Photo‐ and pH‐Triggered Release of Anticancer Drugs from Mesoporous Silica‐Coated Pd@Ag Nanoparticles

A smart drug delivery system integrating both photothermal therapy and chemotherapy for killing cancer cells is reported. The delivery system is based on a mesoporous silica‐coated Pd@Ag nanoplates composite. The Pd@Ag nanoplate core can effectively absorb and convert near infrared (NIR) light into heat. The mesoporous silica shell is provided as the host for loading anticancer drug, doxorubicin (DOX). The mesoporous shell consists of large pores, ～10 nm in diameter, and allows the DOX loading as high as 49% in weight. DOX loaded core–shell nanoparticles exhibit a higher efficiency in killing cancer cells than free DOX. More importantly, DOX molecules are loaded in the mesopores shell through coordination bonds that are responsive to pH and heat. The release of DOX from the core‐shell delivery vehicles into cancer cells can be therefore triggered by the pH drop caused by endocytosis and also NIR irradiation. A synergistic effect of combining chemotherapy and photothermal therapy is observed in our core‐shell drug delivery system. The cell‐killing efficacy by DOX‐loaded core–shell particles under NIR irradiation is higher than the sum of chemotherapy by DOX‐loaded particles and photothermal therapy by core–shell particles without DOX.     

Engineering Inorganic Nanoemulsions/Nanoliposomes by Fluoride‐Silica Chemistry for Efficient Delivery/Co‐Delivery of Hydrophobic Agents

A novel drug‐formulation protocol is developed to solve the delivery problem of hydrophobic drug molecules by using inorganic mesoporous silica nanocapsules (IMNCs) as an alternative to traditional organic emulsions and liposomes while preserving the advantages of inorganic materials. The unique structures of IMNCs are engineered by a novel fluoride‐silica chemistry based on a structural difference‐based selective etching strategy. The prepared IMNCs combine the functions of organic nanoemulsions or nanoliposomes with the properties of inorganic materials. Various spherical nanostructures can be fabricated simply by varying the synthetic parameters. The drug loading amount of a typical highly hydrophobic anticancer drug‐camptothecin (CPT) in IMNCs reaches as high as 35.1 wt%. The intracellular release of CPT from carriers is demonstrated in situ. In addition, IMNCs can play the role of organic nanoliposome (multivesicular liposome) in co‐encapsulating and co‐delivering hydrophobic (CPT) and hydrophilic (doxorubicin, DOX) anticancer drugs simultaneously. The co‐delivery of multi‐drugs in the same carrier and the intracellular release of the drug combinations enables a drug delivery system with efficient enhanced chemotherapeutic effect for DOX‐resistant MCF‐7/ADR cancer cells. The special IMNCs‐based “inorganic nanoemulsion”, as a proof‐of‐concept, can also be employed successfully to encapsulate and deliver biocompatible hydrophobic perfluorohexane (PFH) molecules for high intensity focused ultrasound (HIFU) synergistic therapy ex vivo and in vivo. Based on this novel design strategy, a wide range of inorganic material systems with similar “inorganic nanoemulsion or nanoliposome” functions will be developed to satisfy varied clinical requirements.     

Real‐Time Imaging Tracking of Engineered Macrophages as Ultrasound‐Triggered Cell Bombs for Cancer Treatment

Cell‐based drug delivery systems are a promising platform for tumor‐targeted therapy due to their high drug‐loading capacities and inherent tumor‐homing abilities. However, the real‐time tracking of these carrier cells and controlled release of the encapsulated drugs are still challenging. Here, ultrasound‐activatable cell bombs are developed by encapsulating doxorubicin (DOX) and phase transformable perfluoropentane (PFP) into hollow mesoporous organosilica nanoparticles (HMONs) to prepare DOX/PFP‐loaded HMONs (DPH), followed by internalization into macrophages (RAW 264.7 cells). The resulting cell bombs (DPH‐RAWs) can maintain viability and actively home to the tumor. Especially, their migration can be tracked in real time using ultrasound due to the vaporization of a small portion of PFP during cell incubation at 37 °C. After accumulation at the tumor site, the further vaporization of remaining PFP can be triggered by a short‐pulsed high intensity focused ultrasound (HIFU) sonication, resulting in the generation of several large microbubbles, which destroys DPH‐RAWs and allows drug release out of these cells. The DPH‐RAWs combined with short‐pulsed HIFU sonication significantly inhibit tumor growth and prolong survival of tumor‐bearing mice. In conclusion, this study provides a new approach to cell‐based drug delivery systems for real‐time tracking of their migration and targeted cancer treatment.     

Redox Sensitive Hyaluronic Acid‐Decorated Graphene Oxide for Photothermally Controlled Tumor‐Cytoplasm‐Selective Rapid Drug Delivery

Nanocarriers capable of circumventing various biological barriers between the site of administration and the therapeutic target hold great potential for cancer treatment. Herein, a redox‐sensitive, hyaluronic acid‐decorated graphene oxide nanosheet (HSG) is developed for tumor cytoplasm‐specific rapid delivery using near‐infrared (NIR) irradiation controlled endo/lysosome disruption and redox‐triggered cytoplasmic drug release. Hyaluronic acid (HA) modification through redox‐sensitive linkages permits HSG a range of advantages over the standard graphene oxide, including high biological stability, enhanced drug‐loading capacity for aromatic molecules, HA receptor‐mediated active tumor targeting, greater NIR absorption and thermal energy translation, and a sharp redox‐dependent response for accelerated cargo release. Results of in vivo and in vitro testing indicate a high loading of doxorubicin (DOX) onto HSG. Selective delivery to HA‐receptor overexpressing tumors is achieved through passive and active targeting with minimized unfavorable interactions with blood components. Cytoplasm‐specific DOX delivery is then achieved through NIR controlled endo/lysosome disruption along with redox‐triggered release of DOX in glutathione rich areas. HSG's specificity is resulted in enhanced cytotoxicity of chemotherapeutics with minimal collateral damage to healthy tissues in a xenograft animal tumor model. HSG is validated the programmed delivery of therapeutic agents in a spatiotemporally controlled manner to overcome multiple biological barriers results in specific and enhanced cancer treatment.     

Structure‐Invertible Nanoparticles for Triggered Co‐Delivery of Nucleic Acids and Hydrophobic Drugs for Combination Cancer Therapy

Here, a new type of structure‐invertible, redox‐responsive polymeric nanoparticle for the efficient co‐delivery of nucleic acids and hydrophobic drugs in vitro and in vivo is reported for the first time, to combat the major challenges facing combination cancer therapy. The co‐delivery vector, which is prepared by conjugating branched poly(ethylene glycol) with dendrimers of two generations (G2) through disulfide linkages, is able to complex nucleic acids and load hydrophobic drugs with high loading capacity through structure inversion. The cleavage of disulfide linkages at intracellular glutathione‐rich reduction environment significantly decreases the cytotoxicity, and promotes more efficient drug release and gene transfection in vitro and in vivo. The co‐delivery carrier also displays enhanced endosomal escape capability and improved serum stability in vitro as compared with G2, and exhibits prolonged residence time and stronger transfection activity in vivo. Most importantly, co‐delivery of doxorubicin (DOX) and B‐cell lymphoma 2 (Bcl‐2) small interfering RNA (siRNA) exerts a combinational effect against tumor growth in murine tumor models in vivo, which is much more effective than either DOX or Bcl‐2 siRNA‐based monotherapy. The structure‐invertible nanoparticles may constitute a promising stimuli‐responsive system for the efficacious co‐delivery of multiple cargoes in future clinical applications of combination cancer therapies.     

Light‐Responsive,Singlet‐Oxygen‐Triggered On‐Demand Drug Release from Photosensitizer‐Doped Mesoporous Silica Nanorods for Cancer Combination Therapy

Smart drug delivery systems with on‐demand drug release capability are rather attractive to realize highly specific cancer treatment. Herein, a novel light‐responsive drug delivery platform based on photosensitizer chlorin e6 (Ce6) doped mesoporous silica nanorods (CMSNRs) is developed for on‐demand light‐triggered drug release. In this design, CMSNRs are coated with bovine serum albumin (BSA) via a singlet oxygen (SO)‐sensitive bis‐(alkylthio)alkene (BATA) linker, and then modified with polyethylene glycol (PEG). The obtained CMSNR‐BATA‐BSA‐PEG, namely CMSNR‐B‐PEG, could act as a drug delivery carrier to load with either small drug molecules such as doxorubicin (DOX), or larger macromolecules such as cis‐Pt (IV) pre‐drug conjugated third generation dendrimer (G3‐Pt), both of which are sealed inside the mesoporous structure of nanorods by BSA coating. Upon 660 nm light irradiation with a rather low power density, CMSNRs with intrinsic Ce6 doping would generate SO to cleave BATA linker, inducing detachment of BSA‐PEG from the nanorod surface and thus triggering release of loaded DOX or G3‐Pt. As evidenced by both in vitro and in vivo experiments, such CMSNR‐B‐PEG with either DOX or G3‐Pt loading offers remarkable synergistic therapeutic effects in cancer treatment, owing to the on‐demand release of therapeutics specifically in the tumor under light irradiation.     

Codelivery of a π–π Stacked Dual Anticancer Drug Combination with Nanocarriers for Overcoming Multidrug Resistance and Tumor Metastasis

The multidrug resistance (MDR) of cancer cells is a major obstacle in cancer chemotherapy and very few strategies are available to overcome it. Here, a new strategy is developed to codeliver a π–π stacked dual anticancer drug combination with an actively targeted, pH‐ and reduction‐sensitive polymer micellar platform for combating multidrug resistance and tumor metastasis. In contrast to other methods, two traditional chemotherapeutics, doxorubicin (DOX) and 10‐hydroxycamptothecin with complex aromatic π–π conjugated structures, are integrated into one drug delivery system via a π–π stacking interaction, which enables the released drugs to evade the recognition of drug pumps due to a slight change in the drug's molecular structure. The micelles exhibit active targeting of DOX‐resistant human breast cancer MCF‐7 cells (MCF‐7/ADR) and have the ability to control the release of the drug in response to the microenvironmental stimuli of tumor cells. As a result, the codelivery of the π–π stacked dual anticancer drug combination displays high therapeutic efficacy in the MCF‐7/ADR tumor model and successfully prevents the lung metastasis of tumor cells. The mechanism underlying the reversal of MDR is investigated, and the results reveal that the synergistic effect of the π–π stacked dual drugs promotes mitochondria‐dependent apoptosis.     

Cancer Cell Membrane‐Coated Gold Nanocages with Hyperthermia‐Triggered Drug Release and Homotypic Target Inhibit Growth and Metastasis of Breast Cancer

The cell‐specific targeting drug delivery and controlled release of drug at the cancer cells are still the main challenges for anti‐breast cancer metastasis therapy. Herein, the authors first report a biomimetic drug delivery system composed of doxorubicin (DOX)‐loaded gold nanocages (AuNs) as the inner cores and 4T1 cancer cell membranes (CMVs) as the outer shells (coated surface of DOX‐incorporated AuNs (CDAuNs)). The CDAuNs, perfectly utilizing the natural cancer cell membranes with the homotypic targeting and hyperthermia‐responsive ability to cap the DAuNs with the photothermal property, can realize the selective targeting of the homotypic tumor cells, hyperthermia‐triggered drug release under the near‐infrared laser irradiation, and the combination of chemo/photothermal therapy. The CDAuNs exhibit a stimuli‐release of DOX under the hyperthermia and a high cell‐specific targeting of the 4T1 cells in vitro. Moreover, the excellent combinational therapy with about 98.9% and 98.5% inhibiting rates of the tumor volume and metastatic nodules is observed in the 4T1 orthotopic mammary tumor models. As a result, CDAuNs can be a promising nanodelivery system for the future therapy of breast cancer.     

Doxorubicin‐Loaded Single Wall Nanotube Thermo‐Sensitive Hydrogel for Gastric Cancer Chemo‐Photothermal Therapy

Single wall carbon nanotube (SWNT) based thermo‐sensitive hydrogel (SWNT‐GEL) is reported, which provides an injectable drug delivery system as well as a medium for photothermal transduction. SWNT‐hydrogel alone appears to be nontoxic on gastric cancer cells (BGC‐823 cell line) but leads to cell death with NIR radiation through a hyperthermia proapoptosis mechanism. By incorporating hyperthermia therapy and controlled in situ doxorubicin (DOX) release, DOX‐loaded SWNT‐hydrogel with NIR radiation proves higher tumor suppression rate on mice xenograft gastric tumor models compared to free DOX without detectable organ toxicity. The developed system demonstrates improved efficacy of chemotherapeutic drugs which overcomes systemic adverse reactions and presents immense potential for gastric cancer treatment.     

Integrated Combination Treatment Using a “Smart” Chemotherapy and MicroRNA Delivery System Improves Outcomes in an Orthotopic Colorectal Cancer Model

Mesoporous silica nanoparticles (MSN) can load and deliver potentially synergistic anticancer agents such as small molecule cytotoxics (like doxorubicin, DOX) and nucleic acids (like microRNA, miRNA). However, these cargos have different underlying chemical properties so overcoming respective intracellular delivery barriers is a key consideration. Strategies to deliver DOX from MSN frequently employ pH‐driven mechanisms that are restricted to the acidic environment of lysosomes. Conversely, strategies to deliver miRNA make use of approaches that deliberately compromise lysosomal membrane integrity to enable cytosolic delivery of the payload. To reconcile these two needs (lysosomal delivery of DOX and intracellular delivery of miRNA), a new methodology by “weaving” polyethylenimine on the MSN surface through disulfide bonds to achieve superior delivery of chemotherapy (DOX) and miRNA therapy (using miRNA‐145) is developed. Furthermore, an active targeting strategy based on a peptide ligand with affinity to glucose‐regulated protein 78 (GRP78), a cell surface protein overexpressed in colorectal carcinoma, is developed. The active targeting approach results in enhanced synergistic antitumor effect both in vitro and in vivo in an orthotopic murine model of colorectal cancer. Taken together, this work demonstrates the capability and advantages of “smart” MSN delivery systems to deliver anticancer cargo appropriately to targeted cancer cells.     

Fabricating Aptamer‐Conjugated PEGylated‐MoS2/Cu1.8S Theranostic Nanoplatform for Multiplexed Imaging Diagnosis and Chemo‐Photothermal Therapy of Cancer

Fabricating theranostic nanoparticles combining multimode disease diagnosis and therapeutic has become an emerging approach for personal nanomedicine. However, the diagnostic capability, biocompatibility, and therapeutic efficiency of theranostic nanoplatforms limit their clinic widespread applications. Targeting to the theme of accurate diagnosis and effective therapy of cancer cells, a multifunctional nanoplatform of aptamer and polyethylene glycol (PEG) conjugated MoS₂ nanosheets decorated with Cu_1.8S nanoparticles (ATPMC) is developed. The ATPMC nanoplatform accomplishes photoluminescence imaging, photoacoustic imaging, and photothermal imaging for in vitro and in vivo tumor cells imaging diagnosis. Meanwhile, the ATPMC nanoplatform facilitates selective delivery of gene probe to detect intracellular microRNA aberrantly expressed in cancer cells and anticancer drug doxorubicin (DOX) for chemotherapy. Moreover, the synergistic interaction of MoS₂ and Cu_1.8S renders the ATPMC nanoplatform with superb photothermal conversion efficiency. The ATPMC nanoplatform loaded with DOX displays near‐infrared laser‐induced programmed chemotherapy and advanced photothermal therapy, and the targeted chemo‐photothermal therapy presents excellent antitumor efficiency.     

Cell Membrane Camouflaged Hollow Prussian Blue Nanoparticles for Synergistic Photothermal‐/Chemotherapy of Cancer

Nanodrug‐based cancer therapy has been actively developed in the past decades. The main challenges faced by nanodrugs include poor drug loading capacity, rapid clearance from blood circulation, and low antitumor efficiency with high risk of recurrence. In this work, red blood cell (RBC) membrane camouflaged hollow mesoporous Prussian blue nanoparticles (HMPB@RBC NPs) are fabricated for combination therapy of cancer. The stability, immune evading capacity, and blood retention time of HMPB@RBC NPs are significantly enhanced compared with those of bare HMPB NPs. Doxorubicin (DOX), as a model drug is encapsulated within HMPB@RBC NPs with loading capacity up to 130% in weight. In addition, DOX loaded HMPB@RBC NPs show pH‐/photoresponsive release. The in vivo studies demonstrate the outstanding performance of DOX@HMPB@RBC NPs in synergistic photothermal‐/chemotherapy of cancer.     

Gel–Liposome‐Mediated Co‐Delivery of Anticancer Membrane‐Associated Proteins and Small‐Molecule Drugs for Enhanced Therapeutic Efficacy

A programmed drug‐delivery system that can transport different anticancer therapeutics to their distinct targets holds vast promise for cancer treatment. Herein, a core–shell‐based “nanodepot” consisting of a liposomal core and a crosslinked‐gel shell (designated Gelipo) is developed for the sequential and site‐specific delivery (SSSD) of tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) and doxorubicin (Dox). As a small‐molecule drug intercalating the nuclear DNA, Dox is loaded in the aqueous core of the liposome, while TRAIL, acting on the death receptor (DR) on the plasma membrane, is encapsulated in the outer shell made of crosslinked hyaluronic acid (HA). The degradation of the HA shell by HAase that is concentrated in the tumor environment results in the rapid extracellular release of TRAIL and subsequent internalization of the liposomes. The parallel activity of TRAIL and Dox show synergistic anticancer efficacy. The half‐maximal inhibitory concentration (IC₅₀) of TRAIL and Dox co‐loaded Gelipo (TRAIL/Dox‐Gelipo) toward human breast cancer (MDA‐MB‐231) cells is 83 ng mL^–1 (Dox concentration), which presents a 5.9‐fold increase in the cytotoxicity compared to 569 ng mL^–1 of Dox‐loaded Gelipo (Dox‐Gelipo). Moreover, with the programmed choreography, Gelipo significantly improves the inhibition of the tumor growth in the MDA‐MB‐231 xenograft tumor animal model.     

pH‐Responsive Peptide Mimic Shell Cross‐Linked Magnetic Nanocarriers for Combination Therapy

The design and development of water dispersible, pH responsive peptide mimic shell cross‐linked magnetic nanocarriers (PMNCs) using a facile soft‐chemical approach is reported. These nanocarriers have an average size about 10 nm, are resistant to protein adsorption in physiological medium, and transform from a negatively charged to a positively charged form in the acidic environment. The terminal amino acid on the shell of the magnetic nanocarriers allows us to create functionalized exteriors with high densities of organic moieties (both amine and carboxyl) for conjugation of drug molecules. The drug‐loading efficiency of the nanocarriers is investigated using doxorubicin hydrochloride (DOX) as a model drug to evaluate their potential as a carrier system. Results show high loading affinity of nanocarriers for anticancer drug, their sustained release profile, magnetic‐field‐induced heating, and substantial cellular internalization. Moreover, the enhanced toxicity to tumor cells by DOX‐loaded PMNCs (DOX‐PMNCs) under an AC magntic field suggest their potential for combination therapy involving hyperthermia and chemotherapy.     

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.     

The Application of Stimuli‐Responsive VEGF‐ and ATP‐Aptamer‐Based Microcapsules for the Controlled Release of an Anticancer Drug,and the Selective Targeted Cytotoxicity toward Cancer Cells

The synthesis of microcapsules consisting of DNA shells crosslinked by anti‐VEGF (vascular epithelial growth factor) or anti‐ATP (adenosine triphosphate) aptamers and loaded with tetramethylrhodamine‐modified dextran, TMR‐D, and Texas Red‐modified dextran, TR‐D, respectively, as fluorescence labels acting as models for drug loads, is described. The aptamer‐functionalized microcapsules act as stimuli‐responsive carriers for the triggered release of the fluorescent labels in the presence of the overexpressed cancer cell biomarkers VEGF or ATP. The VEGF‐ and ATP‐responsive microcapsules are, also, loaded with the anticancer drug doxorubicin (DOX), in the form of DOX‐functionalized dextran, DOX‐D. The release of DOX‐D from the respective microcapsules proceeds in the presence of VEGF or ATP as triggers. Preliminary cell experiments reveal that the ATP‐responsive DOX‐D‐loaded microcapsules undergo effective endocytosis into MDA‐MB‐231 cancer cells. The ATP‐responsive DOX‐D‐loaded microcapsules incorporated into the MDA‐MB‐231 cancer cells reveal impressive cytotoxicity as compared to normal epithelial MCF‐10A breast cells (50% vs 0% cell death after 24 h, respectively). The cytotoxicity of the ATP‐responsive DOX‐D‐loaded microcapsules toward the cancer cells is attributed to the effective unlocking of the microcapsules by overexpressed ATP, and to the subsequent release of DOX from the dextran backbone under acidic conditions present in cancer cells (pH = 6.2).     

One‐Pot Synthesis of Dual Stimulus‐Responsive Degradable Hollow Hybrid Nanoparticles for Image‐Guided Trimodal Therapy

Exploiting exogenous and endogenous stimulus‐responsive degradable nanoparticles as drug carriers can improve drug delivery systems (DDSs). The use of hollow nanoparticles may facilitate degradation, and combination of DDS with photodynamic therapy (PDT) and photothermal therapy (PTT) may enhance the anticancer effects of treatments. Here, a one‐pot synthetic method is presented for an anticancer drug (doxorubicin [DOX]) and photosensitizer‐containing hollow hybrid nanoparticles (HNPs) with a disulfide and siloxane framework formed in response to exogenous (light) and endogenous (intracellular glutathione [GSH]) stimuli. The hollow HNPs emit fluorescence within the near‐infrared window and allow for the detection of tumors in vivo by fluorescence imaging. Furthermore, the disulfides within the HNP framework are cleaved by intracellular GSH, deforming the HNPs. Light irradiation facilitates penetration of GSH into the HNP framework and leads to the collapse of the HNPs. As a result, DOX is released from the hollow HNPs. Additionally, the hollow HNPs generate singlet oxygen (¹O₂) and heat in response to light; thus, fluorescence imaging of tumors combined with trimodal therapy consisting of DDS, PDT, and PTT is feasible, resulting in superior therapeutic efficacy. Thus, this method may have several applications in imaging and therapeutics in the future.     

Cancer‐Targeted Monodisperse Mesoporous Silica Nanoparticles as Carrier of Ruthenium Polypyridyl Complexes to Enhance Theranostic Effects

Mesoporous silica nanoparticles (MSNs) have been well‐demonstrated as excellent carriers for anticancer drug delivery. Presented here is a cancer‐targeted MSNs drug delivery system that allows the direct fluorescence monitoring of the cellular uptake and localization of theranostic agents in cancer cells. Specifically, the anticancer action mechanisms of RGD peptide‐functionalized MSNs carrying ruthenium polypyridyl complexes (RuPOP@MSNs) are elucidated in detail. RGD peptide surface decoration significantly enhances the cellular uptake of the nanoparticles through receptor‐mediated endocytosis, and increases the selectivity between cancer and normal cells. RuPOP@MSNs exhibits unprecedented enhanced cytotoxicity toward cancer cells overexpressing integrin receptor, which is significantly higher than that of free RuPOP, through induction of apoptosis. The important contribution of extrinsic pathway to cell apoptosis is confirmed by increase in expression levels of death receptors, activation of caspase‐8 and truncation of Bid. The internalized nanoparticles release free RuPOP into the cytoplasm, where they modulate the phosphorylation of p53, AKT, and MAPKs pathways to promote cell apoptosis. Moreover, the strong autofluorescence of RuPOP permits the direct monitoring of drug delivery, and extends the power of theranostics to subcellular level. Taken together, this study provides an effective strategy for the design and development of cancer‐targeted theranostic agents.     

pH‐ and NIR Light‐Responsive Micelles with Hyperthermia‐Triggered Tumor Penetration and Cytoplasm Drug Release to Reverse Doxorubicin Resistance in Breast Cancer

The acquisition of multidrug resistance (MDR) is a major hurdle for the successful chemotherapy of tumors. Herein, a novel hybrid micelle with pH and near‐infrared (NIR) light dual‐responsive property is reported for reversing doxorubicin (DOX) resistance in breast cancer. The hybrid micelles are designed to integrate the pH‐ and NIR light‐responsive property of an amphiphilic diblock polymer and the high DOX loading capacity of a polymeric prodrug into one single nanocomposite. At physiological condition (i.e., pH 7.4), the micelles form compact nanostructure with particle size around 30 nm to facilitate blood circulation and passive tumor targeting. Meanwhile, the micelles are quickly dissociated in weakly acidic environment (i.e., pH ≤ 6.2) to release DOX prodrug. When exposed to NIR laser irradiation, the hybrid micelles can trigger notable tumor penetration and cytosol release of DOX payload by inducing tunable hyperthermia effect. In combination with localized NIR laser irradiation, the hybrid micelles significantly inhibit the growth of DOX‐resistant MCF‐7/ADR breast cancer in an orthotopic tumor bearing mouse model. Taken together, this pH and NIR light‐responsive micelles with hyperthermia‐triggered tumor penetration and cytoplasm drug release can be an effective nanoplatform to combat cancer MDR.     

Doxorubicin‐Conjugated Immuno‐Nanoparticles for Intracellular Anticancer Drug Delivery

A polymeric nanoparticle comprised of surface furan groups is used to bind, by Diels–Alder (DA) coupling chemistry, both targeting anti‐human epidermal growth factor receptor 2 (anti‐HER2) antibodies and chemotherapeutic doxorubicin (DOX) for targeted, intracellular delivery of DOX. In this new approach for delivery, where both chemotherapeutic and targeting ligand are attached, for the first time, to the surface of the delivery vehicle, the nuclear localization of DOX in HER2‐overexpressing breast cancer SKBR‐3 cells is demonstrated, as determined by confocal laser scanning microscopy. Flow cytometric analysis shows that the conjugated DOX maintains its biological function and induces similar apoptotic progression in SKBR‐3 cells as free DOX. The viable cell counts of SKBR‐3 cancer cells following incubation with different nanoparticle formulations demonstrates that the combined DOX and anti‐HER2 nanoparticle is more efficacious than the nanoparticle formulation with either DOX or anti‐HER2 alone. While free DOX shows similar cytotoxicity against both cancerous SKBR‐3 cells and healthy HMEC‐1 cells, the combined DOX‐anti‐HER2 nanoparticle is significantly more cytotoxic against SKBR‐3 cells than HMEC‐1 cells, suggesting the benefit of nanoparticle‐conjugated DOX for cell type‐specific targeting. The DOX‐conjugated immuno‐nanoparticle represents an entirely new method for localized co‐delivery of chemotherapeutics and antibodies.