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.     

A Multifunctional Nanodevice Capable of Imaging,Magnetically Controlling,and In Situ Monitoring Drug Release

The multifunctional nanodevice described here integrates nanoscaled imaging, targeting, and controlled drug delivery, as well as the capability to monitor, in situ, the amount of drug released from the nanodevice with single‐cell resolution. The nanodevice is composed of a polymer core/single‐crystal iron oxide shell nanostructure bonded to a quantum dot. It shows outstanding release and retention characteristics via an external on/off manipulation of a high‐frequency magnetic field. Upon magnetic stimulation, the single‐crystal iron oxide shell demonstrates formation of nanometer‐sized polycrystal domains of varying orientation. This allows a variation between retention and slow release of the drug. Further stimulation causes permanent rupturing of the shell, causing release of the drug in a burst‐like manner. The quantum dot bonded to the nanodevice provides optical information for in situ monitoring of the drug release through use of a magnetic field. Remote control drug release from the nanodevice in a cancerous cell line (HeLa) was successfully accomplished using the same induction scenario. When nanodevices equipped with quantum dots are taken into cancerous cells, they are able to provide real‐time drug dose information through a corresponding variation in emission spectrum. The nanodevice designed in this study has achieved its potential as a cell‐based drug‐delivery system for therapeutic applications.     

Temperature‐Sensitive Nanocapsules for Controlled Drug Release Caused by Magnetically Triggered Structural Disruption

Self‐assembled nanocapsules containing a hydrophilic core and a crosslinked yet thermosensitive shell are successfully prepared using poly(ethylene‐oxide)‐poly(propylene‐oxide)‐poly(ethylene‐oxide) block copolymers, 4‐nitrophenyl chloroformate, gelatin, and 1‐ethyl‐3‐(3‐dimethylaminopropyl) carbodiimide. The core is further rendered magnetic by incorporating iron oxide nanoparticles via internal precipitation to enable externally controlled actuation under magnetic induction. The spherical nanocapsules exhibit a hydrophilic‐to‐hydrophobic transition at a characteristic but tunable temperature reaching 40 °C, triggering a size contraction and shrinkage of the core. The core content experiences very little leakage at 25 °C, has a half life about 5 h at 45 °C, but bursts out within a few minutes under magnetic heating due to iron oxide coarsening and core/shell disruption. Such burst‐like response may be utilized for controlled drug release as illustrated here using a model drug Vitamin B12.     

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.     

Iron Oxide Nanotubes for Magnetically Guided Delivery and pH‐Activated Release of Insoluble Anticancer Drugs

Low solubility in water is an intrinsic property of many drugs, which hinders the clinical use of those active ingredients. To break this bottleneck, we attempt to develop an iron oxide nanoparticle‐based multifunctional system. Firstly, we perform PEG coating and compare the feasibility of spherical and rod‐like iron oxide nanoparticles in a view of carcinoma cellular uptake; rod‐like nanoparticles attracted our interest since they could be quickly and massively internalized. For paclitaxel (PTX) loading, we next transform the nanorods into a tube structure by a hydrothermal method. The results show that drug crystals can be successfully loaded in the inner voids of these nanotubes (PMNTs) by controlling the crystallization process of PTX. The acquired nanocomplexes not only escape phagocytosis of macrophage cells by a PEG stealth effect, but also exhibit an increased cellular uptake with magnetic field exposure. In addition, this iron oxide‐based drug carrier possesses a low pH‐activated release profile, which would accelerate drug release in the carcinoma cells and minimize non‐specific drug release. Owing to these advantages, PMNTs promote the anticancer efficacy of PTX and clearly exhibit promising potential for using as high‐efficiency insoluble drug delivery system in clinical applications.     

Chitosan–Alginate Microcapsules Provide Gastric Protection and Intestinal Release of ICAM‐1‐Targeting Nanocarriers,Enabling GI Targeting In Vivo

When administered intravenously, active targeting of drug nanocarriers (NCs) improves biodistribution and endocytosis. Targeting may also improve NC oral delivery to treat gastrointestinal (GI) pathologies or for systemic absorption. However, GI instability of targeting moieties compromises this strategy. This study explores whether encapsulation of antibody‐coated NCs in microcapsules would protect against gastric degradation, providing NC release and targeting in intestinal conditions. Nanoparticles coated with antibodies against intercellular adhesion molecule‐1 (anti‐ICAM) or nonspecific immunoglobulin G (IgG) are encapsulated in chitosan (shell) ‐ alginate (core) microcapsules. Encapsulation efficiency is >95% and NC relase from microcapsules in storage is <10%. There is minimal NC release at gastric pH (<10%) and burst release at intestinal pH (75%–85%). Encapsulated NCs afford increased protection against degradation (threefold to fourfold) and increased cell targeting (8–20‐fold) after release versus the nonencapsulated NCs. Mouse oral gavage shows that microencapsulation provides 38%–65% greater protection of anti‐ICAM NCs in the GI tract, 40% lower gastric retention, and fourfold to ninefold enhanced intestinal biodistribution versus nonencapsulated NCs. Therefore, microencapsulation of antibody‐targeted NCs may enable active targeting strategies to be effective in the context of oral drug delivery.     

Biopebbles: DNA‐Functionalized Core–Shell Silica Nanospheres for Cellular Uptake and Cell Guidance Studies

The development of a versatile class of silica nanoparticles for cell studies is reported. The particles contain a fluorescent dye‐encoded core and a single‐stranded DNA oligonucleotide‐displaying shell. They are accessible in arbitrary size and color through robust protocols for Stöber‐based colloidal synthesis and sturdy chemical surface functionalization. Silica particles in the size range of 100 nm to 1.5 µm diameter containing fluorescein, Cy3 oder Cy5 dye‐encoded cores are synthesized and functionalized with DNA oligonucleotides. These silica biopebbles are conveniently traceable by microscopy and have a high affinity to live cells, which makes them ideal for cell uptake studies, as demonstrated for MCF7 and A431 cancer cells. The biopebbles can be utilized as building blocks for the self‐assembled formation of arbitrary surface patterns on glass substrates. With these architectures, the privileged internalization of the biopebbles can be exploited for improved adhesion and guidance of cells because the particles are no longer ingested by adhered cells due to their physical connection with the solid support. It is believed that the biopebble approach will be useful for a variety of applications, fundamental studies in cell biology and tissue engineering.     

Remotely Controlled Red Blood Cell Carriers for Cancer Targeting and Near‐Infrared Light‐Triggered Drug Release in Combined Photothermal–Chemotherapy

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

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.     

Bioinspired Nanoparticles with NIR‐Controlled Drug Release for Synergetic Chemophotothermal Therapy of Metastatic Breast Cancer

Optimal nanosized drug delivery systems (NDDS) require long blood circulation and controlled drug release at target lesions for efficient anticancer therapy. Red blood cell (RBC) membrane‐camouflaged nanoparticles (NPs) can integrate flexibility of synergetic materials and highly functionality of RBC membrane, endowed with many unique advantages for drug delivery. Here, new near‐infrared (NIR)‐responsive RBC membrane‐mimetic NPs with NIR‐activated cellular uptake and controlled drug release for treating metastatic breast cancer are reported. An NIR dye is inserted in RBC membrane shells, and the thermoresponsive lipid is employed to the paclitaxel (PTX)‐loaded polymeric cores to fabricate the RBC‐inspired NPs. The fluorescence of dye in the NPs can be used for in vivo tumor imaging with an elongated circulating halftime that is 12.3‐folder higher than that of the free dye. Under the NIR laser stimuli, the tumor cellular uptake of NPs is significantly enhanced to 2.1‐fold higher than that without irradiation. The structure of the RBC‐mimetic NPs can be destroyed by the light‐induced hyperthermia, triggered rapid PTX release (45% in 30 min). These RBC‐mimetic NPs provide a synergetic chemophotothermal therapy, completely inhibited the growth of the primary tumor, and suppress over 98% of lung metastasis in vivo, suggesting it to be an ideal NDDS to fight against metastatic breast cancer.     

Self‐Assembling Peptide as a Potential Carrier for Hydrophobic Anticancer Drug Ellipticine: Complexation,Release and In Vitro Delivery

The self‐assembling peptide EAK16‐II is capable of stabilizing hydrophobic compounds to form microcrystal suspensions in aqueous solution. Here, the ability of this peptide to stabilize the hydrophobic anticancer agent ellipticine is investigated. The formation of peptide‐ellipticine suspensions is monitored with time until equilibrium is reached. The equilibration time is found to be dependent on the peptide concentration. When the peptide concentration is close to its critical aggregation concentration, the equilibration time is minimal at 5 h. With different combinations of EAK16‐II and ellipticine concentrations, two molecular states (protonated or cyrstalline) of ellipticine could be stabilized. These different states of ellipticine significantly affect the release kinetics of ellipticine from the peptide‐ellipticine complex into the egg phosphatidylcholine vesicles, which are used to mimic cell membranes. The transfer rate of protonated ellipticine from the complex to the vesicles is much faster than that of crystalline ellipticine. This observation may also be related to the size of the resulting complexes as revealed from the scanning electron micrographs. In addition, the complexes with protonated ellipticine are found to have a better anticancer activity against two cancer cell lines, A549 and MCF‐7. This work forms the basis for studies of the peptide‐ellipticine suspensions in vitro and in vivo leading to future development of self‐assembling peptide‐based delivery of hydrophobic anticancer drugs.     

Biocompatible,Uniform, and Redispersible Mesoporous Silica Nanoparticles for Cancer‐Targeted Drug Delivery In Vivo

Engineering multifunctional nanocarriers for targeted drug delivery shows promising potentials to revolutionize the cancer chemotherapy. Simple methods to optimize physicochemical characteristics and surface composition of the drug nanocarriers need to be developed in order to tackle major challenges for smooth translation of suitable nanocarriers to clinical applications. Here, rational development and utilization of multifunctional mesoporous silica nanoparticles (MSNPs) for targeting MDA‐MB‐231 xenograft model breast cancer in vivo are reported. Uniform and redispersible poly(ethylene glycol)‐incorporated MSNPs with three different sizes (48, 72, 100 nm) are synthesized. They are then functionalized with amino‐β‐cyclodextrin bridged by cleavable disulfide bonds, where amino‐β‐cyclodextrin blocks drugs inside the mesopores. The incorporation of active folate targeting ligand onto 48 nm of multifunctional MSNPs (PEG‐MSNPs48‐CD‐PEG‐FA) leads to improved and selective uptake of the nanoparticles into tumor. Targeted drug delivery capability of PEG‐MSNPs48‐CD‐PEG‐FA is demonstrated by significant inhibition of the tumor growth in mice treated with doxorubicin‐loaded nanoparticles, where doxorubicin is released triggered by intracellular acidic pH and glutathione. Doxorubicin‐loaded PEG‐MSNPs48‐CD‐PEG‐FA exhibits better in vivo therapeutic efficacy as compared with free doxorubicin and non‐targeted nanoparticles. Current study presents successful utilization of multifunctional MSNP‐based drug nanocarriers for targeted cancer therapy in vivo.     

Engineering of Mesoporous Silica Coated Carbon‐Based Materials Optimized for an Ultrahigh Doxorubicin Payload and a Drug Release Activated by pH,T, and NIR‐light

Among the challenges in nanomedicine, engineering nanomaterials able to combine imaging and multitherapies is hugely needed to address issues of a personalized treatment. In that context, a novel class of drug releasing and remotely activated nanocomposites based on carbon‐based materials coated with mesoporous silica (MS) and loaded with an outstanding level of the antitumoral drug doxorubicin (DOX) is designed. First, carbon nanotubes (CNTs) and graphene sheets (called “few‐layer graphene” FLG) are processed to afford a distribution size that is more suitable for nanomedicine applications. Then, the controlled coating of MS shells having a thickness tailored with the sol–gel parameters (amount of precursor, sol–gel time) around the sliced CNTs and exfoliated FLGs is reported. Furthermore, the drug loading in such mesoporous nanocomposites is investigated and the surface modification with an aminopropyltriethoxysilane (APTS) coating leading to a controlled polysiloxane layer provides an ultrahigh payload of DOX (up to several folds the mass of the initial composites). Such new CNT‐based nanocomposites are demonstrated to release DOX at low acidic pH, high temperature (T), and remotely when they are excited by near infrared (NIR) light. Such nanoconstructs may find applications as components of innovative biomedical scaffolds for phototherapy combined with drug delivery.     

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.