Templated Assembly of pH‐Labile Polymer‐Drug Particles for Intracellular Drug Delivery

The preparation of pH‐labile polymer‐drug particles via mesoporous silica‐templated assembly for anticancer drug delivery into cancer cells is reported. The polymer‐drug conjugate is synthesized via thiol‐maleimide click chemistry using thiolated poly(methacrylic acid) (PMA_SH) and a pH‐labile doxorubicin (Dox) derivative. Drug‐loaded polymer particles that are stable under physiological conditions are obtained through infiltration of the conjugates into mesoporous silica particles, followed by cross‐linking the PMA_SH chains, and subsequent removal of the porous silica templates. The encapsulated Dox is released from the particles through cleavage of the hydrazone bonds between Dox and PMA_SH at endosomal/lysosomal pH. Cell viability assays show that the assembled PMA_SH particles have negligible cytotoxicity to LIM1899 human colorectal cancer cells. In comparison, Dox‐loaded PMA_SH particles cause significant cell death following internalization. The reported particles represent a novel and versatile class of stimuli‐responsive carriers for controlled drug delivery.     

A Smart Nanoassembly for Multistage Targeted Drug Delivery and Magnetic Resonance Imaging

Efficient delivery of DNA‐toxin anticancer drugs into nucleus of targeted tumor cells while simultaneously minimizing the side effects to normal tissue is a major challenge for cancer therapy. Herein, a multistage continuous targeting strategy based on magnetic mesoporous silica nanoparticles to overcome the challenge is demonstrated. At the initial‐stage, the magnetic nanoparticle is capable of efficiently accumulating in tumor tissue guided by magnet. Following by the magnetic targeting, the targeting ligand gets it right into the cancer cell by receptor‐mediated endocytosis. Accompanied by endocytosis into the lysosomes, the nanoparticle reverses its surface charge from negative to positive which leads to the separation of charge‐conversional polymer from the nanoparticle to re‐expose the nuclear‐targeting TAT peptide. Finally, TAT peptide facilitates the carriers to enter nucleus and the DNA‐toxin camptothecin can inhibit topoisomerase I to induce cell apoptosis. Furthermore, the nano‐drug delivery system can be simultaneously used as predominant contrast agents for magnetic resonance imaging. This proof of concept might open the door to a new generation of carrier materials in the fields of targeted drug transport platform for cancer theranostics.     

Amphiphilic Polymeric Nanocarriers with Luminescent Gold Nanoclusters for Concurrent Bioimaging and Controlled Drug Release

Multifunctional theranostic systems with good biocompatibility, strong clinical imaging capability, and target specificity are the desired features of future medicine. Here, the design of a theranostic nanocomposite capable of simultaneous targeting and imaging of the cancer cells is presented. It releases its drug payload by a controlled release mechanism. The nanocomposite contains luminescent gold nanocluster (L‐AuNC) photostable and biocompatible diagnostic probes conjugated to a folic acid (FA)‐modified pH‐responsive amphiphilic polymeric system for controlled drug release. The nanocomposite uses a core‐satellite structure to encapsulate hydrophobic drugs and releases the drug payload in mildly acidic endosomal/lysosomal compartments by the action of the pH‐labile linkages in the polymer. In vivo studies show the selective accumulation of the FA‐conjugated nanocomposite in tumor tissues by folate‐receptor‐mediated endocytosis. These findings demonstrate the potential of the nanocomposite as a nontoxic, folate‐targeting, pH‐responsive drug carrier that is useful for the early detection and therapy of folate‐overexpressing cancerous cells.     

Water‐Soluble Poly(N‐isopropylacrylamide)–Graphene Sheets Synthesized via Click Chemistry for Drug Delivery

Covalently functionalized graphene sheets are prepared by grafting a well‐defined thermo‐responsive poly(N‐isopropylacrylamide) (PNIPAM) via click chemistry. The PNIPAM‐grafted graphene sheets (PNIPAM‐GS) consist of about 50% polymer, which endows the sheets with a good solubility and stability in physiological solutions. The PNIPAM‐GS exhibits a hydrophilic to hydrophobic phase transition at 33 °C, which is relatively lower than that of a PNIPAM homopolymer because of the interaction between graphene sheets and grafted PNIPAM. Moreover, through π–π stacking and hydrophobic interaction between PNIPAM‐GS and an aromatic drug, the PNIPAM‐GS is able to load a water‐insoluble anticancer drug, camptothecin (CPT), with a superior loading capacity of 15.6 wt‐% (0.185 g CPT per g PNIPAM‐GS). The in vitro drug release behavior of the PNIPAM‐GS‐CPT complex is examined both in water and PBS at 37 °C. More importantly, the PNIPAM‐GS does not exhibit a practical toxicity and the PNIPAM‐GS‐CPT complex shows a high potency of killing cancer cells in vitro. The PNIPAM‐GS is demonstrated to be an effective vehicle for anticancer drug delivery.     

Triphenylphosphonium‐Conjugated Poly(ε‐caprolactone)‐Based Self‐Assembled Nanostructures as Nanosized Drugs and Drug Delivery Carriers for Mitochondria‐Targeting Synergistic Anticancer Drug Delivery

For mitochondria‐targeting delivery, a coupling reaction between poly(ε‐caprolactone) diol (PCL diol) and 4‐carboxybutyltriphenylphosphonium (4‐carboxybutyl TPP) results in the synthesis of amphiphilic TPP‐PCL‐TPP (TPCL) polymers with a bola‐like structure. In aqueous environments, the TPCL polymer self‐assembled via cosolvent dispersion and film hydration, resulting in the formation of cationic nanoparticles (NPs) less than 50 nm in size with zeta‐potentials of approximately 40 mV. Interestingly, different preparation methods for TPCL NPs result in various morphologies such as nanovesicles, nanofibers, and nanosheets. In vitro cytotoxicity results with TPCL NPs indicate IC₅₀ values of approximately 10–60 μg mL^?1, suggesting their potential as anticancer nanodrugs. TPCL NPs can be loaded both with hydrophobic doxorubicin (Dox) and its hydrophilic salt form (Dox·HCl), and their drug loading contents are approximately 2–10 wt% depending on the loading method and the hydrophilicity/hydrophobicity of the drugs. Although Dox·HCl exhibits more cellular and nuclear uptake, resulting in greater antitumor effects than Dox, most drug‐loaded TPCL NPs exhibit higher mitochondrial uptake and approximately 2–7‐fold higher mitochondria‐to‐nucleus preference than free drugs, resulting in superior (approximately 7.5–18‐fold) tumor‐killing activity for most drug‐loaded TPCL NPs compared with free drugs. In conclusion, TPCL‐based nanoparticles have potential both as antitumor nanodrugs themselves and as nanocarriers for chemical therapeutics.     

Poly(Ferulic Acid) with an Anticancer Effect as a Drug Nanocarrier for Enhanced Colon Cancer Therapy

As colorectal cancer is the fourth leading cause of cancer‐related death worldwide, colorectal cancer therapy requires new strategies for improved therapeutic effects. Recently, nanodrug carriers have emerged to weaken the systemic toxicity of chemotherapy drugs and strengthen the treatment effectiveness against colorectal cancer. In this report, ferulic acid, a plant derivative, is polycondensed into poly(ferulic acid) (PFA) for the first time to serve as an excellent drug carrier with anticancer performance. PFA self‐assembles into nanoparticles by nanoprecipitation, and the screened PFA nanoparticles (NPs) have a diameter of ≈100 nm and possess a reasonable drug‐loading capacity of ≈8.3% of paclitaxel (PTX). Evaluation of CT26 cells and a corresponding mouse model indicates remarkable inhibition of colon cancer with PTX‐loaded PFA nanoparticles (PFA@PTX NPs) treatment both in vitro and in vivo. Meanwhile, evaluation of blank PFA NPs in a tumor mouse model also shows tumor inhibition, confirming that PFA itself has an anticancer effect in vivo. Overall, the novel nanoparticles based on poly(ferulic acid) can not only effectively deliver chemodrugs but also provide additional anticancer therapeutic effects, providing a promising platform for clinical colon cancer therapy.     

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.     

Multistage Nanovehicle Delivery System Based on Stepwise Size Reduction and Charge Reversal for Programmed Nuclear Targeting of Systemically Administered Anticancer Drugs

The nucleus is the final target of many first‐line chemotherapeutics, but the need to overcome multiple physiological barriers imposes conflicting requirements for size and charge on systemically administered drug delivery systems. Here, an N‐(2‐hydroxypropyl) methacrylamide (HPMA) polymer‐based nanovehicle (PNV) that self‐assembles from anionic HPMA copolymers with charge‐reversal ability and cationic HPMA copolymers with intracellularly detachable subgroups (IDS) is described. The IDS, bearing an anticancer drug and nuclear‐homing cell‐penetrating peptide (R8NLS ligand), is grafted onto the HPMA copolymer via hydrazone linkage. The large, neutrally charged, self‐assembled PNV (≈55 nm) shows good blood persistence and preferential tumor accumulation. After tumoral arrival, the extracellular milieu actuates the disassembly of PNV to linear conjugates (≈10 nm/39 kDa). This first‐stage size reduction exposes R8NLS and allows for deeper tissue penetration and greater cellular internalization. After endocytosis, a second‐stage size reduction occurs when the more acidic endolysosomal pH cleaved the ≈2.4 kDa IDS off the HPMA copolymer backbone and guaranteed the successful nuclear entry via nuclear localization signal assistance. Based on the stepwise size reduction and on‐demand R8NLS exposure, the PNV inhibits growth of HeLa tumors in nude mice by 75%. This work gives important insights into the design of systemic nuclear‐targeted delivery via a multistage size/charge changing way.     

Multifunctional Core/Shell Nanoparticles Self‐Assembled from pH‐Induced Thermosensitive Polymers for Targeted Intracellular Anticancer Drug Delivery

Core/shell nanoparticles that display a pH‐sensitive thermal response, self‐assembled from the amphiphilic tercopolymer, poly(N‐isopropylacrylamide‐co‐N,N‐dimethylacrylamide‐co‐10‐undecenoic acid) (P(NIPAAm‐co‐DMAAm‐co‐UA)), have recently been reported. In this study, folic acid is conjugated to the hydrophilic segment of the polymer through the free amine group (for targeting cancer cells that overexpress folate receptors) and cholesterol is grafted to the hydrophobic segment of the polymer. This polymer also self‐assembles into core/shell nanoparticles that exhibit pH‐induced temperature sensitivity, but they possess a more stable hydrophobic core than the original polymer P(NIPAAm‐co‐DMAAm‐co‐UA) and a shell containing folate molecules. An anticancer drug, doxorubicin (DOX), is encapsulated into the nanoparticles. DOX release is also pH‐dependent. DOX molecules delivered by P(NIPAAm‐co‐DMAAm‐co‐UA) and folate‐conjugated P(NIPAAm‐co‐DMAAm‐co‐UA)‐g‐cholesterol nanoparticles enter the nucleus more rapidly than those transported by P(NIPAAm‐co‐DMAAm)‐b‐poly(lactide‐co‐glycolide) nanoparticles, which are not pH sensitive. More importantly, these nanoparticles can recognize folate‐receptor‐expressing cancer cells. Compared to the nanoparticles without folate, the DOX‐loaded nanoparticles with folate yield a greater cellular uptake because of the folate‐receptor‐mediated endocytosis process, and, thus, higher cytotoxicity results. These multifunctional polymer core/shell nanoparticles may make a promising carrier to target drugs to cancer cells and release the drug molecules to the cytoplasm inside the cells.     

Primary Cell Adhesion on RGD‐Functionalized and Covalently Crosslinked Thin Polyelectrolyte Multilayer Films

Polyelectrolyte multilayers (PEMs) are now widely used for biomedical applications. In this work, we investigated the primary osteoblast adhesion properties of PEMs of poly(L ‐lysine) (PLL), poly(L ‐glutamic acid) (PGA), poly(alginic acid) (Palg), and poly(galacturonic acid) (Pgal). In order to compensate for the poor adhesion of the as‐synthesized films, two kinds of film modifications were achieved: a purely physical modification by film crosslinking, and a chemical modification by grafting a arginine–glycine–aspartic acid (RGD) peptide to PGA. Crosslinking was performed using a water‐soluble carbodiimide in combination with N‐hydroxysulfosuccinimide (sulfo‐NHS) to induce amide formation. This reaction was followed by Fourier‐transform IR spectroscopy. For film functionalization, a 15‐amino‐acid peptide was grafted to PGA and deposited as the top layer of the film. PLL/PGA, PLL/Palg, and PLL/Pgal films were crosslinked or functionalized. The films were tested for both short‐term adhesion properties and long‐term proliferation of primary osteoblasts. Whereas the effect of film crosslinking on short‐term adhesion was moderate, it was much more important for the RGD‐functionalized films. On the other hand, the long‐term proliferation was the same or even higher for the crosslinked films as compared with the functionalized films. This effect was particularly enhanced for the PLL/Palg and PLL/Pgal films. Finally, we functionalized PLL/PGA that had been crosslinked prior to PGA‐RGD deposition. These architectures exhibited even higher short‐term adhesion and proliferation. These results clearly show the important role of the physical properties of the films, besides their chemical properties, for the modulation of primary cell‐adhesion behavior.     

Biogenic (R)‐(+)‐Lipoic Acid Only Constructed Cross‐Linked Vesicles with Synergistic Anticancer Potency

Although the drug delivery systems (DDSs) hold great potential for cancer chemotherapy, the drug carriers themselves become redundant substances in the body, once the delivering task is finished. They not only have no therapeutic effect, but even can sometimes cause unexpectedly toxic and side effects, which confine seriously the clinical prospect of DDSs. Herein, a new drug container of cross‐linked lipoic acid vesicles (cLAVs) constructed solely by biogenic (R)‐(+)‐lipoic acid (LA) is developed. Benefited from the structure homology with LA, the cLAVs are no longer the redundant substances after drug delivery, but LA‐like “vitamins” with strong synergistic anticancer potency both in vitro and in vivo, and, thus represent a particularly powerful carrier for cancer chemotherapy.     

Smart Supramolecular “Trojan Horse”‐Inspired Nanogels for Realizing Light‐Triggered Nuclear Drug Influx in Drug‐Resistant Cancer Cells

Efficient nuclear delivery of anticancer drugs evading drug efflux transporters (DETs) on the plasma and nuclear membranes of multidrug‐resistant cancer cells is highly challenging. Here, smart nanogels are designed via a one‐step self‐assembly of three functional components including a biocompatible copolymer, a fluorescent organosilica nanodot, and a photodegradable near‐infrared (NIR) dye indocyanine green (ICG). The rationally designed nanogels have high drug encapsulation efficiency (≈99%) for anticancer drug doxorubicin (Dox), self‐traceability for bioimaging, proper size for passive tumor targeting, prolonged blood circulation time for enhanced drug accumulation in tumor, and photocontrolled disassemblability. Moreover, the Dox‐loaded nanogels can effectively kill multidrug‐resistant cells via two steps: 1) They behave like a “Trojan horse” to escape from the DETs on the plasma membrane for efficiently transporting the anticancer “soldier” (Dox) into the cytoplasm and preventing the drugs from being excreted from the cells; 2) Upon NIR light irradiation, the photodegradation of ICG leads to the disassembly of the nanogels to release massive Dox molecules, which can evade the DETs on the nuclear membrane to exert their intranuclear efficacy in multidrug‐resistant cells. Combined with their excellent biocompatibility, the nanogels may provide an alternative solution for overcoming cancer multidrug resistance.     

Anticancer Activity Driven by Drug Linker Modification in a Polyglutamic Acid‐Based Combination‐Drug Conjugate

Combination nanotherapies for the treatment of breast cancer permits synergistic drug targeting of multiple pathways. However, poor carrier degradability, poor synergism of the combined drugs, low drug release regulation, and a lack of control on final macromolecule solution conformation (which drives the biological fate) limit the application of this strategy. The present study describes the development of a family of drug delivery systems composed of chemotherapeutic (doxorubicin) and endocrine therapy (aromatase inhibitor aminoglutethimide) agents conjugated to a biodegradable poly‐l ‐glutamic acid backbone via various linking moieties. Data from in vitro cytotoxicity and drug release assessments and animal model validation select a conjugate family member with optimal biological performance. Exhaustive physicochemical characterization in relevant media (including the study of secondary structure, size measurements, and detailed small‐angle neutron scattering analysis) correlates biological data with the intrinsic supramolecular characteristics of the conjugate. Overall, this study demonstrates how a small flexible Gly linker can modify the spatial conformation of the entire polymer–drug conjugate, promote the synergistic release of both drugs, and significantly improve biological activity. These findings highlight the need for a deeper understanding of polymer–drug conjugates at supramolecular level to allow the design of more effective polymer–drug conjugates.     

Histone Deacetylase-Triggered Self-Immolative Peptide-Cytotoxins for Cancer-Selective Drug Delivery

Precise delivery and release of therapeutics in the subcellular targets are critical for tumor-selective chemotherapy. Self-immolative structures are sophisticatedly designed to achieve stimuli-responsive drug delivery. Herein, the facile fabrication of self-immolative peptide-camptothecin (CPT) nanoassemblies is reported for cancer-selective drug delivery by utilizing the dual-mode peptide targeting design and amine-catalyzed intramolecular hydrolysis. The dual-mode peptide targeting design is realized by co-assembly of tumor targeting and nuclei-localizing peptide-CPT prodrugs, rendering the nanoassemblies with efficient cancer cell-selective capability. When the nanoassemblies enter cancer cell, the overexpressed endonuclear histone deacetylases (HDACs) cleave the acetyl group to generate primary amines, triggers amine-catalyzed intramolecular hydrolysis, and fast-release drug in the cell nuclei. The peptide-CPT prodrugs release up to 68% CPT in 1 h in the presence of HDACs, while no detectable CPT release is observed in the absence of HDACs at the same time. The peptide-CPT prodrugs selectively kill cancer cells with high HDACs levels. The dual targeting peptide-CPT nanoassemblies exhibit extended blood circulation, excellent tumor accumulation, and potent antitumor activity by inhibiting tumor progression and metastasis in mice bearing 4T1 aggressive breast tumors. Overall, the HDAC-triggered self-immolative strategy is promising for developing cancer-selective drug delivery systems.     

Dual Acid‐Responsive Micelle‐Forming Anticancer Polymers as New Anticancer Therapeutics

Cinnamaldehyde, a major active compound of cinnamon, is known to induce apoptotic cell death in numerous human cancer cells. Here, dual acid‐responsive polymeric micelle‐forming cinnamaldehyde prodrugs, poly[(3‐phenylprop‐2‐ene‐1,1‐diyl)bis(oxy)bis(ethane‐2,1‐diyl)diacrylate]‐co‐4,4’(trimethylene dipiperidine)‐co‐poly(ethylene glycol), termed PCAE copolymers, are reported. PCAE is designed to incorporate cinnamaldehyde via acid‐cleavable acetal linkages in its pH‐sensitive hydrophobic backbone and self assemble to form stable micelles which can encapsulate camptothecin (CPT). PCAE self assembles to form micelles which release CPT and cinnamaldehyde in pH‐dependent manners. PCAE micelles induce apoptotic cell death through the generation of intracellular reactive oxygen species (ROS) and exert synergistic anticancer effects with a payload of CPT in vitro and in vivo model of SW620 human colon tumor‐bearing mice. It is anticipated that dual acid‐sensitive micelle‐forming PCAE with intrinsic anticancer activities has enormous potential as novel anticancer therapeutics.     

Tumor‐Microenvironment‐Adaptive Nanoparticles Codeliver Paclitaxel and siRNA to Inhibit Growth and Lung Metastasis of Breast Cancer

Prolonged circulation, specific and effective uptake by tumor cells, and rapid intracellular drug release are three main factors for the drug delivery systems to win the battle against metastatic breast cancer. In this work, a tumor microenvironment‐adaptive nanoparticle co‐loading paclitaxel (PTX) and the anti‐metastasis siRNA targeting Twist is prepared. The nanoparticle consists of a pH‐sensitive core, a cationic shell, and a matrix metalloproteinase (MMP)‐cleavable polyethylene glycol (PEG) corona conjugated via a peptide linker. PEG will be cut away by MMPs at the tumor site, which endows the nanoparticle with smaller particle size and higher positive charge, leading to more efficient cellular uptake in tumor cells and higher intra‐tumor accumulation of both PTX and siRNA in the 4T1 tumor‐bearing mice models compared to the nanoparticles with irremovable PEG. In addition, acid‐triggered drug release in endo/lysosomes is achieved through the pH‐sensitive core. As a result, the MMP/pH dual‐sensitive nanoparticles significantly inhibit tumor growth and pulmonary metastasis. Therefore, this tumor‐microenvironment‐adaptive nanoparticle can be a promising codelivery vector for effective therapy of metastatic breast cancer due to simultaneously satisfying the requirements of long circulating time, efficient tumor cell targeting, and fast intracellular drug release.     

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.     

NIR‐Triggered Synergic Photo‐chemothermal Therapy Delivered by Reduced Graphene Oxide/Carbon/Mesoporous Silica Nanocookies

A novel photo‐responsive drug carrier that doubles as a photothermal agent with a nanocookie‐like structure is constructed by coating amorphous carbon on a mesoporous silica support self‐assembled on a sheet of reduced graphene oxide. With a large payload (0.88 mmolg^?1) of a hydrophobic anticancer drug, (S)‐(+)‐camptothecin (CPT), nanocookies simultaneously provide a burst‐like drug release and intense heat upon near‐infrared exposure. Being biocompatible yet with a high efficiency for cell uptake, nanocookies have successfully eradicated subcutaneous tumors in 14 days following a single 5 min NIR irradiation without distal damage. These results demonstrate that the nanocookie is an excellent new delivery platform for local, on‐demand, NIR‐responsive, combined chemotherapy/hyperthermia for tumor treatment and other biomedical applications.     

Gadolinium‐Doped Iron Oxide Nanoprobe as Multifunctional Bioimaging Agent and Drug Delivery System

In this study, a high‐performance T₁–T₂ dual‐model contrast agent by gadolinium‐doped iron oxide nanoparticle (GION) is developed. Following its development, the application of this agent in vivo by combining doxorubicin (DOX) and folic acid (FA) (FA–GION–DOX) for targeted drug delivery to monitor cancer treatment is explored. GION showed transverse and longitudinal relaxivities up to 182.7 × 10^?3 and 7.87 × 10^?3m ^?1 s^?1, respectively, upon Gd/Fe ratio in GION at 1/4. DOX released from FA–GION–DOX is pH dependent and only kills cancer cell after FA receptor‐mediated internalization into the acidic environment of endosomes and lysosomes. Systemic delivery of FA–GION–DOX significantly inhibits the growth of tumors and shows good magnetic resonance enhancement in a human cervical cancer xenograft model. Thus, FA–GION–DOX has a potential application for the targeted and magnetic resonance imaging guided therapy of cervical cancer.