Drug‐Conjugation Induced Self‐Assembly of Feather Keratin‐Based Prodrug for Tumor Intracellular Reduction Triggered Drug Delivery

As a kind of natural protein, keratin is widely investigated in the biomedical field. Here, for the first time, a keratin‐based prodrug (PK‐SS‐D) is designed for tumor intracellular reduction triggered drug delivery, by conjugating doxorubicin (DOX) onto poly(ethylene glycol) modified keratin (PEGylated keratin, PK) with a bioreducible disulfide linkage. The protein‐drug conjugate prodrug, with a drug content of 20%, can self‐assemble into micelles with a mean hydrodynamic diameter of 175 nm and a narrow distribution. The in vitro controlled release profiles reveal the reduction triggered thiolated DOX (DOX‐SH) release behavior of the PK‐SS‐D micelles, with a cumulative drug release up to 52% within 10 d in the simulated tumor microenvironment in a sustained releasing mode, and a low drug leakage of 17% in the simulated normal physiological medium. The enhanced tumor growth inhibition of the proposed PK‐SS‐D prodrug micelles is revealed by the methyl tetrazolium (MTT) assays, although the released DOX‐SH prodrug possesses a lower tumor growth inhibition than DOX.     

Magnetic iron oxide nanoparticle-hollow mesoporous silica Spheres:Fabrication and potential application in drug delivery

A facile method is developed for the fabrication of magnetic iron oxide nanoparticle-hollow mesoporous silica spheres (IONP-HMSs) and explored their potential application in drug delivery. Through the self-assembling process of IONPs and the formation of mesoporous silica shells, the IONP-HMSs with hollow interior cavity were obtained. The cetyltrimethyl ammonium bromide (CTAB) encapsulated IONP-containing spheres served as the template to establish the mesoporous silica shells. Typical anti-cancer drug, doxorubicin hydrochloride (DOX) was applied for drug loading and release process of IONP-HMSs, which demonstrated the IONP-HMSs have a high drug loading efficiency and allow pH-trigged release of DOX in vitro. Moreover, the IONP-HMSs exhibited excellent biocompatibility and enhanced DOX therapeutic efficacy to HeLa cells. Compared with traditional methods, the reported microemulsion-based method for the synthesis of IONP-HMSs enables the formation of hollow-structured nanocomposite without any complex template-removing process, which could pave the way to improving the therapeutic efficacy in drug delivery system.     

Photo-activated pheophorbide a inhibits the growth of prostate cancer cells

Pheophorbide a (PhA) was identified as a photosensitizer to exert cytotoxicity on tumor cells. However, the efficacy of this compound on the treatment of prostate cancer remains unknown. The aim of this study was to evaluate the photodynamic effect of PhA on prostate cancer cells. Cellular uptake of PhA and cell viability after photo-activation was studied in LNCaP prostate cancer cells. The corresponding production of reactive oxygen species within cells was determined after photodynamic therapy (PDT). Our results showed that the uptake of PhA into LNCaP cells was in a time-dependent manner and the cytotoxicity of PhA-PDT was photosensitizer dose- and light dose-dependent. The intracellular reactive oxygen species was remarkably induced after PDT treatment, which was responsible for the inhibition effect on prostate cancer cells. This is the first report to evaluate the photodynamic effect of PhA on prostate cancer. Our findings demonstrate that PhA-PDT may be a potentially promising treatment for localized prostate cancer, which can be a therapeutic option after the failures of radiotherapy and hormone therapy.     

Self‐Assembly of Drug–Drug Conjugates as Drug Self‐Delivery System for Tumor‐Specific pH‐Triggered Release

An acid‐labile doxorubicin dimer (D‐DOX) is designed as drug–drug conjugate for tumor intracellular pH‐triggered release, by conjugating doxorubicin (DOX) with adipic acid dihydrazide (ADH). The dimer‐based surfactants modified with polyethylene glycol (PEG), DOX‐ADH‐DOX‐PEG or are synthesized by mono‐PEGylation and bi‐PEGylation, respectively. Then the prodrug nanoparticles are fabricated with different drug contents via dialyzing the mixture solution of D‐DOX and the PEGylated surfactants in dimethyl sulfoxide (DMSO) with different mass ratios against water. It is found that the smaller prodrug nanoparticles (142–163 nm) could be obtained with the mono‐PEGylated surfactant, than those of 157–225 nm with the bi‐PEGylated surfactant. Furthermore, the mono‐PEGylated surfactant results in a higher drug content of 51% due to their lower PEG contents. All prodrug nanoparticles could release DOX completely within 36 h at pH 5.0, with the premature drug leakage of less than 10% at pH 7.4. The 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assays demonstrate the proposed drug self‐delivery system possessed an enhanced anticancer efficacy against HepG2 cells than the free DOX.     

Peptide‐Targeted Gold Nanoparticles for Photodynamic Therapy of Brain Cancer

Targeted drug delivery using epidermal growth factor peptide‐targeted gold nanoparticles (EGF_pep‐Au NPs) is investigated as a novel approach for delivery of photodynamic therapy (PDT) agents, specifically Pc 4, to cancer. In vitro studies of PDT show that EGF_pep‐Au NP‐Pc 4 is twofold better at killing tumor cells than free Pc 4 after increasing localization in early endosomes. In vivo studies show that targeting with EGF_pep‐Au NP‐Pc 4 improves accumulation of fluorescence of Pc 4 in subcutaneous tumors by greater than threefold compared with untargeted Au NPs. Targeted drug delivery and treatment success can be imaged via the intrinsic fluorescence of the PDT drug Pc 4. Using Pc 4 fluorescence, it is demonstrated in vivo that EGF_pep‐Au NP‐Pc 4 impacts biodistribution of the NPs by decreasing the initial uptake by the reticuloendothelial system (RES) and by increasing the amount of Au NPs circulating in the blood 4 h after IV injection. Interestingly, in vivo PDT with EGF_pep‐Au NP‐Pc 4 results in interrupted tumor growth when compared with EGF_pep‐Au NP control mice when selectively activated with light. These data demonstrate that EGF_pep‐Au NP‐Pc 4 utilizes cancer‐specific biomarkers to improve drug delivery and therapeutic efficacy over untargeted drug delivery.     

A Functionalized Hollow Mesoporous Silica Nanoparticles‐Based Controlled Dual‐Drug Delivery System for Improved Tumor Cell Cytotoxicity

Multifunctional nanoparticles for selectively targeting tumor cells and effectively delivering multiple drugs are urgently needed in cancer therapy. Here, a dual‐drug delivery system is prepared, based on functionalized hollow mesoporous silica nanoparticles (HMSNs). Doxorubicin (DOX) hydrochloride is loaded into the hollow core, and dichloro(1,2‐diaminocyclohexane)platinum (II) (DACHPt) is stored in the pores of the shell by the coordination interaction with the carboxyl groups modified on the pore walls, which also serves as barriers to control the DOX release. Detailed studies in vitro indicate that the DACHPt release is triggered by Cl^? through the cleavage of the coordination interaction, and the DOX release depends on the release rate of DACHPt and the environmental pH value. The surface of the mechanized nanoparticles is also modified by transferrin (Tf) to achieve the tumor specificity. Compared with individual drug delivery systems, the dual‐drug delivery system shows synergistic efficacy on the cell cytotoxicity (combination index = 0.30), resulting in improved tumor cell killing. The present dual‐drug delivery system provides a promising strategy to develop controlled and targeted combination therapies for efficient cancer treatment.     

GLUT1-Targeting and GSH-Responsive DOX/L61 Nanodrug Particles for Enhancing MDR Breast Cancer Therapy

Efficient targeting to tumor tissues and subsequent rapid drug release in cancer cells remains a major challenge for nanodrug delivery systems. Herein, smart nanodrug particles with reduction-sensitive and active tumor-targeting ability are constructed based on the nanoprecipitation of glucosamine-grafted pluronic L61 (GA-L61) and disulphide-linked doxorubicin dimer (DOX SS DOX) to overcome tumor multidrug resistance (MDR). These nanoparticles show proper size and excellent stability under neutral conditions, while quickly release DOX due to the breakage of disulfide bonds under reductive medium. In vitro cellular uptake and drug efflux demonstrate that L61 can efficiently increase DOX concentration in MCF/ADR resistant cells by inhibiting the function of drug resistance proteins. In vivo biodistribution reveals that glucose transporter 1 (GLUT1)-mediated tumor-targeting significantly improves tumor accumulation of the glucosamine-contained nanoparticles. Finally, the combination of GLUT1-targeting, glutathione (GSH)-responsive, and MDR-reversal effects in nanoparticles achieve superior antitumor effects, which can provide an efficient, safe, and economic approach for drug delivery and cancer chemotherapy.     

Human‐Serum‐Albumin‐Coated Prussian Blue Nanoparticles as pH‐/Thermotriggered Drug‐Delivery Vehicles for Cancer Thermochemotherapy

Constructing novel multimodal antitumor therapeutic nanoagents has attracted tremendous recent attention. In this work, a new drug‐delivery vehicle based on human‐serum‐albumin (HSA)‐coated Prussian blue nanoparticles (PB NPs) is synthesized. It is demonstrated that doxorubicin (DOX)/HSA is successfully loaded after in situ polymerization of dopamine onto PB NPs, and the PB@PDA/DOX/HSA NPs are highly compatible and stable in various physiological solutions. The NPs possess strong near‐infrared (NIR) absorbance, and excellent capability and stability of photothermal conversion for highly efficient photothermal therapy applications. Furthermore, a bimodal on‐demand drug release sensitively triggered by pH or NIR irradiation has been realized, resulting in a significant chemotherapeutic effect due to the preferential uptake and internalization of the NPs by cancer cells. Importantly, the thermochemotherapy efficacy of the NPs has been examined by a cell viability assay, revealing a remarkably superior synergistic anticancer effect over either monotherapy. Such multifunctional drug‐delivery systems composed of approved materials may have promising biomedical applications for antitumor therapy.     

Construction of a Dual Drug Carrier on the Basis of Hollow Structured Upconversion Nanoparticles for pH‐Responsive Drug Delivery and UCL/MRI Dual Mode Imaging

A series of Gd³⁺ doping hollow upconversion nanoparticles NaYF₄:Yb,Gd,Tm (h‐UNCP) are prepared successfully. The hollow NaYF₄:Yb,Gd,Tm possess excellent upconversion luminescence (UCL) and large longitudinal relativity (r₁ = 128.3 mm ^?1 s^?1), which can be potentially used for UCL/magnetic resonance imaging (MRI) dual mode imaging. On the basis of the optimal h‐UCNP, doxorubicin hydrochloride (DOX) and methotrexate (MTX) are used as drug models to prepare a dual drug carrier. After the encapsulation of DOX on the h‐UCNP, chitosan (CS) is further wrapped and then used to load MTX to obtain a dual drug carrier h‐UCNPs/DOX/CS/MTX. The pH responsive release of DOX and MTX is discussed. The MTX release climbs from 33% to 100% by regulating the pH from 5.8 to 7.4. The DOX release is different at different pH conditions. The synergistic effect of DOX and MTX on the cancer cells is confirmed by cell viability. The h‐UCNPs/DOX/CS/MTX are tracked by cells UCL imaging and vivo MRI imaging. The excellent performance of UCL imaging and positive MRI images demonstrates that h‐UCNPs/DOX/CS/MTX can be used for UCL/MRI dual mode imaging. All the results show the potential application of h‐UCNPs/DOX/CS/MTX in pH responsive release and UCL/MRI dual imaging.     

Photothermal/Photodynamic Therapy with Immune‐Adjuvant Liposomal Complexes for Effective Gastric Cancer Therapy

A diagnosis and therapeutic strategy for gastric cancer is developed herein by combining thermosensitive liposomal (TSL)‐based photothermal/photodynamics therapy (PTT/PDT) with chemotherapy and adjuvant immunotherapy. IR820, a photothermal agent, paclitaxel (PTX), an antitumor drug, and imiquimod (R837), a Toll‐like‐receptor‐7 agonist, are coencapsulated into a TSL drug delivery system. These formed PTX‐R837‐IR820@TSL complexes exhibit excellent optical properties, good dispersibility, and stability. Under NIR light irradiation, the measurement of singlet oxygen production and thermal efficiency indicate promising potential of PTX‐R837‐IR820@TSL complexes for PTT and PDT. Confocal microscopy and small animal NIR imaging demonstrate tumor targeting ability of the liposomal complexes to gastric cancer cells. In vitro cell viability assays and in vivo animal experiments show prominent antitumor efficiency of PTX‐R837‐IR820@TSL complexes upon NIR light irradiation. This excellent therapeutic efficacy is attributed to the simultaneous chemotherapy and PTT/PDT. Furthermore, the liposomal complexes under NIR irradiation would ablate tumors to generate a pool of tumor‐associated antigens, which is able to promote strong antitumor immune responses in the presence of those R837‐containing liposomal complexes acted as adjuvant. These results indicate that the multifunctional liposomal complexes could realize a remarkable synergistic therapeutic outcome in gastric carcinoma.     

具有双重治疗机制的磁性纳米无定型氧化铁基药物递送系统

合成一种具有pH响应性的聚乙二醇(PEG)修饰无定形介孔氧化铁纳米粒子(AFe-PEG). 这种纳米粒子可以高效负载药物分子如阿霉素(DOX),构成新型多功能AFe-PEG/DOX药物递送体系. DOX的负载率高达948 mg/g-纳米粒子. 在酸性溶液中,AFe-PEG/DOX纳米粒子不仅可以有效释放DOX,同时可以释放Fe离子进行Fenton反应,将H₂O₂转变成·OH自由基. 体外实验结果表明,AFe-PEG/DOX纳米粒子对HeLa细胞同时具有化疗和化学动力学疗法的疗效. 同时,由于AFe-PEG/DOX 纳米粒子本身的磁性,使其在外部磁场中的细胞内化效率也得到了提高.     

Encapsulating doxorubicin-intercalated lamellar nanohydroxyapatite into PLGA nanofibers for sustained drug release

In this work, doxorubicin (DOX) was intercalated into layered nanohydroxyapatite (LHAp). The drug loaded LHAp (DOX@LHAp) was then mixed with poly(lactic-co-glycolic acid) (PLGA) and electrospun to yield DOX@LHAp/PLGA composite scaffolds. As control, needle-like nanohydroxyapatite (nHAp) was also used to make an DOX@nHAp/PLGA composite scaffold and bare DOX was used to fabricate DOX/PLGA scaffold. The morphology, release behavior of DOX, and capability to inhibit cancer cells were assessed. The addition of DOX-loaded nHAp to PLGA causes a slight decrease in the average fiber diameter of DOX@LHAp/PLGA as compared to PLGA. The in vitro drug release tests reveal a much faster release of DOX from DOX/PLGA than DOX@LHAp/PLGA. Moreover, DOX@LHAp/PLGA displays a more sustainable release over DOX@nHAp/PLGA due to the storage of DOX in the gallery of LHAp, which is further proved by their cancer cell inhibition results. We believe that the DOX@LHAp/PLGA scaffold has potential as an implantable drug delivery system.     

Glutathione‐Mediated Degradation of Surface‐Capped MnO2 for Drug Release from Mesoporous Silica Nanoparticles to Cancer Cells

Owing to its higher concentration in cancer cells than that in the corresponding normal cells, glutathione (GSH) provides an effective and flexible mechanism to design drug delivery systems. Here a novel GSH‐responsive mesoporous silica nanoparticle (MSN) is reported for controlled drug release. In this system, manganese dioxide (MnO₂) nanostructure, formed by the reduction of KMnO₄ on the surface of carboxyl‐functionalized MSN can block the pores (MSN@MnO₂). By a redox reaction, the capped MnO₂ nanostructure can dissociate into Mn²⁺ in the presence of GSH molecules. The blocked pores are then uncapped, which result in the release of the entrapped drugs. As a proof‐of‐concept, doxorubicin (DOX) as model drug is loaded into MSN@MnO₂. DOX‐loaded MSN@MnO₂ shows an obvious drug release in 10 × 10^?3 m GSH, while no release is observed in the absence of GSH. In vitro studies using human hepatocellular liver carcinoma cell line (HepG2) prove that the DOX‐loaded MSN@MnO₂ can entry into HepG2 cells and efficiently release the loaded DOX, leading to higher cytotoxicity than to that of human normal liver cells (L02). It is believed that further developments of this GSH‐responsive drug delivery system will lead to a new generation of nanodevices for intracellular controlled delivery.     

Polydopamine Nanoparticle as a Multifunctional Nanocarrier for Combined Radiophotodynamic Therapy of Cancer

Combination of different therapeutic strategies to treat cancer has attracted tremendous attention in recent years. Herein, the authors develop polydopamine (PDA) nanoparticles with polyethylene glycol (PEG) modification as a multifunctional nanocarrier for coloading photosensitizer chlorine6 (Ce6) and curcumin (Cur) for combined photodynamic therapy (PDT) and radiotherapy (RT) of cancer. PEGylated PDA nanoparticles (PDA‐PEG) exhibit well water soluble and biocompatible in different physiological solutions and cause no obvious toxicity to cancer cells. In this nanoparticle, the loaded Ce6 can trigger the generation of single oxygen under near‐infrared laser irradiation for PDT, while the loaded Cur can act as an excellent radiosensitizer under X‐ray irradiation for enhanced external RT. As demonstrated by in vitro and in vivo therapeutic efficiency, combined PDT and RT based on PDA‐PEG/Cur/Ce6 nanoparticles exhibits significant inhibition the growth of cancer cells, revealing perfect performance in cancer treatment. Therefore, the study not only presents a polymer‐based theranostic platform for cancer treatment but also demonstrates the potential applications of combined RT and PDT for the future clinic cancer therapy.     

In Vitro Evaluation of Non‐Protein Adsorbing Breast Cancer Theranostics Based on 19F‐Polymer Containing Nanoparticles

Eight fluorinated nanoparticles (NPs) are synthesized, loaded with doxorubicin (DOX), and evaluated as theranostic delivery platforms to breast cancer cells. The multifunctional NPs are formed by self‐assembly of either linear or star‐shaped amphiphilic block copolymers, with fluorinated segments incorporated in the hydrophilic corona of the carrier. The sizes of the NPs confirm that small circular NPs are formed. The release kinetics data of the particles reveals clear hydrophobic core dependence, with longer sustained release from particles with larger hydrophobic cores, suggesting that the DOX release from these carriers can be tailored. Viability assays and flow cytometry evaluation of the ratios of apoptosis/necrosis indicate that the materials are non‐toxic to breast cancer cells before DOX loading; however, they are very efficient, similar to free DOX, at killing cancer cells after drug encapsulation. Both flow cytometry and confocal microscopy confirm the cellular uptake of NPs and DOX‐NPs into breast cancer cells, and in vitro ¹⁹F‐MRI measurement shows that the fluorinated NPs have strong imaging signals, qualifying them as a potential in vivo contrast agent for ¹⁹F‐MRI.     

Temperature and Redox Dual‐Responsive Biodegradable Nanogels for Optimizing Antitumor Drug Delivery

The strategy to efficiently deliver antitumor drugs via nanocarriers to targeted tumor sites and achieve controllable drug release is attracting great research interest in cancer therapy. In this study, a novel type of disulfide‐bonded poly(vinylcaprolactam) (PVCL)‐based nanogels with tunable volume phase transition temperature and excellent redox‐labile property are prepared. The nanogels are hydrophilic and swell at 37 °C, whereas under hyperthermia (e.g., 41 °C), the nanogels undergo sharp hydrophilic/hydrophobic transition and volume collapse, which enhances the cellular uptake and drug release. The incorporation of disulfide bond linkers endows the nanogels with an excellent disassembly property in reducing environments, which greatly facilitates drug release in tumor cells. Nanogels loaded with doxorubicin (DOX) (DOX‐NGs) (DOX‐NGs) are stable in physiological conditions with low drug leakage (15% in 48 h), while burst release of DOX (92% in 12 h) can be achieved in the presence of 10 × 10^?3 m glutathione and under hyperthermia. The DOX‐NGs possess improved cell killing efficiency under hyperthermia (IC₅₀ decreased from 1.58 μg mL^?1 under normothermia to 0.5 μg mL^?1). Further, the DOX‐NGs show a pronounced tumor inhibition rate of 46.6% compared with free DOX, demonstrating that this new dual‐responsive nanogels have great potential as drug delivery carriers for cancer therapy in vivo.     

Carbon Dots‐Cluster‐DOX Nanocomposites Fabricated by a Co‐Self‐Assembly Strategy for Tumor‐Targeted Bioimaging and Therapy

Carbon‐based nanomaterials could afford versatile potential applications in biomedical optical imaging and as nanoparticle drug carriers, owing to their promising optical and biocompatible capabilities. In this paper, it is first found that amphipathic cetylpyridinium chloride (CPC)‐stabilized oil‐soluble carbon dots (CDs) could self‐assemble into hydrophilic CDs clusters with hydrophobic core under ultrasound, in which CPC acts as carbon source, stabilizer, and phase transfer agent. Next, the size‐control (for size‐dependent passive tumor targeting) and doxorubicin (DOX) uploading of aqueous CDs clusters, and subsequent surface charge modification via overcoating with cRGD‐ and octylamine‐modified polyacrylic acid (cRGD‐PAA‐OA) (reversing their surface charges into negative and introducing active tumor‐targeting ability) are explored systematically. Based on this sequential administration mode, CDs‐cluster‐DOX/cRGD‐PAA‐OA nanocomposites exhibit selective human malignant glioma cell line (U87MG) tumor targeting. In in vitro drug release experiments, the nanocomposites could release DOX timely. Owning to the dual tumor targeting effects and seasonable drug release, CDs‐cluster‐DOX/cRGD‐PAA‐OA show remarkably tumor targetability and enhanced antitumor efficacy (and reduced adverse reaction), comparing to free DOX in animal models. These results indicate that fabricating nanocomposite via co‐self‐assembly strategy is efficient toward drug delivery system for tumor‐targeting theranostic.     

Folate-decorated chitosan/doxorubicin poly(butyl)cyanoacrylate nanoparticles for tumor-targeted drug delivery

A novel chitosan coated poly(butyl cyanoacrylate) (PBCA) nanoparticles loaded doxorubicin (DOX) were synthesized and then conjugated with folic acid to produce a folate-targeted drug carrier for tumor-specific drug delivery. Prepared nanoparticles were surface modified by folate for targeting cancer cells, which is confirmed by FTIR spectroscopy and characterized for shape, size, and zeta potential measurements. The size and zeta potential of prepared DOX-PBCA nanoparticles (DOX-PBCA NPs) were almost 174 ± 8.23 nm and +23.14 ± 4.25 mV, respectively with 46.8 ± 3.32% encapsulation capacity. The transmission electron microscopy study revealed that preparation allowed the formation of spherical nanometric and homogeneous. Fluorescent microscopy imaging and flow cytometry analysis revealed that DOX-PBCA NPs were endocytosed into MCF-7 cells through the interaction with overexpressed folate receptors on the surface of the cancer cells. The results demonstrate that folate-conjugated DOX-PBCA NPs drug delivery system could provide increased therapeutic benefit by delivering the encapsulated drug to the folate receptor positive cancer cells.     

A Multifunctional Nanocrystalline CaF2:Tm,Yb@mSiO2 System for Dual‐Triggered and Optically Monitored Doxorubicin Delivery

Daunting challenges in investigating the controlled release of drugs in complicated intracellular microenvironments demand the development of stimuli‐responsive drug delivery systems. Here, a nanoparticle system, CaF₂:Tm,Yb@mSiO₂, made of a mesoporous silica (mSiO₂) nanosphere with CaF₂:Tm,Yb upconversion nanoparticles (UCNPs) is developed, filling its mesopores and with its surface‐modified with polyacrylic acid for binding the anticancer drug molecules (doxorubicin, DOX). The unique design of CaF₂:Tm,Yb@mSiO₂ enables us to trigger the drug release by two mechanisms. One is the pH‐triggered mechanism, where drug molecules are preferentially released from the nanoparticles at acidic conditions unique for the intracellular environment of cancer cells compared to normal cells. Another is the 808 nm near infrared (NIR)‐triggered mechanism, where 808 nm NIR induces the heating of the nanoparticles to weaken the electrostatic interaction between drug molecules and nanoparticles. In addition, luminescence resonance energy transfer occurs from the UCNPs (the energy donor) to the DOX drug (the energy acceptor) in the presence of 980 nm NIR irradiation, allowing us to monitor the drug release by detecting the vanishing blue emission from the UCNPs. This study demonstrates a new multifunctional nanosystem for dual‐triggered and optically monitored drug delivery, which will facilitate the rational design of personalized cancer therapy.     

Coassembled Nanoparticles Composed of Functionalized Mesoporous Silica and Pillar[5]arene-Appended Gold Nanoparticles as Mitochondrial-Selective Dual-Drug Carriers

Coassembled nanoparticles composed of functionalized mesoporous silica and pillar[5]arene-appended Au nanoparticles obtained through the formation of a host–guest complex are designed and synthesized as a mitochondrial-selective dual-drug delivery system. A pyridinium-based ligand and fluorescein isothiocyanate are immobilized onto mesoporous silica to act as the mitochondria-targeting ligand and fluorescence tracker, respectively, of a material dubbed NP-3. Carboxylated pillar[5]arene-capped Au nanoparticles (CP-AuNPs) are fabricated by the templated reduction of Au³⁺. Interestingly, coassembled nanoparticles (NP-1) composed of doxorubicin (DOX) loaded NP-3 and CP-AuNPs are then prepared via the formation of a host–guest complex between the pyridinium-based ligand of NP-3 and the pillar[5]arene of CP-AuNPs. To demonstrate the effectiveness of NP-2 and NP-1 as mitochondrial targeting drug delivery systems, DOX and F16 are employed as model drugs. These drugs loaded onto NP-2 and CP-AuNPs, respectively, are selectively delivered to mitochondria, indicating the usefulness of NP-2 and CP-AuNPs as mitochondrial-specific drug-delivery carriers in cancer cells. More interestingly, the use of NP-1 is also associated with the selective accumulation of DOX and F16 in mitochondria. The selective mitochondrial-targeting of NP-1 is possible by NP-2 and F16 exposed to the cytoplasm, allowing the codelivery of the two drugs to the mitochondria.