging thanks to the gadolinium components. In vivo tests in mice revealed that the nanoclusters localized in tumour microstructures where they could be excited by laser or X-ray beams to damage and repress tumour formation. Afterwards, the nanoparticles were cleared through the kidney harmlessly. In this work, a new theranostics based on GdW10@BSA NCs with ultrasmall size, but versatile properties, were fabricated, which possesses not only significant CT/ MR imaging signal enhancement but also remarkable photothermal therapy (PTT)/radiotherapy (RT) therapeutic effects for tumor. Therefore, our work may open an avenue in developing other POM-based multifunctional nanomedicines with better therapeutic outcome and fewer side effects.

Redox-Sensitive Citronellol-Cabazitaxel Conjugate: Maintained in Vitro Cytotoxicity and Self-Assembled as Multifunctional Nanomedicine.

Citronellol-cabazitaxel (CIT-ss-CTX) conjugate self-assembled nanoparticles (CSNPs) were designed and prepared by conjugating cabazitaxel with citronellol via the disulfide bond that is redox-sensitive to the high concentration of glutathione within tumor cells. Notably, the CSNPs maintained in the cell cytotoxicity. Moreover, the AUC0-t of CSNPs was 6.5-fold higher than that of cabazitaxel solutions and the t1/2 was prolonged 2.3 times. Furthermore, we found that CSNPs could be employed as an efficient carrier for other hydrophobic drugs or imaging agents. Thus, the in vivo targeting study was implemented via using 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide (DiR)-loaded CSNPs as imaging agent, which showed CSNPs could effectively accumulate at the tumor site. Curcumin, a hydrophobic anticancer drug, was successfully loaded in CSNPs which exhibits good stability and synergistic antitumor effects. The citronellol-cabazitaxel conjugate therefore has a promising perspective as a multifunctional nanomedicine for combination therapy and theranostics attributed to its long-circulation property, redox-sensitive mechanism, and high drug coloading capability.

PH and near-infrared light dual-stimuli responsive drug delivery using DNA-conjugated gold nanorods for effective treatment of multidrug resistant cancer cells

A thiolated pH-responsive DNA conjugated gold nanorod (GNR) was developed as a multifunctional nanocarrier for targeted, pH-and near infrared (NIR) radiation dual-stimuli triggered drug delivery. It was further passivated by a thiolated poly(ethylene glycol)-biotin to improve its cancer targeting ability by specific binding to cancer cell over-expressed biotin receptors. Doxorubicin (DOX), a widely used clinical anticancer drug, was conveniently loaded into nanocarrier by intercalating inside the double-stranded pH-responsive DNAs on the GNR surface to complete the construction of the multifunctional nanomedicine. The nanomedicine can rapidly and effectively release its DOX payload triggered by an acidic pH environment (pH~5) and/or applying an 808nm NIR laser radiation. Compared to free DOX, the biotin-modified nanomedicine displayed greatly increased cell uptake and significantly reduced drug efflux by model multidrug resistant (MDR) breast cancer cell lines (MCF-7/ADR). The application of NIR radiation further increased the DOX release and facilitated its nuclear accumulation. As a result, this new DNA-GNR based multifunctional nanomedicine exerted greatly increased potency (~67 fold) against the MDR cancer cells over free DOX.