Novel targeted pH-responsive drug delivery systems based on PEGMA-modified bimetallic Prussian blue analogs for breast cancer chemotherapy

The development of novel nanoparticle-based drug delivery systems (nano-DDSs) with high loading capacity, low toxicity, precise targeting, and excellent biocompatibility remains urgent and important for the treatment of breast cancer (BC). Herein, novel BC-targeted nano-DDSs based on bimetallic Prussian blue analogs (PBA-DDSs) for intracellular doxorubicin (DOX) delivery and pH-responsive release were developed. Two kinds of bimetallic PBA, namely CuFe (copper–iron) PBA and CoFe (cobalt–iron) PBA, were synthesized by a coprecipitation method, followed by modification with polyethyleneglycol methacrylate (PEGMA) via surface-initiated atom transfer radical polymerization and immobilization with the AS1411 aptamer to obtain two kinds of novel BC-targeted nano-DDS. CuFePBA@PEGMA@AS1411 and CoFePBA@PEGMA@AS1411 showed high drug loading efficiency of 80% and 84%, respectively, for DOX, while 56.0% and 75.9% DOX release could be achieved under acidic pH conditions. In vitro cell viability and in vivo experiments proved the good biocompatibility of both PBA-DDSs. Cellular uptake and in vivo distribution suggested that both PBA-DDSs had efficient nucleolin-targeting capability, indicating the targeted delivery of DOX in tumor tissues. In vivo evaluation of anti-BC efficacy further confirmed that the obtained PBA-DDSs exhibited excellent therapeutic efficacy with limited side-effects. Therefore, the proposed novel PBA-DDSs can be used as secure and effective drug nano-DDSs for BC chemotherapy.

Core–shell structured bimetallic PBA@PEGMA@AS1411-based DOX loading and pH-responsive controlled release systems for breast cancer chemotherapy.     

PEGylated ethyl cellulose micelles as a nanocarrier for drug delivery

Natural polymers provide a better alternative to synthetic polymers in the domain of drug delivery systems (DDSs) because of their renewability, biocompatibility, and low immunogenicity; therefore, they are being studied for the development of bulk/nanoformulations. Likewise, current methods for engineering natural polymers into micelles are in their infancy, and in-depth studies are required using natural polymers as controlled DDSs. Accordingly, in our present study, a new micellar DDS was synthesized using ethyl cellulose (EC) grafted with polyethylene glycol (PEG); it was characterized, its properties, cell toxicity, and hemocompatibility were evaluated, and its drug release kinetics were demonstrated using doxorubicin (DOX) as a model drug. Briefly, EC was grafted with PEG to form the amphiphilic copolymers EC-PEG1 and EC-PEG2 with varying PEG concentrations, and nano-micelles were prepared with and without the drug (DOX) via a dialysis method; the critical micelle concentrations (CMCs) were recorded to be 0.03 mg mL⁻¹ and 0.00193 mg mL⁻¹ for EC-PEG1 and EC-PEG2, respectively. The physicochemical properties of the respective nano-micelles were evaluated via various characterization techniques. The morphologies of the nano-micelles were analyzed via transmission electron microscopy (TEM), and the average size of the nano-micelles was recorded to be ∼80 nm. In vitro, drug release studies were done for 48 h, where 100% DOX release was recorded at pH 5.5 and 52% DOX release was recorded at pH 7.4 from the micelles. In addition, cytotoxicity studies suggested that DOX-loaded micelles were potent in killing MDA-MB-231 and MCF-7 cancer cells, and the blank micelles were non-toxic toward cancerous and normal cells. A cellular uptake study via fluorescence microscopy indicated the internalization of DOX-loaded micelles by cancer cells, delivering the DOX into the cellular compartments. Based on these studies, we concluded that the developed material should be studied further via in vivo studies to understand its potential as a controlled DDS to treat cancer.

Ethyl cellulose was developed as an amphiphilic polymer by PEGylation and fabricated as nanomicelles for delivery of active molecules. This polymeric system can be used as next generation nano drug delivery system (nanoDDS) for cancer therapy.     

Investigation of pH-responsive block glycopolymers with different structures for the delivery of doxorubicin

To understand the influence of the construction of pH-responsive glycopolymer carriers on loading and release behaviors of the drug, three types of block glycopolymers with similar compositions but different constructions, PEG-b-P(DEA-co-GAMA), PEG-b-PDEA-b-PGAMA and PEG-b-PGAMA-b-PDEA, were successfully synthesized via atom transfer radical polymerization (ATRP) method. The compositions and structures of the three glycopolymers were characterized using ¹H NMR (nuclear magnetic resonance) and GPC (gel permeation chromatography), while the morphology and size of aggregates from pH-sensitive block glycopolymers were measured using TEM (transmission electron microscopy) and DLS (dynamic light scattering). The results indicated that the micelles prepared from PEG-b-PGAMA-b-PDEA had a more compact shell structure. The drug-loaded micelles were prepared using the diafiltration method at pH 10, and the loading content and loading efficiency were analyzed using a UV-visible spectrophotometer. DOX-loaded micelles formed by PEG-b-PGAMA-b-PDEA with the more compact shell construction showed the highest loading content and loading efficiency (12.0 wt% and 58.0%) compared with the other two micelles. Moreover, the DOX release tests of these micelles were carried out under two PBS conditions (pH 7.4 and pH 5.5), and the DOX release amount in a certain time was analyzed using a UV-visible spectrophotometer. The results showed that the more compact shell construction of the three layered micelle obstructed the diffusion of a proton into the PDEA core at pH 5.5 and delayed the drug from releasing under both conditions. Moreover the two-layered micelle with a PDEA and PGAMA mixed core showed a relatively high release amount owing to the porous core permitting unimpeded releasing at pH 7.4 and promoted the protonation of PDEA at pH 5.5. Insights gained from this study show that the structure of block copolymers, leading to different constructions of micelles, could adjust the drug loading and release behavior to certain extent, thus it may contribute to improving the design of desirable drug delivery systems.

Synthesized a pH-responsive block glycopolymers micelles, for the DOX loading and release behavior enhancing the design of drug delivery systems.     

Polymer micelles with cross-linked polyanion core for delivery of a cationic drug doxorubicin

Polymer micelles with cross-linked ionic cores were prepared by using block ionomer complexes of poly(ethylene oxide)-b-poly(methacrylic acid) (PEO-b-PMA) copolymer and divalent metal cations as templates. Doxorubicin (DOX), an anthracycline anticancer drug, was successfully incorporated into the ionic cores of such micelles via electrostatic interactions. A substantial drug loading level (up to 50 w/w%) was achieved and it was strongly dependent on the structure of the cross-linked micelles and pH. The drug-loaded micelles were stable in aqueous dispersions exhibiting no aggregation or precipitation for a prolonged period of time. The DOX-loaded polymer micelles exhibited noticeable pH-sensitive behavior with accelerated release of DOX in acidic environment due to the protonation of carboxylic groups in the cores of the micelles. The attempt to protect the DOX-loaded core with the polycationic substances resulted in the decrease of loading efficacy and had a slight effect on the release characteristics of the micelles. The DOX-loaded polymer micelles exhibited a potent cytotoxicity against human A2780 ovarian carcinoma cells. These results point to a potential of novel polymer micelles with cross-linked ionic cores to be attractive carriers for the delivery of DOX.     

Block copolymer micelles with acid-labile ortho ester side-chains: Synthesis, characterization, and enhanced drug delivery to human glioma cells

A new type of block copolymer micelles for pH-triggered delivery of poorly water-soluble anticancer drugs has been synthesized and characterized. The micelles were formed by the self-assembly of an amphiphilic diblock copolymer consisting of a hydrophilic poly(ethylene glycol) (PEG) block and a hydrophobic polymethacrylate block (PEYM) bearing acid-labile ortho ester side-chains. The diblock copolymer was synthesized by atom transfer radical polymerization (ATRP) from a PEG macro-initiator to obtain well-defined polymer chain-length. The PEG-b-PEYM micelles assumed a stable core-shell structure in aqueous buffer at physiological pH with a low critical micelle concentration as determined by proton NMR and pyrene fluorescence spectroscopy. The hydrolysis of the ortho ester side-chain at physiological pH was minimal yet much accelerated at mildly acidic pHs. Doxorubicin (Dox) was successfully loaded into the micelles at pH 7.4 and was released at a much higher rate in response to slight acidification to pH 5. Interestingly, the release of Dox at pH 5 followed apparently a biphasic profile, consisting of an initial fast phase of several hours followed by a sustained release period of several days. Dox loaded in the micelles was rapidly taken up by human glioma (T98G) cells in vitro, accumulating in the endolysosome and subsequently in the nucleus in a few hours, in contrast to the very low uptake of free drug at the same dose. The dose-dependent cytotoxicity of the Dox-loaded micelles was determined by the MTT assay and compared with that of the free Dox. While the empty micelles themselves were not toxic, the IC₅₀ values of the Dox-loaded micelles were approximately ten-times (by 24 h) and three-times (by 48 h) lower than the free drug. The much enhanced potency in killing the multi-drug-resistant human glioma cells by Dox loaded in the micelles could be attributed to high intracellular drug concentration and the subsequent pH-triggered drug release. These results establish the PEG-b-PEYM block copolymer with acid-labile ortho ester side-chains as a novel and effective pH-responsive nano-carrier for enhancing the delivery of drugs to cancer cells.     

Co-delivery of doxorubicin and shRNA of Beclin1 by folate receptor targeted pullulan-based multifunctional nanomicelles for combinational cancer therapy

Doxorubicin (DOX) is a widely-used effective antitumor agent. However, its clinical application is limited due to its side effects including anti-apoptotic defense of cancer cells caused by DOX-induced autophagy and deleterious effects in normal tissues. Therefore, in this study, a new folate (FA)-decorated amphiphilic bifunctional pullulan-based copolymer (named as FPDP) was developed as an efficient nano-carrier for the co-delivery of DOX and short hairpin RNA of Beclin1, a pivotal autophage-related gene, to enhance the anticancer effect of DOX by the blockade of the Beclin1 protein mediated autophagy process. In FPDP molecules, pullulan was modified with lipophilic desoxycholic acid for the formation of micelles, the introduced low molecular weight (1 kDa) branched polyethylenimine (PEI) was for shBeclin1 delivery, and folate (FA) was employed as the tumor-targeting group. FPDP micelles demonstrated an average diameter of 161.9 nm, good biocompatibility, applicable storage stability, excellent loading capacities for both DOX and shBeclin1 and a sustained drug release profile. In vitro cell culture experiments demonstrated that the uptake amount of FPDP/DOX micelles in folate receptor positive (FR⁺) HeLa cells was more than that in folate receptor negative (FR⁻) HepG2 cells, leading to significantly higher cytotoxicity against FR⁺ HeLa cells. The simultaneous co-delivery of shBeclin1 and DOX to HeLa cells with FPDP micelles led to efficient reduction in the expression level of Beclin1 as well as synergistic cell apoptotic induction. Furthermore, in vivo studies revealed superior antitumor efficacy of tumor-targeted FPDP/DOX/shBeclin1 in comparison with non-FR-targeted PDP micelles and free DOX. These results highlighted that co-delivery of DOX and shRNA of Beclin1 with FPDP micelles has the potential to overcome the limitations of DOX in clinical cancer therapy.

New folate receptor targeted nano-micelles enhanced the anticancer effect of doxorubicin by shBeclin1 with the blockade of the autophagy process.     

Short-wave near-infrared emissive GdPO4:Nd3+ theranostic probe for in vivo bioimaging beyond 1300 nm

The optical probes working in the second near-infrared (NIR-II) window have attracted increasing research interest for their advantages of high tissue penetration depth, low autofluorescence, and unprecedentedly improved imaging sensitivity and spatial resolution. Therefore, it is of great significance to design a new nanoplatform by integration of NIR-II optical imaging and drug delivery functions. Herein, a multifunctional nanoplatform based on GdPO₄:Nd³⁺ yolk–shell sphere was developed for dual-modal in vivo NIR-II/X-ray bioimaging and pH-responsive drug delivery. The in vivo NIR-II bioimaging and real-time tracking presented that these probes were mainly accumulated in liver and spleen. Moreover, owing to the large X-ray absorption coefficient of Gd³⁺, these probes are successfully used as superior X-ray imaging agents than iobitridol. The in vivo toxicity assessments demonstrate the low biotoxicity of the GdPO₄:Nd³⁺ spheres in living animals. More importantly, apart from the excellent dual-modal bioimaging, these yolk–shell-structured probes were also used as ideal nanotransducer for pH-responsive drug delivery of doxorubicin (DOX). These findings open up the opportunity of designing theranostic nanoplatform with integration of imaging-based diagnosis and therapy.

A multifunctional theranostic nanoplatform based on GdPO₄:Nd³⁺ yolk–shell sphere was developed for dual-modal in vivo NIR-II/X-ray bioimaging and pH-responsive drug delivery.     

Reduction responsive and surface charge switchable polyurethane micelles with acid cleavable crosslinks for intracellular drug delivery

Previously we synthesized redox sensitive polyurethane micelles, core crosslinked by diisocyanates (PU-CCL). To improve the intracellular drug release and tumor cellular toxicity of anticancer drugs loaded into polyurethane micelles, we now describe redox sensitive polyurethane micelles with tunable surface charge switchabilities, crosslinked with pH cleavable Schiff bonds, as anticancer drug carriers. Different amounts of 1,6-diaminohexane were connected onto the pendant carboxyl groups of amphiphilic multi-blocked polyurethane (PU-SS-COOH), resulting in polyurethanes with various ratios of pendant carboxyl and amine groups (denoted as PU-SS-COOH-NH₂-1, PU-SS-COOH-NH₂-2 and PU-SS-COOH-NH₂-3). The surface charge switched as the pH was increased for PU-SS-COOH-NH₂-1, PU-SS-COOH-NH₂-2 and PU-SS-COOH-NH₂-3. Then the PU-SS-COOH-NH₂-3 micelles, dissolved in water, were crosslinked by glutaraldehyde resulting in surface charge switchable and reduction responsive polyurethane micelles with acid cleavable crosslinks (PU-ACCL). The crosslinked polyurethane micelles (PU-ACCL) demonstrated superior particle stability in phosphate buffered saline (PBS, pH = 7.4) solution without reducing agents, whereas the drug release rate was markedly accelerated by the addition of glutathione (GSH). Notably, the drug release from PU-ACCL was further accelerated in acidic fluid as the result of acid induced cleavage of the crosslinks. In vitro cytotoxicity studies demonstrated that doxorubicin (DOX)-loaded PU-ACCL micelles displayed increased cytotoxicity against tumor cells which was comparable to that obtained for DOX loaded into uncrosslinked polyurethane micelles. The reduction responsive and surface charge switchable polyurethane micelles with acid cleavable crosslinks, which have superior extracellular stability and provide rapid intracellular drug release, may hold great potential as a bio-triggered drug delivery system for cancer therapy.

Previously we synthesized redox sensitive polyurethane micelles, core crosslinked by diisocyanates (PU-CCL).     

Synthesis of crosslinkable diblock terpolymers PDPA-b-P(NMS-co-OEG) and preparation of shell-crosslinked pH/redox-dual responsive micelles as smart nanomaterials

Crosslinked polymer nanomaterials have attracted great attention due to their stability and highly controllable drug delivery; herein, a series of well-defined amphiphilic PDPA-b-P(NMS-co-OEG) diblock terpolymers (P1–P3) were designed and prepared via RAFT polymerization and were self-assembled into non-cross-linked (NCL) nanomicelles, which were further prepared into shell-cross-linked (SCL) micelles via cystamine-based in situ shell cross-linking. Using P3 as an optimized polymer, SCL-P3 micelles were prepared, which demonstrated remarkable pH/redox-dual responsive behaviour. For drug delivery, camptothecin (CPT)-loaded SCL-P3 micelles were prepared and showed much higher CPT-loading capability than their NCL-P3 counterparts. Notably, the SCL-P3 micelles showed good synergistic pH/redox-dual responsive CPT release properties, making them potential “smart” nanocarriers for drug delivery.

A series of well-defined amphiphilic PDPA-b-P(NMS-co-OEG) diblock terpolymers were prepared via RAFT polymerization and self-assembled into non-cross-linked nanomicelles, and then shell-cross-linked micelles via cystamine-based in situ shell cross-linking.     

Fabrication of a hyaluronic acid conjugated metal organic framework for targeted drug delivery and magnetic resonance imaging

Since metal organic frameworks (MOF) have exhibited fascinating potential in biomedical applications, it is worthwhile to construct a MOF-based multifunctional drug delivery system. In the present study, the anticancer drug doxorubicin (DOX) was loaded into zeolitic imidazolate framework-8 (ZIF-8) via a one-pot process. The formed DOX@ZIF-8 was then coated with polydopamine, successively chelated with Fe³⁺ and conjugated with hyaluronic acid (HA), finally resulting in a multifunctional ZIF-8 nanocarrier. The characterization results confirmed the successful formation of the hybrid nanocarrier. pH-responsive drug release of DOX was observed due to the innate pH-dependent stability of ZIF-8. Importantly, the flow cytometry and confocal laser scanning microscope results both verified the targeting ability of DOX@ZIF-HA toward prostate cancer PC-3 cells. The improved therapeutic efficacy of DOX@ZIF-HA when compared to the inhibited group was also demonstrated. Furthermore, the chelation of Fe³⁺ by PDA makes the prepared DOX@ZIF-HA a good contrast agent for magnetic resonance (MR) imaging. Hence, we hope the constructed ZIF-8 based multifunctional nanocarrier could be a candidate for cancer theranostics.

DOX-doped MOF nanoparticles were prepared via a one-pot reaction and successively anchored with Fe³⁺ and HA for simultaneous targeted drug delivery and MR imaging.     

Spermine modified polymeric micelles with pH-sensitive drug release for targeted and enhanced antitumor therapy

Tumor targeting delivery of chemotherapeutic drugs by nanocarriers has been demonstrated to be a promising strategy for cancer therapy with improved therapeutic efficacy. In this work, we reported a novel type of active targeting micelle with pH-responsive drug release by using biodegradable poly(lactide)-poly(2-ethyl-2-oxazoline) di-block copolymers functionalized with spermine (SPM). SPM has been considered as a tumor binding ligand through its specific interaction with the polyamine transport system (PTS), a transmembrane protein overexpressed on various types of cancer cell, while its application in nano-drug delivery systems has rarely been explored. The micelles with spherical shape (∼110 nm) could load hydrophobic paclitaxel (PTX) with high capacity, and release the payload much faster at acidic pH (4.5–6.5) than at pH 7.4. This pH-responsive property assisted the rapid escape of drug from the endo/lysosome after internalization as demonstrated by confocal laser scanning microscopy images using coumarin-6 (Cou-6) as a fluorescent probe. With surface SPM modification, the micelles displayed much higher cellular uptake than SPM lacking micelles in various types of cancer cells, demonstrating tumor targeting ability. The uptake mechanism of SPM modified micelles was explored by flow cytometry, which suggested an energy-consuming sag vesicle-mediated endocytosis pathway. As expected, the micelles displayed significantly enhanced anti-cancer activity. This work demonstrates that SPM modified pH-sensitive micelles may be potential drug delivery vehicles for targeting and effective cancer therapy.

Tumor targeting delivery of SPM functionalized micelles via PTS binding and their endocytosis and pH-triggered endo/lysosome drug release for anti-cancer therapy.     

Novel azobenzene-based amphiphilic copolymers: synthesis,self-assembly behavior and multiple-stimuli-responsive properties

A series of novel azobenzene-based amphiphilic random copolymers P(POSSMA-co-AZOMA-co-DMAEMA) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. A light and reduction dual-responsive azo group, pH-responsive tertiary amine group and super hydrophobic POSS moiety were incorporated into the polymer chain to generate multi-stimuli-responsiveness. Self-assembly of these amphiphilic copolymers led to the formation of spherical micelles in aqueous solution. The light, pH and reduction responsive properties of the micelles were investigated systematically by DLS, TEM, UV-vis, FTIR and NMR. The azo groups can undergo trans–cis isomerization under UV light irradiation, thus causing a diameter change of the micelles. Owing to the large proportion of tertiary amine groups in amphiphiles, these micelles showed sensitive pH-response behavior. The hydrophobic azo pendant in the polymer chain completely reduced to a more hydrophilic substituted aniline in a reductive environment, resulting in the increase of overall hydrophilicity of amphiphiles and the disassembly of polymeric micelles. Owing to these multi-stimuli–responses, the polymeric micelles showed rapid and efficient release properties of hydrophobic molecules in response to pH and reductive stimuli.

Polymeric micelles encapsulating and releasing hydrophobic guest molecules.     

Polymeric micellar pH-sensitive drug delivery system for doxorubicin.

A novel polymeric micellar pH-sensitive system for delivery of doxorubicin (DOX) is described. Polymeric micelles were prepared by self-assembly of amphiphilic diblock copolymers in aqueous solutions. The copolymers consist of a biocompatible hydrophilic poly(ethylene oxide) (PEO) block and a hydrophobic block containing covalently bound anthracycline antibiotic DOX. The starting block copolymers poly(ethylene oxide)-block-poly(allyl glycidyl ether) (PEO-PAGE) with a very narrow molecular weight distribution (Mw/Mn ca. 1.05) were prepared by anionic ring opening polymerization using sodium salt of poly(ethylene oxide) monomethyl ether as macroinitiator and allyl glycidyl ether as functional monomer. The copolymers were covalently modified via reactive double bonds by the addition of methyl sulfanylacetate. The resulting ester subsequently reacted with hydrazine hydrate yielding polymer hydrazide. The hydrazide was coupled with DOX yielding pH-sensitive hydrazone bonds between the drug and carrier. The resulting conjugate containing ca. 3 wt.% DOX forms micelles with Rh(a)=104 nm in phosphate-buffered saline. After incubation in buffers at 37 degrees C DOX was released faster at pH 5.0 (close to pH in endosomes; 43% DOX released within 24 h) than at pH 7.4 (pH of blood plasma; 16% DOX released within 24 h). Cleavage of hydrazone bonds between DOX and carrier continues even after plateau in the DOX release from micelles incubated in aqueous solutions is reached.     

Tumor targeted quantum dot-mucin 1 aptamer-doxorubicin conjugate for imaging and treatment of cancer

In this study, we report the design and delivery of a tumor-targeted, pH-responsive quantum dot-mucin1 aptamer-doxorubicin (QD-MUC1-DOX) conjugate for the chemotherapy of ovarian cancer. To achieve active cancer targeting, QD was conjugated with a DNA aptamer specific for mutated MUC1 mucin overexpressed in many cancer cells including ovarian carcinoma. DOX was attached to QD via a pH-sensitive hydrazone bond in order to provide the stability of the complex in systemic circulation and drug release in acidic environment inside cancer cells. The data show that this bond is stable at neutral and slightly basic pH and undergoes rapid hydrolysis in mildly acidic pH. Confocal microscopy and in vivo imaging studies show that the developed QD-MUC1-DOX conjugate had higher cytotoxicity than free DOX in multidrug resistant cancer cells and preferentially accumulated in ovarian tumor. Data obtained demonstrate a high potential of the proposed conjugate in treatment of multidrug resistant ovarian cancer.     

ATRP-based synthesis of a pH-sensitive amphiphilic block polymer and its self-assembled micelles with hollow mesoporous silica as DOX carriers for controlled drug release

The atom transfer radical polymerization (ATRP)-based synthesis of a pH-sensitive fluorescent polymer (PSDMA-b-POEGMA) was successfully prepared using 3,6-dibromo-isobutyramide acridine (DIA), an initiator with a fluorescent chromophore, to initiate a lipophilic monomer 2-styryl-1,3-dioxan-5-yl methacrylate (SDMA) and a hydrophilic monomer oligo(ethylene glycol) methyl ether (OEGMA), which contained a cinnamic aldehyde acetal structure. With the addition of hollow mesoporous silicon (HMS@C18), the pH-sensitive core–shell nanoparticles (HMS@C18@PSDMA-b-POEGMA) were developed via a self-assembly process as carriers for the anticancer drug doxorubicin (DOX) for drug loading and controlled release. The nanocomposites showed a higher drug loading capacity which was much higher than that observed using common micelles. At the same time, the polymer coated on the surface of the nanoparticles contains the fluorescent segment of an initiator, which can be used for fluorescence contrast of the cells. The nanocomposite carrier selectively inhibits human melanoma cell A375 relative to human normal fibroblasts GM. The in vitro results suggested that a smart pH sensitive nanoparticles drug delivery system was successfully prepared for potential applications in cancer diagnosis and therapy.

A pH-sensitive core–shell nanoparticle (HMS@C18@PSDMA-b-POEGMA) was developed via a self-assembly process as the carrier of anticancer drug doxorubicin (DOX) for drug loading and controlled release.     

In vivo targeting of breast cancer with a vasculature-specific GQDs/hMSN nanoplatform

According to our previous experiment, graphene quantum dots capped in hollow mesoporous silica nanoparticles, denoted as GQDs@hMSN, and its conjugates exhibited great potential for medical applications due to their commendable biocompatibility. Due to the fluorescence and structural stability, and enormous porosity, polyethylene glycol (PEG) modified GQDs@hMSN (GQDs@hMSN-PEG) is a good candidate in a drug carrying and delivery system. However, the goal of targeted drug delivery couldn''t be achieved simply by utilizing the enhanced permeability and retention (EPR) effect of tumors. In this study, GQDs@hMSN-PEG was further functionalized with vascular endothelial growth factor antibodies (VEGF Abs) for VEGF targeting of breast tumors. Doxorubicin (DOX) was loaded into GQDs@hMSN-VEGF Abs with a drug loading capacity of 0.80 mg DOX per mg GQDs@hMSN. With GQDs as the fluorescent source, GQDs@hMSN-VEGF Abs demonstrated strong fluorescence intensity in VEGF-positive cells. Results from in vitro and in vivo targeting experiments indicated that GQDs@hMSN-VEGF Abs had high specificity on tumor vasculature, and it could be used as an image-guidable, tumor-selective delivery nanoplatform for breast cancer.

According to our previous experiment, graphene quantum dots capped in hollow mesoporous silica nanoparticles, denoted as GQDs@hMSN, and its conjugates exhibited great potential for medical applications due to their commendable biocompatibility.     

Polymer grafted magnetic graphene oxide as a potential nanocarrier for pH-responsive delivery of sparingly soluble quercetin against breast cancer cells

In this work, polymer grafted magnetic graphene oxide (GO–PVP–Fe₃O₄) was successfully synthesized for efficient delivery of anticancer drug. Firstly, GO was functionalized with the hydrophilic and biocompatible polymer polyvinylpyrrolidone (PVP) and then grafted with magnetic nanoparticles (Fe₃O₄) through an easy and effective chemical co-precipitation method. Quercetin (QSR) as an anticancer drug was loaded onto the surface of GO–PVP–Fe₃O₄via non-covalent interactions. The drug loading capacity was as high as 1.69 mg mg⁻¹ and the synthesized magnetic nanocarrier shows pH-responsive controlled release of QSR. The cellular cytotoxicity of the synthesized nanocarrier with and without drugs was investigated in human breast cancer MDA MB 231 cells and their effects compared on non-tumorigenic epithelial HEK 293T cells. These results reveal that the drug loaded GO–PVP–Fe₃O₄ nanohybrid was found to be more toxic than the free drug towards MDA MB 231 cells and exhibits biocompatibility towards HEK 293T cells. Overall, a smart drug delivery system including polymer grafted magnetic graphene oxide as a pH-responsive potential nanocarrier could be beneficial for targeted drug delivery, controlled by an external magnetic field as an advancement in chemotherapy against cancer.

Polymer grafted magnetic graphene oxide (GO–PVP–Fe₃O₄) as an efficient nanocarrier for the delivery of anticancer drug quercetin.     

Conjugation of a smart polymer to doxorubicin through a pH-responsive bond for targeted drug delivery and improving drug loading on graphene oxide

Polymeric nanoparticles have emerged as efficient carriers for anticancer drug delivery because they can improve the solubility of hydrophobic drugs and also can increase the bio-distribution of drugs throughout the bloodstream. In this work, a computational study is performed on a set of new pH-sensitive polymer–drug compounds based on an intelligent polymer called poly(β-malic acid) (PMLA). The molecular dynamics (MD) simulation is used to explore the adsorption and dynamic properties of PMLA–doxorubicin (PMLA–DOX) interaction with the graphene oxide (GOX) surface in acidic and neutral environments. The PMLA is bonded to DOX through an amide bond (PMLA-ami-DOX) and a hydrazone bond (PMLA-hz-DOX) and their adsorption behavior is compared with free DOX. Our results confirm that the polymer–drug prodrug shows unique properties. Analysis of the adsorption behavior reveals that this process is spontaneous and the most stable complex with a binding energy of −1210.262 kJ mol⁻¹ is the GOX/PMLA-hz-DOX complex at normal pH. On the other hand, this system has a great sensitivity to pH so that in an acidic environment, its interaction with GOX became weaker while such behavior is not observed for the PMLA-ami-DOX complex. The results obtained from this study provide accurate information about the interaction of the polymer–drug compounds and nanocarriers at the atomic level, which can be useful in the design of smart drug delivery systems.

Polymeric nanoparticles have emerged as efficient carriers for anticancer drug delivery because they can improve the solubility of hydrophobic drugs and also can increase the bio-distribution of drugs throughout the bloodstream.     

Dual responsive PMEEECL–PAE block copolymers: a computational self-assembly and doxorubicin uptake study

The self-assembly behaviour of dual-responsive block copolymers and their ability to solubilize the anticancer drug doxorubicin (DOX) has been investigated using all-atom molecular dynamics (MD) simulations, MARTINI coarse-grained (CG) force field simulation and Scheutjens–Fleer self-consistent field (SCF) computations. These diblock copolymers, composed of poly{γ-2-[2-(2-methoxyethoxy)ethoxy]ethoxy-ε-caprolactone} (PMEEECL) and poly(β-amino ester) (PAE) are dual-responsive: the PMEEECL block is thermoresponsive (becomes insoluble above a certain temperature), while the PAE block is pH-responsive (becomes soluble below a certain pH). Three MEEECL₂₀–AE_M compositions with M = 5, 10, and 15, have been studied. All-atom MD simulations have been performed to calculate the coil-to-globule transition temperature (T_cg) of these copolymers and finding appropriate CG mapping for both PMEEECL–PAE and DOX. The output of the MARTINI CG simulations is in agreement with SCF predictions. The results show that DOX is solubilized with high efficiency (75–80%) at different concentrations inside the PMEEECL–PAE micelles, although, interestingly, the loading efficiency is reduced by increasing the drug concentration. The non-bonded interaction energy and the RDF between DOX and water beads confirm this result. Finally, MD simulations and SCF computations reveal that the responsive behaviour of PMEEECL–PAE self-assembled structures take place at temperature and pH ranges appropriate for drug delivery.

The self-assembly behaviour of dual-responsive block copolymers and their ability to solubilize the drug doxorubicin is demonstrated using molecular dynamics simulations, coarse-grained force field simulations and self-consistent field theory.