NIR-triggered drug delivery system based on phospholipid coated ordered mesoporous carbon for synergistic chemo-photothermal therapy of cancer cells

Chemo-photothermal treatment is one of the most efficient strategies for cancer therapy. However, traditional drug carriers without near-infrared absorption capacity need to be loaded with materials behaving photothermal properties, as it results in complicated synthesis process, inefficient photothermal effects and hindered NIR-mediated drug release. Herein we report a facile synthesis of a polyethylene glycol (PEG) linked liposome (PEG-liposomes) coated doxorubicin (DOX)-loaded ordered mesoporous carbon (OMC) nanocomponents (PEG-LIP@OMC/DOX) by simply sonicating DOX and OMC in PEG-liposomes suspensions. The as-obtained PEG-LIP@OMC/DOX exhibits a nanoscale size (600±15 nm), a negative surface potential (-36.70 mV), high drug loading (131.590 mg/g OMC), and excellent photothermal properties. The PEG-LIP@OMC/DOX can deliver loaded DOX to human MCF-7 breast cancer cells (MCF-7) and the cell toxicity viability shows that DOX unloaded PEG-LIP@OMC has no cytotoxicity, confirming the PEG-LIP@OMC itself has excellent biocompatibility. The NIR-triggered release studies demonstrate that this NIR-responsive drug delivery system enables on-demand drug release. Furthermore, cell viability results using human MCF-7 cells demonstrated that the combination of NIR-based hyperthermal therapy and triggered chemotherapy can provide higher therapeutic efficacy than respective monotherapies. With these excellent features, we believe that this phospholipid coating based multifunctional delivery system strategy should promote the application of OMC in nanomedical applications.     

Dual‐Targeted Selenium Nanoparticles for Synergistic Photothermal Therapy and Chemotherapy of Tumors

A combination of chemo‐ and photothermal therapy has emerged as a promising tactic for cancer therapy. However, the intricacy of accurate delivery and the ability to initiate drug release in specific tumor sites remains a challenging puzzle. Hence, to assure that the chemotherapeutic drug and photothermal agent are synchronously delivered to a tumor area for their synergistic effect, dual‐target (RC‐12 and PG‐6 peptides) functionalized selenium nanoparticles loaded with both doxorubicin (DOX) and indocyanine green (ICG) were designed and successfully synthesized. The as‐synthesized nanoparticles exhibited good monodispersity, size stability, and consistent spectral characteristics compared with those of ICG or DOX alone. The nanoparticles underwent self‐immolated cleavage under irradiation from a near‐IR laser and released the loaded drug owing to sufficient hyperthermia. Moreover, the internalized nanoparticles triggered the overproduction of intracellular reactive oxygen species to induce cell apoptosis. Taken together, this study provides a sequentially triggered nanosystem to achieve precise drug delivery by chemo‐photothermal combination.     

Doxorubicin Encapsulated in TPGS-Modified 2D-Nanodisks Overcomes Multidrug Resistance

Multidrug resistance (MDR) is regarded as a main obstacle for effective chemotherapy, and P-glycoprotein (P-gp)-mediated drug efflux has been demonstrated to be the key factor responsible for MDR. In this study, a novel pH-responsive hybrid drug delivery system was developed by conjugating d -α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a kind of P-gp inhibitor, on the surface of laponite nanodisks to overcome MDR. The prepared LM-TPGS display excellent colloidal stability, a high encapsulation efficiency of doxorubicin (DOX), and a pH-responsive drug release profile. In vitro experiments verified that LM-TPGS/DOX could exhibit significantly enhanced therapeutic efficacy in treating DOX-resistant breast cancer cells (MCF-7/ADR) through inhibiting the activity of P-gp-mediated drug efflux and effectively accumulating DOX within cancer cells. In vivo results revealed that LM-TPGS/DOX outstandingly suppressed MCF-7/ADR tumors with low side effects. Therefore, the high drug payload, enhanced inhibition efficacy to drug-resistant cells, and low side effects make the LM-TPGS/DOX a promising nanoplatform to reverse MDR for effective chemotherapy.     

Silk Fibroin-Coated Liposomes as Biomimetic Nanocarrier for Long-Term Release Delivery System in Cancer Therapy

Despite much progress in cancer therapy, conventional chemotherapy can cause poor biodistribution and adverse side-effects on healthy cells. Currently, various strategies are being developed for an effective chemotherapy delivery system. Silk fibroin (SF) is a natural protein used in a wide range of biomedical applications including cancer therapy due to its biocompatibility, biodegradability, and unique mechanical properties. In this study, SF-coated liposomes (SF-LPs) were prepared as a biomimetic drug carrier. Physicochemical properties of SF-LPs were characterized by Fourier-transform infrared spectroscopy (FTIR), dynamic light scattering, zeta potential measurement, and transmission electron microscopy (TEM). In vitro release of SF-LPs loaded with doxorubicin (DOX-SF-LPs) was evaluated over 21 days. Anticancer activity of DOX-SF-LPs was determined against MCF-7 and MDA-MB231 cells using the MTT assay. SF-LPs containing 1% SF exhibited favorable characteristics as a drug carrier. SF coating modified the kinetics of drug release and reduced the cytotoxic effect against L929 fibroblasts as compared to the uncoated liposomes containing cationic lipid. DOX-SF-LPs showed anticancer activity against breast cancer cells after 48 h or 72 h at 20 μM of DOX. This approach provides a potential platform of long-term release that combines biocompatible SF and phospholipids for cancer therapy, achieving efficient drug delivery and reducing side-effects.     

Metal–organic frameworks as efficient materials for drug delivery: Synthesis,characterization, antioxidant,anticancer, antibacterial and molecular docking investigation

Metal–organic framework (MOF) nano particles are a class of promising porous nano materials for biomedical applications. Owing to its high loading potential and pH-sensitive degradation, most promising of the MOFs is the zeolitic imidazolate crystal framework (ZIF-8), a progressive useful material for small molecule distribution. Doxorubicin (DOX), designated as a classical drug, was jobwise entrapped in ZIF-8 nano particles. ZIF-8 nano particles, as a novel carrier, were used to monitor the release of the anticancer drug DOX and prevent it from dissipating before reaching its goal. ZIF-8 nano particles with encapsulated DOX (DOX@ZIF-8) can be synthesized in a single pot by incorporation of DOX into the reaction mixture. MOFs and the designed drug delivery (DOX@ZIF-8) system were characterized by Fourier transfer infrared, scanning electron microscopy, N₂ sorption isotherm and X-ray diffraction. The impact of MOFs and the engineered drug delivery system on the viability of human breast and liver cancer cell lines was evaluated. The loaded drug was released at pH 5 faster than at pH 7.4. The nano particles of ZIF-8 showed low cytotoxicity, while DOX@ZIF-8 showed high cytotoxicity to HepG-2 and MCF-7 cells compared with free DOX at the equivalent concentration of DOX of >12.5 μg/ml. These findings indicate that DOX@ZIF-8 nano particles are a promising method for the delivery of cancer cells to drugs. Furthermore, ZIF-8, DOX and encapsulated DOX@ZIF-8 compounds were screened for their potential antibacterial activities against pathogenic bacteria compared with standard antibiotics by the agar well diffusion technique. The results demonstrate that the DOX@ZIF-8 exhibits a strong inhibition zone against Gram-negative strains (Escherichia coli) in comparison with the reference drug gentamycin. The docking active site interactions were evaluated to predict the binding between DOX with the receptor of breast cancer 3hb5-oxidoreductase and liver cancer 2h80-lipid binding protein for anticancer activity.     

Spindle‐Like Polypyrrole Hollow Nanocapsules as Multifunctional Platforms for Highly Effective Chemo–Photothermal Combination Therapy of Cancer Cells in Vivo

The monodispersed spindle‐like polypyrrole hollow nanocapsules (PPy HNCs) as the multifunctional platforms for combining chemotherapy with photothermal therapy for cancer cells are reported. Whereas the hollow cavity of nanocapsules can be used to load the anticancer drug (i.e., doxorubicin) for chemotherapy, the PPy shells can convert NIR light into heat for photothermal therapy. The release of the drug from the spindle‐like PPy HNCs is pH‐sensitive and near‐infrared (NIR) light‐enhanced. More importantly, the spindle‐like PPy HNCs can penetrate cells more rapidly and efficiently in comparison with the spherical PPy HNCs. Both in vitro and in vivo experiments demonstrated that the combination of DOX‐loaded spindle‐like PPy HNCs and NIR light provide a highly effective and feasible chemo‐photothermal therapy cancer method with a synergistic effect. Owing to their high photothermal conversion efficiency, large hollow cavity, and good biocompatibility, the spindle‐like PPy HNCs could be used as a promising new cancer drug‐nanocarrier and photothermal agent for localized tumorous chemo‐photothermal therapy.     

Multiple-mRNA-controlled and heat-driven drug release from gold nanocages in targeted chemo-photothermal therapy for tumors

Multifunctional drug delivery systems enabling effective drug delivery and comprehensive treatment are critical to successful cancer treatment. Overcoming nonspecific release and off-target effects remains challenging in precise drug delivery. Here, we design triple-interlocked drug delivery systems to perform specific cancer cell recognition, controlled drug release and effective comprehensive therapy. Gold nanocages (AuNCs) comprise a novel class of nanostructures possessing hollow interiors and porous walls. AuNCs are employed as a drug carrier and photothermal transducer due to their unique structure and photothermal properties. A smart triple-interlocked I-type DNA nanostructure is modified on the surface of the AuNCs, and molecules of the anticancer drug doxorubicin (DOX) are loaded as molecular cargo and blocked. The triple-interlocked nanostructure can be unlocked by binding with three types of tumor-related mRNAs, which act as “keys” to the triple locks, sequentially, which leads to precise drug release. Additionally, fluorescence-imaging-oriented chemical–photothermal synergistic treatment is achieved under illumination with infrared light. This drug delivery system, which combines the advantages of AuNCs and interlocked I-type DNA, successfully demonstrates effective and precise imaging, drug release and photothermal therapy. This multifunctional triple-interlocked drug delivery system could be used as a potential carrier for effective cancer-targeting comprehensive chemotherapy and photothermal therapy treatments.

Schematic illustration of the multiple-mRNA-controlled and heat-driven drug release from gold nanocages.     

Self‐Assembled Supramolecular Nanogels as a Safe and Effective Drug Delivery Vector for Cancer Therapy

Simple construction and manipulation of low‐molecular‐weight supramolecular nanogels, based on the introduction of multiple hydrogen bonding interactions, with the desired physical properties to achieve effective and safe delivery of drugs for cancer therapy remain highly challenging. Herein, a novel supramolecular oligomer cytosine (Cy)‐polypropylene glycol containing self‐complementary multiple hydrogen‐bonded Cy moieties is developed, which undergoes spontaneous self‐assembly to form nanosized particles in an aqueous environment. Phase transitions and scattering studies confirm that the supramolecular nanogels can be readily tailored to obtain the desired phase‐transition temperature and temperature‐induced release of the anticancer drug doxorubicin (DOX). The resulting nanogels exhibit an extremely high load carrying capacity (up to 24.8%) and drug‐entrapment stability, making the loading processes highly efficient. Importantly, in vitro cytotoxicity assays indicate that DOX‐loaded nanogels possess excellent biosafety for drug delivery applications under physiological conditions. When the environmental temperature is increased to 40 °C, DOX‐loaded nanogels trigger rapid DOX release and exert cytotoxic effects, significantly reducing the dose required compared to free DOX. Given its simplicity, low cost, high reliability, and efficiency, this newly developed temperature‐responsive nanocarrier has highly promising potential for controlled release drug delivery systems.

     

Micro- and Nanosecond Pulses Used in Doxorubicin Electrochemotherapy in Human Breast and Colon Cancer Cells with Drug Resistance

(1) Background: Pulsed electric field (PEF) techniques are commonly used to support the delivery of various molecules. A PEF seems a promising method for low permeability drugs or when cells demonstrate therapy resistance and the cell membrane becomes an impermeable barrier. (2) Methods: In this study, we have used doxorubicin-resistant and sensitive models of human breast cancer (MCF-7/DX, MCF-7/WT) and colon cancer cells (LoVo, LoVoDX). The study aimed to investigate the susceptibility of the cells to doxorubicin (DOX) and electric fields in the 20–900 ns pulse duration range. The viability assay was utilized to evaluate the PEF protocols’ efficacy. Cell confluency and reduced glutathione were measured after PEF protocols. (3) Results: The obtained results showed that PEFs significantly supported doxorubicin delivery and cytotoxicity after 48 and 72 h. The 60 kV/cm ultrashort pulses × 20 ns × 400 had the most significant cytotoxic anticancer effect. The increase in DOX concentration provokes a decrease in cell viability, affected cell confluency, and reduced GSSH when combined with the ESOPE (European Standard Operating Procedures of Electrochemotherapy) protocol. Additionally, reactive oxygen species after PEF and PEF-DOX were detected. (4) Conclusions: Ultrashort electric pulses with low DOX content or ESOPE with higher DOX content seem the most promising in colon and breast cancer treatment.     

“Two‐Step” Raman Imaging Technique To Guide Chemo‐Photothermal Cancer Therapy

Graphene oxide‐wrapped gold nanorods (GO@AuNRs) offer efficient drug delivery as well as NIR laser photothermal therapy (PTT) in vitro and in vivo. However, no real‐time observation of drug release has been reported to better understand the synergy of chemotherapy and PTT. Herein, surface‐enhance Raman spectroscopy (SERS) is employed to guide chemo‐photothermal cancer therapy by a two‐step mechanism. In the presence of GO as an internal standard, SERS signals of DOX (doxorubicin) loaded onto GO@AuNRs are found to be pH‐responsive. Both DOX and GO show strong SERS signals before the DOX@GO@AuNRs are endocytic. However, when the DOX@GO@AuNRs enter acidic microenvironments such as endosomes and/or lysosomes, the DOX signals start decreasing while the GO signals remain the same. This plasmonic antenna could be used to identify the appropriate time to apply the PTT laser during chemo‐photothermal therapy.     

Ultrasound-Triggered Delivery of Iproplatin from Microbubble-Conjugated Liposomes

The Pt^IV prodrug iproplatin has been actively loaded into liposomes using a calcium acetate gradient, achieving a 3-fold enhancement in drug concentration compared to passive loading strategies. A strain-promoted cycloaddition reaction (azide- dibenzocyclooctyne) was used to attach iproplatin-loaded liposomes L(Pt) to gas-filled microbubbles (M), forming an ultrasound-responsive drug delivery vehicle [M−L(Pt)]. Ultrasound-triggered release of iproplatin from the microbubble-liposome construct was evaluated in cellulo. Breast cancer (MCF-7) cells treated with both free iproplatin and iproplatin-loaded liposome−microbubbles [M−L(Pt)] demonstrated an increase in platinum concentration when exposed to ultrasound. No appreciable platinum uptake was observed in MCF-7 cells following treatment with L(Pt) only or L(Pt)+ultrasound, suggesting that microbubble-mediated ultrasonic release of platinum-based drugs from liposomal carriers enables greater control over drug delivery.     

Hyperbranched copolymer micelles as delivery vehicles of doxorubicin in breast cancer cells

Four types of drug nanoparticles (NPs) based on amphiphilic hyperbranched block copolymers were developed for the delivery of the chemotherapeutic doxorubicin (DOX) to breast cancer cells. These carriers have their hydrophobic interior layer composed of the hyperbranched aliphatic polyester, Boltorn^® H30 or Boltorn^® H40, that are polymers of poly 2,2‐bis (methylol) propionic acid (bis‐MPA), while the outer hydrophilic shell was composed of about 5 poly(ethylene glycol) (PEG) segments of 5 or 10 kDa molecular weight. A chemotherapeutic drug DOX, was further encapsulated in the interior of these polymer micelles and was shown to exhibit a controlled release profile. Dynamic light scattering and transmission electron microscopy analysis confirmed that the NPs were uniformly sized with a mean hydrodynamic diameter around 110 nm. DOX‐loaded H30‐PEG10k NPs exhibited controlled release over longer periods of time and greater cytotoxicity compared with the other materials developed against our tested breast cancer cell lines. Additionally, flow cytometry and confocal scanning laser microscopy studies indicated that the cancer cells could internalize the DOX‐loaded H30‐PEG10k NPs, which contributed to the sustained drug release, and induced more apoptosis than free DOX did. These findings indicate that the H30‐PEG10k NPs may offer a very promising approach for delivering drugs to cancer cells. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Folate‐Conjugated and Dual Stimuli‐Responsive Mixed Micelles Loading Indocyanine Green for Photothermal and Photodynamic Therapy

A folic acid targeted mixed micelle system based on co‐assembly of poly(ε‐caprolactone)‐b‐poly(methoxytri(ethylene glycol) methacrylate‐co‐N‐(2‐methacrylamido)ethyl folatic amide) and poly(ε‐caprolactone)‐b‐poly(diethylene glycol monomethyl ether methacrylate) is developed to encapsulate indocyanine green (ICG) for photothermal therapy and photodynamic therapy. In this study, the use of folic acid is not only for specific cancer cell recognition, but also in virtue of the carboxylic acid on folic acid to regulate the pH‐dependent thermal phase transition of polymeric micelles for controlled drug release. The prepared ICG‐loaded mixed micelles possess several superior properties such as a preferable thermoresponsive behavior, excellent storage stability, and good local hyperthermia and reactive oxygen species generation under near‐infrared (NIR) irradiation. The photototoxicity induced by the ICG‐loaded micelles has efficiently suppressed the growth of HeLa cells (folate receptor positive cells) under NIR irradiation compared to that of HT‐29, which has low folate receptor expression. Hence, this new type of mixed micelles with excellent features could be a promising delivery system for controlled drug release, effective cancer cell targeting, and photoactivated therapy.     

Tumour‐Targeted Drug Delivery with Mannose‐Functionalized Nanoparticles Self‐Assembled from Amphiphilic β‐Cyclodextrins

Multivalent mannose‐functionalized nanoparticles self‐assembled from amphiphilic β‐cyclodextrins (β‐CDs) facilitate the targeted delivery of anticancer drugs to specific cancer cells. Doxorubicin (DOX)‐loaded nanoparticles equipped with multivalent mannose target units were efficiently taken up via receptor‐mediated endocytosis by MDA‐MB‐231 breast cancer cells that overexpress the mannose receptor. Upon entering the cell, the intracellular pH causes the release of DOX, which triggers apoptosis. Targeting by multivalent mannose significantly improved the capability of DOX‐loaded nanoparticles to inhibit the growth of MDA‐MB‐231 cancer cells with minimal side effects in vivo. This targeted and controlled drug delivery system holds promise as a nanotherapeutic for cancer treatment.     

pH‐sensitive carbon quantum dots−doxorubicin nanoparticles for tumor cellular targeted drug delivery

A kind of pH‐responsive carbon quantum dots?doxorubicin nanoparticles drug delivery platform (D‐Biotin/DOX‐loaded mPEG‐OAL/N‐CQDs) was designed and synthesized. The system consists of fluorescent carbon dots as cross‐linkers, and D‐Biotin worked as targeting groups, which made the system have a pH correspondence, doxorubicin hydrochloride (DOX) as the target drug, oxidized sodium alginate (OAL) as carrier materials. Ultraviolet (UV)‐Vis spectrum showed that the drug‐loading rate of DOX is 10.5%, and the drug release in vitro suggested that the system had a pH response and tumor cellular targeted, the drug release rate is 65.6% at the value of pH is 5.0, which is much higher than that at the value of pH is 7.4. The cytotoxicity test and laser confocal fluorescence imaging showed that the synthesized drug delivery system has high cytotoxicity to cancer cells, and the drug‐loaded nanoparticles could enter the cells through endocytosis.     

Near‐Infrared Light and pH‐Responsive Polypyrrole@Polyacrylic acid/Fluorescent Mesoporous Silica Nanoparticles for Imaging and Chemo‐Photothermal Cancer Therapy

We have rationally designed a new theranostic agent by coating near‐infrared (NIR) light‐absorbing polypyrrole (PPY) with poly(acrylic acid) (PAA), in which PAA acts as a nanoreactor and template, followed by growing small fluorescent silica nanoparticles (fSiO₂ NPs) inside the PAA networks, resulting in the formation of polypyrrole@polyacrylic acid/fluorescent mesoporous silica (PPY@PAA/fmSiO₂) core–shell NPs. Meanwhile, DOX‐loaded PPY@PAA/fmSiO₂ NPs as pH and NIR dual‐sensitive drug delivery vehicles were employed for fluorescence imaging and chemo‐photothermal synergetic therapy in vitro and in vivo. The results demonstrate that the PPY@PAA/fmSiO₂ NPs show high in vivo tumor uptake by the enhanced permeability and retention (EPR) effect after intravenous injection as revealed by in vivo fluorescence imaging, which is very helpful for visualizing the location of the tumor. Moreover, the obtained NPs inhibit tumor growth (95.6 % of tumors were eliminated) because of the combination of chemo‐photothermal therapy, which offers a synergistically improved therapeutic outcome compared with the use of either therapy alone. Therefore, the present study provides new insights into developing NIR and pH‐stimuli responsive PPY‐based multifunctional platform for cancer theranostics.     

A Near‐Infrared Photothermal Effect‐Responsive Drug Delivery System Based on Indocyanine Green and Doxorubicin‐Loaded Polymeric Micelles Mediated by Reversible Diels–Alder Reaction

Near‐infrared light (NIR) possesses great advantages for light‐responsive controllable drug release, such as deep tissue penetration and low damage to healthy tissues. Herein, a NIR‐responsive drug delivery system is developed based on a NIR dye, indocyanine green (ICG), and anticancer drug, doxorubicin (DOX)‐loaded thermoresponsive block copolymer micelles, in which the drug release can be controlled via NIR irradiation. First, block copolymers, poly(oligo(ethylene glycol) methacrylate)‐block‐poly(furfuryl methacrylate) (POEGMA‐b‐PFMA), are synthesized by sequential reversible addition‐fragmentation chain‐transfer (RAFT) polymerization, followed by modification with N‐octyl maleimide through Diels–Alder (DA) reaction to produce POEGMA‐b‐POMFMA. The self‐assembly of POEGMA‐b‐POMFMA by nano­precipitation in aqueous solution affords the polymeric micelles which are used to simultaneously encapsulate ICG and DOX. Upon irradiation by NIR light (805 nm), the loaded DOX is released rapidly from the micelles due to partial retro DA reaction and local temperature increase‐induced faster drug diffusion by the photothermal effect. Cytotoxicity evaluation and intracellular distribution observation demonstrate significant synergistic effects of NIR‐triggered drug release, photothermal, and chemotherapy toward cancer cells under NIR irradiation.

     

Loading-free supramolecular organic framework drug delivery systems (sof-DDSs)for doxorubicin: normal plasm and multidrug resistant cancer cell-adaptive delivery and release

Four water-soluble porous supramolecular organic framework drug delivery systems(sof-DDSs)have been used to adsorb doxorubicin(DOX)in water at physiological pH of 7.4,which is driven exclusively by hydrophobicity.The resulting complexes DOX@SOFs are formed instantaneously upon dissolving the components in water.The drug-adsorbed sof-DDSs can undergo plasm circulation with important maintenance of the drug and overcome the multidrug resistance of human breast MCF-7/Adr cancer cells. DOX is released readily in the cancer cells due to the protonation of its amino group in the acidic medium of cancer cells.In vitro and in vivo experiments reveal that the delivery of SOF-a-d remarkably improve the cytotoxicity of DOX for the MCF-7/Adr cells and tumors,leading to 13-19-fold reduction of the IC50 values as compared with that of DOX.This new sof-DDSs strategy omits the indispensable loading process required by most of reported nano-scaled carriers for neutral hydrophobic chemotherapeutic agents,and thus should be highly valuable for future development of low-cost delivery systems.     

Hollow‐Core Magnetic Colloidal Nanocrystal Clusters with Ligand‐Exchanged Surface Modification as Delivery Vehicles for Targeted and Stimuli‐Responsive Drug Release

The fabrication of hierarchical magnetic nanomaterials with well‐defined structure, high magnetic response, excellent colloidal stability, and biocompatibility is highly sought after for drug‐delivery systems. Herein, a new kind of hollow‐core magnetic colloidal nanocrystal cluster (HMCNC) with porous shell and tunable hollow chamber is synthesized by a one‐pot solvothermal process. Its novelty lies in the “tunability” of the hollow chamber and of the pore structure within the shell through controlled feeding of sodium citrate and water, respectively. Furthermore, by using the ligand‐exchange method, folate‐modified poly(acrylic acid) was immobilized on the surface of HMCNCs to create folate‐targeted HMCNCs (folate‐HMCNCs), which endowed them with excellent colloidal stability, pH sensitivity, and, more importantly, folate receptor‐targeting ability. These assemblages exhibited excellent colloidal stability in plasma solution. Doxorubicin (DOX), as a model anticancer agent, was loaded within the hollow core of these folate‐HMCNCs (folate‐HMCNCs‐DOX), and drug‐release experiments proved that the folate‐HMCNCs‐DOX demonstrated pH‐dependent release behavior. The folate‐HMCNCs‐DOX assemblages also exhibited higher potent cytotoxicity to HeLa cells than free doxorubicin. Moreover, folate‐HMCNCs‐DOX showed rapid cell uptake apart from the enhanced cytotoxicity to HeLa cells. Experimental results confirmed that the synthesized folate‐HMCNCs are smart nanovehicles as a result of their improved folate receptor‐targeting abilities and also because of their combined pH‐ and magnetic‐stimuli response for applications in drug delivery.     

Drug Self‐Delivery Systems Based on Hyperbranched Polyprodrugs towards Tumor Therapy

Amphiphilic hyperbranched polyprodrugs (DOX‐S‐S‐PEG) with drug repeat units in hydrophobic core linked by disulfide bonds were developed as drug self‐delivery systems for cancer therapy. The hydroxyl groups and the amine group in doxorubicin (DOX) were linked by 3,3′‐dithiodipropanoic acid as hydrophobic hyperbranched cores, then amino‐terminated polyethylene glycol monomethyl ether (mPEG‐NH₂) as hydrophilic shell was linked to hydrophobic cores to form amphiphilic and glutathione (GSH)‐responsive micelle of hyperbranched polyprodrugs. The amphiphilic micelles can be disrupted under GSH (1 mg mL^?1) circumstance. Cell viability of A549 cells and 293T cells was evaluated by CCK‐8 and Muse Annexin V & Dead Cell Kit. The disrupted polyprodrugs maintained drug activity for killing tumor cells. Meanwhile, the undisrupted polyprodrugs possessed low cytotoxicity to normal cells. The cell uptake experiments showed that the micelles of DOX‐S‐S‐PEG were taken up by A549 cells and distributed to cell nuclei. Thus, the drug self‐delivery systems with drug repeat units in hydrophobic cores linked by disulfide bonds showed significant special advantages: 1) facile one‐pot synthesis; 2) completely without toxic or non‐degradable polymers; 3) DOX itself functions as fluorescent labeled molecule and self‐delivery carrier; 4) drug with inactive form in hyperbranched cores and low cytotoxicity to normal cells. These advantages make them excellent drug self‐delivery systems for potential high efficient cancer therapy.