Hierarchically Targeted and Penetrated Delivery of Drugs to Tumors by Size‐Changeable Graphene Quantum Dot Nanoaircrafts for Photolytic Therapy

Theranostic nanohybrids are promising for effective delivery of therapeutic drug or energy and for imaging‐guided therapy of tumors, which is demanded in personalized medicine. Here, a size‐changeable graphene quantum dot (GQD) nanoaircraft (SCNA) that serves as a hierarchical tumor‐targeting agent with high cargo payload is developed to penetrate and deliver anticancer drug into deep tumors. The nanoaircraft is composed of ultrasmall GQDs (less than 5 nm) functionalized with a pH‐sensitive polymer that demonstrates an aggregation transition at weak acidity of tumor environment but is stable at physiological pH with stealth function. A size conversion of the SCNA at the tumor site is further actuated by near‐infrared irradiation, which disassembles 150 nm of SCNA into 5 nm of doxorubicin (DOX)/GQD like a bomb‐loaded jet, facilitating the penetration into the deep tumor tissue. At the tumor, the penetrated DOX/GQD can infect neighboring cancer cells for repeated cell killing. Such a SCNA integrated with combinational therapy successfully suppresses xenograft tumors in 18 d without distal harm. The sophisticated strategy displays the hierarchically targeted and penetrated delivery of drugs and energy to deep tumor and shows potential for use in other tumor therapy.     

Metal-Coordinated Adsorption of Nanoparticles to Macrophages for Targeted Cancer Therapy

Living cell-based drug delivery systems (LC-DDSs) are limited by adverse interactions between drugs and carrier cells, typically drug-induced toxicity to carrier cells and restriction of carrier cells on drug release. Here, a method is established to adsorb nanocarriers externally to living cells, thereby reducing cytotoxicity caused by drug uptake and realizing improved drug release at the disease site. It is found that a divalent metal ion-phenolic network (MPN) affords adhesion of poly (lactic-co-glycolic acid) nanoparticles onto macrophage (Mφ) surfaces with minimized intracellular uptake and no negative effect on cell proliferation. On this basis, an Mφ-DDS with doxorubicin-loaded nanoparticles on cell surface (DOX-NP@Mφ) is constructed. Compared to intracellular loading via endocytosis, this method well-maintains bioactivity (viability and migration chemotaxis) of the carrier cell. By virtue of the photothermal effect of MPN at the tumor site, DOX-NP-associated vesicles are liberated for improved chemotherapy. This facile, benign, and efficient method (ice bath, 2 min) for extracellular nanoparticle attachment and minimizing intracellular uptake provides a platform technology for LC-DDS development.     

Multifunctional Mesoporous Silica Nanoparticles for Cancer‐Targeted and Controlled Drug Delivery

Multifunctional mesoporous silica nanoparticles are developed in order to deliver anticancer drugs to specific cancer cells in a targeted and controlled manner. The nanoparticle surface is functionalized with amino‐β‐cyclodextrin rings bridged by cleavable disulfide bonds, blocking drugs inside the mesopores of the nanoparticles. Poly(ethylene glycol) polymers, functionalized with an adamantane unit at one end and a folate unit at the other end, are immobilized onto the nanoparticle surface through strong β‐cyclodextrin/adamantane complexation. The non‐cytotoxic nanoparticles containing the folate targeting units are efficiently trapped by folate‐receptor‐rich HeLa cancer cells through receptormmediated endocytosis, while folate‐receptor‐poor human embryonic kidney 293 normal cells show much lower endocytosis towards nanoparticles under the same conditions. The nanoparticles endocytosed by the cancer cells can release loaded doxorubicin into the cells triggered by acidic endosomal pH. After the nanoparticles escape from the endosome and enter into the cytoplasm of cancer cells, the high concentration of glutathione in the cytoplasm can lead to the removal of the β‐cyclodextrin capping rings by cleaving the pre‐installed disulfide bonds, further promoting the release of doxorubicin from the drug carriers. The high drug‐delivery efficacy of the multifunctional nanoparticles is attributed to the co‐operative effects of folate‐mediated targeting and stimuli‐triggered drug release. The present delivery system capable of delivering drugs in a targeted and controlled manner provides a novel platform for the next generation of therapeutics.     

Multifunctional DNA Polycatenane Nanocarriers for Synergistic Targeted Therapy of Multidrug‐Resistant Human Leukemia

Chemotherapy, as one of the principal modalities for cancer therapy, is limited by its inefficient delivery, serious side effects as well as multidrug resistance (MDR). Herein, multifunctional aptamer‐tethered deoxyribonucleic acids (DNA) polycatenanes (AptDPCs) is reported to combat MDR human leukemia. By rational design, the DNA polycatenanes (DPCs) are first constructed by a one‐step self‐assembly approach, during which DPCs are incorporated with fluorophores for bioimaging, abundant doxorubicin (DOX) intercalation sites for drug delivery, and antisense oligonucleotides (AS ODNs) for inhibiting the expression of P‐glycoprotein (P‐gp) and further reversing MDR. In addition, to endow the DPCs with specific recognition toward the target cancer cells and high purity, aptamers are tethered to the DPCs via the magnetic separation method based on the toehold‐mediated strand displacement (TMSD) reaction, which not only improves the purity and reproducibility of the AptDPCs, but also realizes the recycle of magnetic carriers. The results confirm that the AptDPCs can deliver drugs and AS ODNs into the target cancer cells and synergistically inhibit the MDR tumor growth without apparent systematic toxicity. The proposed AptDPC‐based drug delivery system can effectively reduce side effects and reverse MDR, which provides a promising platform for codelivery of therapeutic genes and chemodrugs in targeted cancer therapy.     

Graphene Oxide Based Fluorescent DNA Aptasensor for Liver Cancer Diagnosis and Therapy

Graphene oxide (GO)-based fluorescent DNA aptasensors are promising nanomaterials in bioassays owing to the fluorescent ultrasensitivity and target identification ability. However, their in vivo application remains an appealing yet significantly challenging task. In this contribution, for the first time, a nanomaterial for in vivo diagnosis and therapy of liver tumors is demonstrated. A DNA nanomaterial consisting of DNA tetrahedron and aptamers, aggregation-induced emission luminogens, and antitumor drug doxorubicin, is fabricated and attached on the GO surface. This developed hybrid with good biocompatibility exhibits high selectivity to target liver cancer cells, and performs well in in vitro and in vivo liver tumor fluorescence imaging diagnosis and chemotherapy. Additionally, a GO-based fluorescent DNA nanodevice is also constructed by using microfluidic chips for liver tumor cell screening.     

Polydopamine as a Biocompatible Multifunctional Nanocarrier for Combined Radioisotope Therapy and Chemotherapy of Cancer

Development of biodegradable nanomaterials for drug delivery and cancer theranostics has attracted great attention in recent years. In this work, polydopamine (PDA), a biocompatible polymer, is developed as a promising carrier for loading of both radionuclides and an anticancer drug to realize nuclear‐imaging‐guided combined radioisotope therapy (RIT) and chemotherapy of cancer in one system. It is found that PDA nanoparticles after modification with poly(ethylene glycol) (PEG) can successfully load several different radionuclides such as ^99mTc and ¹³¹I, as well as an anticancer drug doxorubicin (DOX). While labeling PDA‐PEG with ^99mTc (^99mTc‐PDA‐PEG) enables in vivo single photon emission computed tomography imaging, nanoparticles co‐loaded with ¹³¹I and DOX (¹³¹I‐PDA‐PEG/DOX) can be utilized for combined RIT and chemotherapy, which offers effective cancer treatment efficacy in a remarkably synergistic manner, without rendering significant toxicity to the treated animals. Therefore, this study presents an interesting class of biocompatible nanocarriers, which allow the combination of RIT and chemotherapy, the two extensively applied cancer therapeutic strategies, promising for future clinic translations in cancer treatment.     

Mesoporous Silica Coated Single‐Walled Carbon Nanotubes as a Multifunctional Light‐Responsive Platform for Cancer Combination Therapy

The development of cancer combination therapies, many of which rely on nanoscale theranostic agents, has received increasing attention in recent years. In this work, polyethylene glycol (PEG) modified mesoporous silica (MS) coated single‐walled carbon nanotubes (SWNTs) are fabricated and utilized as a multifunctional platform for imaging guided combination therapy of cancer. A model chemotherapy drug, doxorubicin (DOX), could be loaded into the mesoporous structure of the obtained SWNT@MS‐PEG nano‐carriers with high efficiency. Upon stimulation under near‐infrared (NIR) light, photothermally triggered drug release from DOX loaded SWNT@MS‐PEG is observed inside cells, resulting in a synergistic cancer cell killing effect. As revealed by both photoacoustic (PA) and magnetic resonance (MR) imaging, we further uncover efficient tumor accumulation of SWNT@MS‐PEG/DOX after intravenous injection into mice. In vivo combination therapy using this agent is further demonstrated in a mouse tumor model, achieving a remarkable synergistic anti‐tumor effect superior to that obtained by mono‐therapy. Our work presents a new type of theranostic nano‐platform, which could load therapeutic molecules with high efficiency, be responsive to external NIR stimulation, and at the same time serve as a diagnostic imaging agent.     

Ultrafast Fabrication of Covalently Cross‐linked Multifunctional Graphene Oxide Monoliths

Stable graphene oxide monoliths (GOMs) have been fabricated by exploiting epoxy groups on the surface of graphene oxide (GO) in a ring opening reaction with amine groups of poly(oxypropylene) diamines (D₄₀₀). This method can rapidly form covalently bonded GOM with D₄₀₀ within 60 s. FTIR and XPS analyses confirm the formation of covalent C‐N bonds. Investigation of the GOM formation mechanism reveals that the interaction of GO with a diamine cross‐linker can result in 3 different GO assemblies depending on the ratio of D₄₀₀ to GO, which have been proven both by experiment and molecular dynamics calculations. Moreover, XRD results indicate that the interspacial distance between GO sheets can be tuned by varying the diamine chain length and concentration. We demonstrate that the resulting GOM can be moulded into various shapes and behaves like an elastic hydrogel. The fabricated GOM is non‐cyctotoxic to L929 cell lines indicating a potential for biomedical applications. It could also be readily converted to graphene monolith upon thermal treatment. This new rapid and facile method to prepare covalently cross‐linked GOM may open the door to the synthesis and application of next generation multifunctional 3D graphene structures.     

Enhanced Intracellular Protein Transduction by Sequence Defined Tetra‐Oleoyl Oligoaminoamides Targeted for Cancer Therapy

Intracellular protein delivery presents a novel promising prospect for cell biology research and cancer therapy. However, inefficient cellular uptake and lysosomal sequestration hinder productive protein delivery into the cytosol. Here, a library of 16 preselected sequence‐defined oligoaminoamide oligomers is evaluated for intracellular protein delivery. All oligomers, containing polyethylene glycol (PEG) for shielding and optionally folic acid as targeting ligand, manifest cellular internalization of disulfide‐conjugated enhanced green fluorescent protein (EGFP). However, only a PEGylated folate‐receptor targeted two‐arm oligomer (729) containing both arms terminally modified with two oleic acids shows persistent intracellular protein survival and nuclear import of nlsEGFP (which contains a nuclear localization sequence) in folate‐receptor‐positive KB carcinoma cells, validating both effective endolysosomal escape and following subcellular transport. Furthermore, using ribonuclease A as a therapeutic cargo protein, among the tested oligomers, the oleic acid modified targeted two‐arm oligomers exert the most significant tumor cell killing of KB tumor cells. An investigation of structure–activity relationship elucidates that the incorporated oleic acids play a vital role in the enhanced intracellular protein delivery, by promoting stable formation of 25–35 nm lipo‐oligomer protein nanoparticles and by membrane‐active characteristics facilitating intracellular cytosolic delivery.     

Dual‐Targeted Photopenetrative Delivery of Multiple Micelles/Hydrophobic Drugs by a Nanopea for Enhanced Tumor Therapy

A photoresponsive pea‐like capsule (nanopea) that also represents a photothermal agent is constructed by wrapping multiple polymer micelles (polyvinyl alcohol, PVA) in reduced graphene oxide nanoshells through a double emulsion approach. Resulting nanopeas can transport multiple PVA micelles containing the fully concealed hydrophobic drug docetaxel (DTX) which can be later released by a near‐infrared photoactuation trigger. Through integrating the rod‐shaped adhesion and lactoferrin (Lf) targeting, the nanopea enhances both uptake by cancer cellc in vitro and particle accumulation at tumor in vivo. A photopenetrative delivery of micelles/DTX to the tumor site is actuated by NIR irradiation which ruptures the nanopeas as well as releases nanosized micelles/DTX. This trigger also results in thermal damage to the tumor and increases the micelles/DTX permeability, facilitating drug penetration into the deep tumor far from blood vessels for thermal chemotherapy. This nanopea with the capability of imaging, enhanced tumor accumulation, NIR‐triggered tumor penetration, and hyperthermia ablation for photothermal chemotherapy boosts tumor treatment and shows potential for use in other biological applications.     

Electrospun Fibrous Architectures for Drug Delivery,Tissue Engineering and Cancer Therapy

The versatile electrospinning technique is recognized as an efficient strategy to deliver active pharmaceutical ingredients and has gained tremendous progress in drug delivery, tissue engineering, cancer therapy, and disease diagnosis. Numerous drug delivery systems fabricated through electrospinning regarding the carrier compositions, drug incorporation techniques, release kinetics, and the subsequent therapeutic efficacy are presented herein. Targeting for distinct applications, the composition of drug carriers vary from natural/synthetic polymers/blends, inorganic materials, and even hybrids. Various drug incorporation approaches through electrospinning are thoroughly discussed with respect to the principles, benefits, and limitations. To meet the various requirements in actual sophisticated in vivo environments and to overcome the limitations of a single carrier system, feasible combinations of multiple drug‐inclusion processes via electrospinning could be employed to achieve programmed, multi‐staged, or stimuli‐triggered release of multiple drugs. The therapeutic efficacy of the designed electrospun drug‐eluting systems is further verified in multiple biomedical applications and is comprehensively overviewed, demonstrating promising potential to address a variety of clinical challenges.     

Multifunctional Molecular Beacon Micelles for Intracellular mRNA Imaging and Synergistic Therapy in Multidrug‐Resistant Cancer Cells

Multidrug resistance (MDR) resulting from overexpression of P‐glycoprotein (Pgp) transporters increases the drug efflux and thereby limits the chemotherapeutic efficacy. It is desirable to administer both an MDR1 gene silencer and a chemotherapeutic agent in a sequential way to generate a synergistic therapeutic effect in multidrug‐resistant cancer cells. Herein, an anti‐MDR1 molecular beacon (MB)‐based micelle (a‐MBM) nanosystem is rationally designed. It is composed of a diacyllipid core densely packed with an MB corona. One of Pgp‐transportable agents, doxorubicin (DOX), is encapsulated in the hydrophobic core of the micelle and in the stem sequence of MB. The a‐MBM‐DOX nanosystem shows an efficient self‐delivery, enhanced enzymatic stability, excellent target selectivity, and high drug‐loading capacity. With its relatively high enzymatic stability, a‐MBM‐DOX initially facilitates intracellular MDR1 mRNA imaging to distinguish multidrug‐resistant and non‐multidrug‐resistant cells and subsequently downregulates the MDR1 gene expression owing to an antisense effect. After that, the MB corona is degraded, destroying the micellar nanostructure and releasing DOX, which result in a high accumulation of DOX in OVCAR8/ADR cells and a high chemotherapeutic efficacy because of successful restoration of drug sensitivity. This micelle approach has the potential for both visualizing MDR1 mRNA and overcoming MDR in a sequential and synergistic way.     

A Multifunctional Nanoplatform against Multidrug Resistant Cancer: Merging the Best of Targeted Chemo/Gene/Photothermal Therapy

Synergistic therapy that combines chemo‐, gene‐, or photothermal means shows great potential for enhancing the therapeutic effects on cancers. Tumor‐targeted nanoparticles based on a doxorubicin (DOX)‐gated mesoporous silica nanocore (MSN) encapsulated with permeability glycoprotein (P‐gp) small interfering RNA (siRNA) and a polydopamine (PDA) outer layer for DOX loading and folic acid decoration are designed. The multifunctional nanoplatform tactfully integrates chemo‐ (DOX), gene‐ (P‐gp siRNA), and photothermal (PDA layer) substances in one system. In vitro results reveal that DOX release behaviors are both pH‐ and thermal‐responsive and the release of co‐delivered P‐gp siRNA is also pH‐dependent due to the pH‐cleavable DOX gatekeeper on MSN. In addition, due to the near‐infrared light‐responsive PDA outer layer and folic acid conjugation, the nanoparticles exhibit outstanding photothermal activity and selective cell targeting ability. Subsequently, in vitro and in vivo antitumor experiments both demonstrate the enhanced antitumor efficacy of the multifunctional nanoparticles, indicating the significance of synergistic therapy combining chemo‐, gene‐, and photothermal treatments in one system.     

New Generation of Multifunctional Nanoparticles for Cancer Imaging and Therapy

Advances in nanotechnology have contributed to the development of novel nanoparticles that enable the tumor‐specific delivery of imaging probes and therapeutic agents in cancer imaging and therapy. Nanobiotechnology combines nanotechnology with molecular imaging, which has led to the generation of new multifunctional nanoparticles for cancer imaging and therapy. Multifunctional nanoparticles hold great promise for the future of cancer treatment because they can detect the early onset of cancer in each individual patient and deliver suitable therapeutic agents to enhance therapeutic efficacy. The combination of tumor‐targeted imaging and therapy in an all‐in‐one system provides a useful multimodal approach in the battle against cancer. Novel multifunctional nanoparticles thus offer a new avenue in the application of personalized medicine in the near future. Herein, new trends and the significance of novel multifunctional nanoparticles in cancer imaging and therapy are reviewed.

     

Biodegradable Nanoscale Coordination Polymers for Targeted Tumor Combination Therapy with Oxidative Stress Amplification

Nowadays various inorganic nanoparticles that generate highly reactive hydroxyl radical ( · OH) on the basis of Fenton‐like catalytic activity of metal ions have been designed for chemodynamic therapy. However, the high level of adaptive antioxidants [glutathione (GSH)] in cancer cells could effectively consume · OH to compromise the treatment efficiency and biosafety of these inorganic nanoparticles, and this is a general concern in chemodynamic therapy. Herein, a new biodegradable nanoscale coordination polymer (NCP) is developed by integration of cisplatin prodrug (DSCP) and iron (III) ions through a reverse microemulsion method. The DSCP in the NCPs could react with GSH to release free cisplatin, while the iron (III) ions could be reduced by GSH into iron (II) to enable Fenton reaction, subsequently leading to amplified intracellular oxidative stress. After surface modification of polyethylene glycol (PEG) and cyclo[Arg‐Gly‐Asp‐D‐Phe‐Lys(mpa)] peptide (cRGD), Fe‐DSCP‐PEG‐cRGD shows an excellent targeting effect against α_vβ₃‐integrin overexpressed tumor cells. Furthermore, Fe‐DSCP‐PEG‐cRGD enables significant chemo and chemodynamic therapy with dramatically enhanced therapeutic efficiency in comparison to relative monotherapies. Importantly, Fe‐DSCP‐PEG‐cRGD could be efficiently cleared out from mice through feces and urine postinjection 7 days. The NCP presented in this work is simple and economical, which shows great biodegradability and biosafety for potential clinical translation.     

Multifunctional Graphene Oxide‐based Triple Stimuli‐Responsive Nanotheranostics

Construction of multifunctional stimuli‐responsive nanosystems intelligently responsive to inner physiological and/or external irradiations based on nanobiotechnology can enable the on‐demand drug release and improved diagnostic imaging to mitigate the side‐effects of anticancer drugs and enhance the diagnostic/therapeutic outcome simultaneously. Here, a triple‐functional stimuli‐responsive nanosystem based on the co‐integration of superparamagnetic Fe₃O₄ and paramagnetic MnO_x nanoparticles (NPs) onto exfoliated graphene oxide (GO) nanosheets by a novel and efficient double redox strategy (DRS) is reported. Aromatic anticancer drug molecules can interact with GO nanosheets through supramolecular π stacking to achieve high drug loading capacity and pH‐responsive drug releasing performance. The integrated MnO_x NPs can disintegrate in mild acidic and reduction environment to realize the highly efficient pH‐responsive and reduction‐triggered T₁‐weighted magnetic resonance imaging (MRI). Superparamagnetic Fe₃O₄ NPs can not only function as the T₂‐weighted contrast agents for MRI, but also response to the external magnetic field for magnetic hyperthermia against cancer. Importantly, the constructed biocompatible GO‐based nanoplatform can inhibit the metastasis of cancer cells by downregulating the expression of metastasis‐related proteins, and anticancer drug‐loaded carrier can significantly reverse the multidrug resistance (MDR) of cancer cells.     

Albumin Biomimetic Nanocorona Improves Tumor Targeting and Penetration for Synergistic Therapy of Metastatic Breast Cancer

The synergistic combination of photothermal and RNA interference therapy demonstrates great potential for effective treatment of metastatic breast cancer, but their efficacy is limited by the poor delivery efficiency to tumor. Herein, it is reported that an albumin biomimetic nanocorona (DRI‐S@HSA) can accomplish the high accumulation and deep penetration within tumor tissues, thereby holding great promise for synergistic therapy. DRI‐S@HSA is prepared by camouflaging human serum albumin (HSA) onto an IR‐780 and small interfering RNA‐loaded cell‐penetrating peptide nanoassembly (DRI‐S). In metastatic 4T1 breast cancer cells, DRI‐S@HSA can be largely internalized, and cause significant inhibition on cell migration and proliferation in combination with laser irradiation. Surprisingly, in vivo, the albumin camouflage in DRI‐S@HSA produces a 2.5‐fold enhancement on tumor accumulation compared to the undecorated DRI‐S, and dramatically improves the deep penetration capacity in tumor mass. Moreover, a single DRI‐S@HSA treatment plus 808 nm laser irradiation results in an 83.6% inhibition on tumor growth and efficient prevention of lung metastases. Taken together, the findings can provide an encouraging biomimetic tumor‐targeted drug delivery strategy to inhibit tumor progression and prevent lung metastases of breast cancer.     

Towards Novel Multifunctional Pillared Nanostructures: Effective Intercalation of Adamantylamine in Graphene Oxide and Smectite Clays

Multifunctional pillared materials are synthesized by the intercalation of cage‐shaped adamantylamine (ADMA) molecules into the interlayer space of graphite oxide (GO) and aluminosilicate clays. The physicochemical and structural properties of these hybrids, determined by X‐ray diffraction (XRD), Fourier transform infrared (FTIR), Raman and X‐ray photoemission (XPS) spectroscopies and transmission electron microscopy (TEM) show that they can serve as tunable hydrophobic/hydrophilic and stereospecific nanotemplates. Thus, in ADMA‐pillared clay hybrids, the phyllomorphous clay provides a hydrophilic nanoenvironment where the local hydrophobicity is modulated by the presence of ADMA moieties. On the other hand, in the ADMA‐GO hybrid, both the aromatic rings of GO sheets and the ADMA molecules define a hydrophobic nanoenvironment where sp³‐oxo moieties (epoxy, hydroxyl and carboxyl groups), present on GO, modulate hydrophilicity. As test applications, these pillared nanostructures are capable of selective/stereospecific trapping of small chlorophenols or can act as cytotoxic agents.