Effects of pore size on in vitro and in vivo anticancer efficacies of mesoporous silica nanoparticles

Mesoporous silica nanoparticles (MSN) have been widely applied for drug delivery systems. To investigate the effects of pore size on anticancer efficacies, MSN with different pore sizes but similar particle sizes and surface charges were synthesized via a microemulsion method. The pore structures of MSN were characterized by transmission electron microscopy (TEM), small-angle X-ray scattering (SAXS), and N₂ adsorption–desorption isotherms. Doxorubicin loaded MSN (DOX/MSN) were prepared and the minimum drug loading capacity was detected in DOX/MSN with a pore size of 2.3 nm (DOX/MSN2). DOX/MSN with a pore size of 8.2 nm (DOX/MSN8) showed a comparable drug loading amount in comparison with ones with a pore size of 5.4 nm (DOX/MSN5). In vitro drug release profiles showed that DOX/MSN5 could release DOX quickly and completely. Compared with DOX/MSN2 and DOX/MSN8, DOX/MSN5 showed the higher cellular uptake and nucleic concentration of DOX in QGY-7703 cells, which led to efficient cell-apoptosis induction and anti-proliferation effect, and thus the optimal in vivo anticancer activities. Taken together, these results highlighted the importance of pore size in anticancer efficacies, which would serve as a guideline in the rational design of MSN for cancer therapy.

MSN with suitable pore sizes achieved an outstanding performance for in vitro and in vivo antitumor efficacies.     

Disulfur-bridged polyethyleneglycol/DOX nanoparticles for the encapsulation of photosensitive drugs: a case of computational simulations on the redox-responsive chemo-photodynamic drug delivery system

Tumor redox stimulus-responsive nanoparticulate drug delivery systems (nano-DDSs) have attracted considerable attention due to their thermodynamically stable microstructures and well-controlled drug release properties. However, drug-loading nanoparticle conformation and redox-triggered drug release mechanisms at the molecular level remain unclear. Herein, doxorubicin-conjugated polymers were constructed using disulfide bonds as linkages (PEG–SS–DOX), which loaded photosensitizer chlorin e6 (Ce6). We integrated multiple scale dynamic simulations (density functional theory (DFT) calculation, atomistic molecular dynamics (MD) simulation and dissipative particle dynamics (DPD) simulations) to elucidate the assembly/drug release dynamic processing. First, it was revealed that the emergence of the calculated bond flexible angle of disulfide bonds facilitated the assembly behavior and improved the stability of conformation. Sorted by the binding model, hydrogen bonding accounted for the major interactions between polymers and photosensitive drugs. DPD simulations were further delved into to acquire knowledge regarding the drug-free self-aggregation and Ce6-loaded assembly mechanism. The results show that nano-assembly conformation not only depended on the concentration of polymers, but also were associated with the polymer–drug ratio. Different from dicarbon bond-bridging polymers, disulfide bonds would contribute to the breakage of the polymer and the rapid release of DOX and Ce6. Our findings provide deep insights into the influence of redox-responsive chemical linkages and offer theoretical guidance to the rational design of specific stimulus-responsive nano-DDSs for cancer therapy.

Schematic of disulfide/dicarbide-bridged DOX polymer-encapsulated photosensitive drugs Ce6: a case of computational simulations on the redox-responsive chemo-photodynamic drug delivery system.     

Surface design and preparation of multi-functional magnetic nanoparticles for cancer cell targeting,therapy, and imaging

Recently, theranostic candidates based on superparamagnetic iron oxide nanoparticles (SPIONs) providing the combination of therapy and diagnosis have become one of the most promising system in cancer research. However, poor stability, premature drug release, lack of specific tumor cell targeting, and complicated multi-step synthesis processes still hinder them for potential clinical applications. In this research, the multi-functional magnetic nanoparticles (MNPs-DOX) were prepared via a simple assembly process for targeted delivery of doxorubicin (DOX) and enhanced magnetic resonance (MR) imaging detection. Firstly, the multi-functional copolymer coating, polyamidoamine (PAMAM), was designed and synthesized by Michael addition reaction, where N,N-bis(acryloyl)cystamine served as backbone linker, and DOX, dopamine (DA), and polyethylene glycol (PEG) acted as comonomers. The PAMAM was then directly assembled to the surface of SPIONs by the ligand exchange reaction with SPIONs forming the MNPs-DOX. The hydrophilic PEG moieties provide the nanoparticles with colloidal stability and good-dispersity in aqueous solution. Comparing with the quick release of free DOX, the drug release behavior of MNPs-DOX exhibited a sustained drug release. Because the chemical cleavage of disulfide in the polymer backbone, a high cumulative drug release up to 60% in GSH within 48 h was observed, rather than only 26% in PBS (pH 7.4) without GSH. The MR imaging detection experiment showed that the MNPs-DOX had an enhanced T₂ relaxivity of 126 mM⁻¹ S⁻¹ for MR imaging. The results of the cytotoxicity assays showed a remarkable killing effect of cancer cells by MNPs-DOX due to the FA tumor-targeting ligand, comparing with non-targeted drug molecules. All the results showed that the as prepared multi-functional magnetic nanoparticles may serve as a promising theranostic candidate for targeted anticancer drug delivery and efficient detection through MR imaging in medical application.

Multi-functional magnetic nanoparticles for targeted anticancer drug delivery and efficient MR imaging detection in theranostics.     

pH-responsive polymeric nanoparticles with tunable sizes for targeted drug delivery

Biodegradable nanoparticles (NPs) have shown great promise as intracellular imaging probes, nanocarriers and drug delivery vehicles. In this study, we designed and prepared amphiphilic cellulose derivatives via Schiff base reactions between 2,3-dialdehyde cellulose (DAC) and amino compounds. Polymeric NPs were facilely fabricated via the self-assembly of the as-synthesized amphiphilic macromolecules. The size distribution of the obtained NPs can be tuned by changing the amount and length of the grafted hydrophobic side-chains. Anticancer drugs (DOX) were encapsulated in the NPs and the drug-loaded NPs based on cellulose derivatives were stable in neutral and alkaline environments for at least a month. They rapidly decomposed with the efficient release of the drug in acidic tumor microenvironments. These drug-loaded NPs have the potential for application in cancer treatment.

Novel nanoparticles for efficient drug delivery were designed and constructed using polymeric 2,3-dialdehyde cellulose (DAC). The drug DOX was encapsulated into nanoparticles and underwent thoroughly controlled release in acidic tumor microenvironments.     

UCN–SiO2–GO: a core shell and conjugate system for controlling delivery of doxorubicin by 980 nm NIR pulse

Herein, graphene oxide (GO) has been attached with core–shell upconversion-silica (UCN–SiO₂) nanoparticles (NPs) to form a GO–UCN–SiO₂ hybrid nanocomposite and used for controlled drug delivery. The formation of the nanocomposite has been confirmed by various characterization techniques. To date, a number of reports are available on GO and its drug delivery applications, however, the synergic properties that arise due to the combination of GO, UCNPs and SiO₂ can be used for controlled drug delivery. New composite UCN@SiO₂–GO has been synthesized through a bio-conjugation approach and used for drug delivery applications to counter the lack of quantum efficiency of the upconversion process and control sustained release. A model anticancer drug (doxorubicin, DOX) has been loaded to UCNPs, UCN@SiO₂ NPs and the UCN@SiO₂–GO nanocomposite. The photosensitive release of DOX from the UCN@SiO₂–GO nanocomposite has been studied with 980 nm NIR laser excitation and the results obtained for UCNPs and UCN@SiO₂ NPs compared. It is revealed that the increase in the NIR laser irradiation time from 1 s to 30 s leads to an increase in the amount of DOX release in a controlled manner. In vitro studies using model cancer cell lines have been performed to check the effectiveness of our materials for controlled drug delivery and therapeutic applications. Obtained results showed that the designed UCN@SiO₂–GO nanocomposite can be used for controlled delivery based therapeutic applications and for cancer treatment.

A GO–UCN–SiO₂ hybrid nanocomposite for loading of doxorubicin and its use in in vitro efficiency for killing carcinoma cells.     

One-step in situ growth of ZnS nanoparticles on reduced graphene oxides and their improved lithium storage performance using sodium carboxymethyl cellulose binder

ZnS nanoparticles are in situ grown on reduced graphene oxides (rGO) via a simplified one-step hydrothermal method. Sodium carboxymethyl cellulose (CMC) is firstly applied as the binder for ZnS based anodes and shows a more advantageous binding effect than PVDF. To simplify the synthesis procedure, l-cysteine is added as the sulfur source for ZnS and simultaneously as the reducing agent for rGO. The average diameter of ZnS nanoparticles is measured to be 13.4 nm, and they uniformly disperse on the rGO sheets without any obvious aggregation. As anode materials, the CMC bound ZnS–rGO nanocomposites can maintain a high discharge capacity of 705 mA h g⁻¹ at a current density of 500 mA g⁻¹ for 150 cycles. The significantly improved electrochemical performance mainly derives from the combined effects of the small and uniformly dispersed ZnS nanoparticles, the high conductivity and structural flexibility of rGO and the strong binding ability of CMC.

ZnS nanoparticles are in situ grown on reduced graphene oxides (rGO) via a simplified one-step hydrothermal method.     

Biocompatible supramolecular pseudorotaxane hydrogels for controllable release of doxorubicin in ovarian cancer SKOV-3 cells

A series of injectable and biocompatible delivery DOX-loaded supramolecular hydrogels were fabricated by using presynthesized DOX-2N-β-CD, Pluronic F-127 and α-CD through host–guest interactions and cooperative multivalent hydrogen bonding interactions. The compositions and morphologies of these hydrogels were confirmed by PXRD and SEM measurements. Moreover, the Rheological measurements of these hydrogels were studied and the studies found that they showed a unique thixotropic behavior, indicting a fast self-healing property after the continuous oscillatory shear stress. Using α-CD as a capping agent, slow and sustained DOX release was observed at different pH values after 72 h. The amount of DOX released at pH 7.4 was determined to be 49.0% for hydrogel 1, whereas the releasing amount of the DOX was increased to 66.3% for hydrogel 1 during the same period at pH 5.5 (P < 0.05), indicating a higher release rate of the drug under more acidic conditions. Taking hydrogel 1 as a representative material, the toxicities of DOX and hydrogel 1 on ovarian cancer cells (SKOV-3) at different exposure durations were examined. The results revealed that hydrogel 1 was less cytotoxic than free DOX to SKOV-3 cells (P < 0.05), suggesting sustained release by these hydrogels in the presence of ovarian cancer cells. It is anticipated that this exploration can provide a new strategy for preparing drug delivery systems.

A series of injectable and biocompatible delivery DOX-loaded supramolecular hydrogels were fabricated by using presynthesized DOX-2N-β-CD, Pluronic F-127 and α-CD through host–guest interactions and cooperative multivalent hydrogen bonding interactions.     

Fabrication and characterization of novel macroporous hydrogels based on the polymerizable surfactant AAc-Span80 and their enhanced drug-delivery capacity

In this study, macroporous pH-sensitive poly[N-isopropylacrylamide-co-acrylic acid-sorbitan monooleate] hydrogels, termed as PNIPAM-co-AAc-Span80 hydrogels, with an enhanced hydrophobic property and a rich pore structure were prepared by free-radical polymerization in an ethanol/water mixture. The polymerizable surfactant AAc-Span80 was obtained by the esterification of acrylic acid (AAc) and sorbitan monooleate (Span80), which was used to copolymerize with N-isopropylacrylamide (NIPAM). The chemical structure, thermal stability, morphology, and amphipathy of the PNIPAM-co-AAc-Span80 hydrogels were characterized. The results showed that the polymerizable surfactant AAc-Span80 macromolecule introduced into the hydrogels could not only increase the hydrophobic property but also ameliorate the porous network morphology, which was conducive to high adsorption capacity for adriamycin hydrochloride (DOX). The adsorption results showed that the equilibrium adsorption capacity of DOX reached 467.5 mg g⁻¹ within 48 h at pH 7.4, and the hydrophobic interactions and intermolecular hydrogen bonds were the main force in the adsorption process of DOX. The release results demonstrated that the macroporous pH-sensitive hydrogels loaded with DOX could release 98.7% of DOX at pH 5.0, which would be highly beneficial for the release of anti-cancer drugs in the environment of cancer cells. All the results demonstrate that the PNIPAM-co-AAc-Span80 hydrogels have great potential for the delivery of anti-cancer drugs.

PNIPAM-co-AAc-Span80 shows an enhanced hydrophobic property, rich pore structure, and good adsorption performance for DOX. The desorption results demonstrate that 98.7% of DOX can be released efficiently in an acidic environment.     

Designing a high-performance smart drug delivery system for the synergetic co-absorption of DOX and EGCG on ZIF-8

Due to the extreme pore volume and valuable surface area, zeolitic imidazole frameworks (ZIFs) are promising vehicles that enhance the delivery of therapeutic agents to tissues. Furthermore, these nanoporous materials have high stability in the pH and temperature of the surrounding healthy cells (37 °C and pH = 7) and an exotic potential to deform in carcinogenic environment (T > 37 °C and pH ∼ 5.5), which make them perfect smart drug delivery vehicle candidates. In this work, a series of molecular dynamics (MD) and metadynamics simulations have been performed to gain molecular insight into the mechanisms involved in the process of co-loading of doxorubicin (DOX) and EpiGalloCatechin-3 Gallate (EGCG) on ZIF-8, which form a smart drug delivery system (SDDS). The obtained results revealed that DOX was adsorbed on the carrier mostly through electrostatic interactions (E_coul = ∼−1200 kJ mol⁻¹, E_tot = −1700 kJ mol⁻¹), and EGCG was stacked on ZIF-8 mainly via van der Waals interactions (E_L-J = ∼−600 kJ mol⁻¹, E_tot = ∼−1200 kJ mol⁻¹). It is worth mentioning that the drug–drug L-J interactions (E_L-J = ∼500 kJ mol⁻¹) were also important in the co-loading process. The insertion of DOX and EGCG as additive agents to the initial ZIF-8/EGCG and ZIF-8/DOX systems led to the enhancement of the drug–carrier pair interactions to about ∼−2300 kJ mol⁻¹ and ∼−2000 kJ mol⁻¹, respectively. This finding implied that the drug–drug interactions had a complementary role in the development of SDDS via ZIF-8. From the metadynamics simulation, it was found that the geometry of the drugs is a determining factor in an efficient co-loading SDDS.

Adsorption free energy of a molecule depends on where and how the molecule meets ZIF-8 surface.     

Catalytic and anti-bacterial properties of biosynthesized silver nanoparticles using native inulin

Silver nanoparticles (Ag NPs) were green synthesized using native inulin as the reducing and capping agent with varied incubation temperatures, incubation times and Ag⁺ concentrations. The biosynthesized Ag NPs were characterized using UV-visible spectroscopy, Field Emission Transmission Electron Microscopy (FE-TEM) and X-ray powder diffraction. The UV visible spectra of the Ag NPs revealed a characteristic surface plasmon resonance peak at 420 nm. FE-TEM showed that the biosynthesized Ag NPs were spherically shaped and monodispersed nanoparticles. The sizes were 18.5 ± 0.9 nm and 20.0 ± 1.2 nm for the Ag NPs synthesized at 80 °C and 100 °C for 2 h using 0.1% inulin and 2 mM Ag⁺. Their PDIs were 0.180 ± 0.05 and 0.282 ± 0.13, respectively. Improving the incubation temperature, incubation time and silver nitrate concentration promoted Ag NP synthesis. The prepared Ag NPs were effective in the catalytic reduction of 4-NP and in inhibiting the growth of bacteria. The inhibition zone could reach 10.21 ± 2.12 mm and 9.92 ± 0.50 mm for Escherichia coli and Staphylococcus aureus. The kinetic rate constant (k_app) could reach 0.0113 s⁻¹, and the maximum inhibitory zones were 10.21 ± 2.12 mm and 9.92 ± 0.50 mm, respectively, for the two microorganisms. This biosynthesis illustrates that native inulin could be a potential candidate in the green fabrication of Ag NPs, and this is promising in catalytic and bacteriostatic fields.

Silver nanoparticles (Ag NPs) were green synthesized using native inulin as the reducing and capping agent with varied incubation temperatures, incubation times and Ag⁺ concentrations.     

Magnetic mesoporous bioactive glass for synergetic use in bone regeneration,hyperthermia treatment,and controlled drug delivery

A combination of chemotherapy with hyperthermia can produce remarkable success in treating advanced cancers. For this purpose, magnetite (Fe₃O₄)-doped mesoporous bioactive glass nanoparticles (Fe₃O₄-MBG NPs) were synthesized by the sol–gel method. Fe₃O₄-MBG NPs were found to possess spherical morphology with a size of approximately 50 ± 10 nm and a uniform pore size of 9 nm. The surface area (309 m² g⁻¹) was sufficient for high drug loading capacity and mitomycin C (Mc), an anticancer drug, was entrapped in the Fe₃O₄-MBG NPs. A variable rate of drug release was observed at different pH values (6.4, 7.4 & 8.4) of the release media. No significant death of normal human fibroblast (NHFB) cells was observed during in vitro analysis and for Mc-Fe₃O₄-MBG NPs considerable inhibitory effects on the viability of cancer cells (MG-63) were observed. When Fe₃O₄-MBG NPs were immersed in simulated body fluid (SBF), hydroxycarbonate apatite (HCA) was formed, as confirmed by XRD and FTIR spectra. A negligible value of coercivity and zero remanence confirms that Fe₃O₄-MBG NPs are superparamagnetic. Fe₃O₄-MBG NPs showed a hyperthermia effect in an alternating magnetic field (AMF), and a rise of 11.5 °C in temperature during the first 6 min, making it suitable for hyperthermia applications. Fe₃O₄-MBG NPs expressed excellent biocompatibility and low cytotoxicity, therefore, they are a safe biomaterial for bone tissue regeneration, drug delivery, and hyperthermia treatment.

A combination of chemotherapy with hyperthermia can produce remarkable success in treating advanced cancers.     

Mechanism of sulfidation of small zinc oxide nanoparticles

ZnO has industrial utility as a solid sorbent for the removal of polluting sulfur compounds from petroleum-based fuels. Small ZnO nanoparticles may be more effective in terms of sorption capacity and ease of sulfidation as compared to bulk ZnO. Motivated by this promise, here, we study the sulfidation of ZnO NPs and uncover the solid-state mechanism of the process by crystallographic and optical absorbance characterization. The wurtzite-structure ZnO NPs undergo complete sulfidation to yield ZnS NPs with a drastically different zincblende structure. However, in the early stages, the ZnO NP lattice undergoes only substitutional doping by sulfur, while retaining its wurtzite structure. Above a threshold sulfur-doping level of 30 mol%, separate zincblende ZnS grains nucleate, which grow at the expense of the ZnO NPs, finally yielding ZnS NPs. Thus, the full oxide to sulfide transformation cannot be viewed simply as a topotactic place-exchange of anions. The product ZnS NPs formed by nucleation-growth share neither the crystallographic structure nor the size of the initial ZnO NPs. The reaction mechanism may inform the future design of nanostructured ZnO sorbents.

In the sulfidation of small ZnO nanoparticles, the nanoparticles first undergo sulfur doping followed by the nucleation-growth of ZnS domains.

Zinc oxide (ZnO) nanoparticles (NPs), due to their cost-effectiveness and biodegradability, have a multitude of applications^1–3 including coatings^4–8 and pigments,^9,10 catalysis,^11,12 energy storage,^13,14 and environmental remediation.^15–22 ZnO NPs have particular appeal as sorbents for scavenging polluting sulfur compounds such as mercaptans and hydrogen sulfide (H₂S) from petroleum-based fuels:^23–27 ZnO + H₂S → ZnS + H₂O. Lattice O²⁻ in the ZnO is replaced with S²⁻ scavenged from the pollutant. Bulk powders of ZnO have already been used for adsorptive removal of H₂S,^28,29 but NPs have specific advantages. With smaller grain sizes, mass transport limitations are lifted.²³ Whereas sulfidation is limited to the surface of bulk ZnO, with NPs, the entire mass of ZnO can undergo sulfidation, enabling high sorbent capacity.²³ Volume and morphology changes resulting from restructuring of the solid can also be more easily accommodated with NPs,²³ allowing regenerable use of the sorbent. Finally, the high specific surface area of NPs allows more enhanced kinetics of the sulfidation reaction, potentially facilitating much lower desulfurization temperatures as compared to the conventional operating temperatures of 650–800 °C.^23,29In this context, small few-nm size ZnO NPs can be expected to be particularly promising, but it is important to understand the manner in which these NPs undergo sulfidation. The structural mechanism of the sulfidation process³⁰ may have critical differences compared to bulk ZnO powders or even larger NPs of tens of nm in size²⁴ and may therefore influence sorbent design. In a seminal study, Park et al.³⁰ studied the sulfidation of hexagonal-shaped 14 nm ZnO nanocrystals (NCs) at high temperature (235 °C) using hexamethyldisilathiane. The reaction was found to involve the anion exchange of O²⁻ with S²⁻ in the NC lattice. The overall shape and crystallography of ZnS NCs was templated by the initial ZnO NCs. However, due to the faster outward diffusion of Zn²⁺ as compared to the inward diffusion of S²⁻, the exchange reaction was accompanied by a nanoscale Kirkendall phenomenon, as a result of which the ZnS NCs formed were hollow.Here, we track the step-wise sulfidation of smaller (ca. 5 nm) ZnO NPs using optical spectroscopy and X-ray crystallography. Prior to the onset of sulfidation, O²⁻ in wurtzite ZnO NPs undergoes substitutional doping with S²⁻ without any major change in its structure. Upon reaching a critical concentration of sulfur doping, separate zincblende ZnS grains form and grow into ZnS NPs. Thus, the sulfidation of these small ZnO NPs studied here is not simply a topotactic or templated place-exchange of anions; rather the nucleation and growth of a separate ZnS crystallite is involved in the latter stages.     

Mitochondria-targeted alginate/triphenylphosphonium-grafted-chitosan for treatment of hepatocellular carcinoma

Mitochondrial targeting of anticancer drugs can effectively eradicate chemotherapy-refractory cells through different mechanisms. This work presents the rational designing of mitochondria-targeted core–shell polymeric nanoparticles (NPs) for efficient delivery of doxorubicin (DOX) to the hepatic carcinoma mitochondria. DOX was electrostatically nano-complexed with sodium alginate (SAL) then coated with mitotropic triphenylphosphonium-grafted chitosan (TPP⁺-g-CS) nanoshell. Polyvinyl alcohol (PVA) was co-solubilized into the TPP⁺-g-CS solution to enhance the stability of the developed NPs. The optimum NPs formula is composed of TPP⁺-g-CS (0.05% w/v) coating a DOX-SAL core complex (0.05% w/v), with 0.2% PVA relative to CS (w/w). The optimum NPs attained an entrapment efficiency of 63.33 ± 10.18%; exhibited a spherical shape with particle size of 70–110 nm and a positive surface charge which enhances mitochondrial uptake. FTIR and DSC studies results were indicative of an efficacious poly-complexation. In vitro biological experiments proved that the developed mitotropic NPs exhibited a significantly lower IC₅₀, effectively induced apoptotic cell death and cell cycle arrest. Moreover, the in vivo studies demonstrated an enhanced antitumor bioactivity for the mitotropic NPs along with a reduced biological toxicity profile. In conclusion, this study proposes a promising nanocarrier system for the efficient targeting of DOX to the mitochondria of hepatic tumors.

Mitochondrial targeting of anticancer drugs can effectively eradicate tumour cells. TPP⁺-grafted-chitosan based core–shell nanoparticles were successfully internalized into the mitochondria of HCC cells. Also exhibited antiproliferative activity against liver cancer.     

Co-delivery of dihydroartemisinin and docetaxel in pH-sensitive nanoparticles for treating metastatic breast cancer via the NF-κB/MMP-2 signal pathway

Metastasis is a major barrier in cancer chemotherapy. Prolonged circulation and rapid, specific intracellular drug release are two main goals in the development of nanoscale drug delivery systems to treat metastatic breast cancer. In this study, we investigated the anti-metastasis effect of docetaxel (DTX) in combination with dihydroartemisinin (DHA) in metastatic breast cancer 4T1 cells. We synthesized a pH-sensitive material 4-arm-PEG-DTX with a hydrazone bond and used it to construct nanoparticles that co-deliver DTX and DHA (D/D NPs). The D/D NPs had a mean size of 142.5 nm and approximately neutral zeta potential. The pH-sensitive nanoparticles allowed acid-triggered drug release at the tumor site, showing excellent cytotoxicity (IC50 = 7.0 μg mL⁻¹), cell cycle arrest and suppression of cell migration and invasion. The mechanisms underlying the anti-metastasis effect of the D/D NPs involved downregulation of the expression of p-AKT, NF-κB and MMP-2. Therefore, D/D NPs represent a new nanoscale drug delivery system for treating metastatic breast cancer, responding to the acidic tumor microenvironment to release the chemotherapeutic drugs.

Co-delivery DTX and DHA as acid-sensitive nanoparticles to exert synergistic effects for metastatic breast cancer therapy.     

One-step dry synthesis of an iron based nano-biocomposite for controlled release of drugs

Bio-based drug carriers have gained significant importance in Control Drug Delivery Systems (CDDS). In the present work, a new iron-based magnetic nano bio-composite (nano-Fe-CNB) is developed in a one-step dry calcination process (solventless) using a seaweed-based biopolymer. The detailed analysis of the developed nano Fe-CNB is carried out using FE-SEM, HR-TEM, P-XRD, XPS, Raman spectroscopy, FTIR etc. and shows that nano-Fe-CNB consists of nanoparticles of 5–10 nm decorated on 7–8 nm thick 2-D graphitic carbon material. The impregnation of nano-Fe-CNB into the calcium alginate (CA) hydrogel beads is found to have good drug loading capacity as well as pH responsive control release behavior which is demonstrated using doxorubicin (DOX) as a model cancer drug. The drug loading experiments exhibit ∼94% loading of DOX and release shows ∼38% and ∼8% release of DOX at pH 5.4 and 7.4 respectively. The developed nano Fe-CNB facilitates strong electrostatic interactions with cationic DOX molecules at pH 7.4 and thereby restricts the release of the drug at physiological pH. However, at cancer cell pH (5.4), the interaction between the drug and nano-Fe-CNB reduces which facilitates more drug release at pH 5.4. Thus, the developed nano-biocomposite has the potential to reduce the undesired side effects associated with faster release of drugs.

Schematics for synthesis and application of magnetic nano-biocomposite for control release of DOX.     

Amino acid-modified PAMAM dendritic nanocarriers as effective chemotherapeutic drug vehicles in cancer treatment: a study using zebrafish as a cancer model

The use of nanomaterials for drug delivery offers many advantages including the targeted delivery of drugs and their controlled release. Nonetheless, entry into the target cells remains a challenge for many nanomaterials used for drug delivery. Moreover, cellular uptake limits the therapeutic efficiency of many anticancer drugs. An important goal is to increase the specific accumulation of these nanoparticles (NPs) at the desired cancerous tissues. Notably, cancer cells show a high demand for some amino acids and we have used this knowledge to develop novel carrier systems. In this study, drug carriers were produced by the conjugation of multiple amino acids such as l-histidine (H) and l-cysteine (C) or single amino acids such as only H with the G4.5 dendrimers (G) to produce GHC aggregates and GH NP carriers, respectively. Doxorubicin was loaded into the G4.5, GH, and GHC dendrimers (G/DOX, GH/DOX and GHC/DOX, respectively) and the release mechanism was demonstrated at pH 7.4 and pH 5.0. GH/DOX and GHC/DOX showed better stability under physiological conditions than the dendrimer alone (G/DOX). GH/DOX and GHC/DOX exhibited higher inhibition of HeLa cell proliferation in in vitro and in vivo studies in zebrafish, confirming the early release of DOX by disrupting the endosomal membrane and triggering the destabilization of carriers at a lower pH of 5.0.

The use of nanomaterials for drug delivery offers many advantages including the controlled release and their targeted delivery.     

Novel reduction-sensitive micelles for triggered intracellular drug release

Novel reduction-sensitive micelles based on poly(ethylene oxide)-b-poly(N-methacryloyl-N′-(t-butyloxycarbonyl)cystamine) (PEO-b-PMABC) diblock copolymers were developed and applied for triggered intracellular drug release. PEO-b-PMABC block copolymers were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization of MABC with dithioester-capped PEO as macroRAFT agent. Gel permeation chromatography (GPC) and ¹H NMR analysis showed that the copolymers have controlled compositions and molecular weights, indicating the living nature of polymerization. These copolymers were self-assembled into micelles. The physicochemical characteristics and reduction-sensitivity of the resultant micelles were investigated by fluorescence measurement, transmission electron microscopy (TEM), and dynamic light scattering (DLS). The results showed that PEO-b-PMABC micelles are stable at normal physiologic condition but readily cleaved into free copolymers under reducing environment. In vitro release of doxorubicin (DOX) and cell experiments showed that the drug-loaded PEO-b-PMABC micelles accomplished much faster drug release under reducing condition and higher anticancer efficacy as compared to the control without reduction-sensitivity, indicating great potential of PEO-b-PMABC micelles for efficient intracellular drug delivery.     

Therapeutic polymeric nanomedicine: GSH-responsive release promotes drug release for cancer synergistic chemotherapy

To obtain an efficient dual-drug release and enhance therapeutic efficiency for combination chemotherapy, a glutathione (GSH)-responsive therapeutic amphiphilic polyprodrug copolymer (mPEG-b-PCPT) is synthesized to load doxorubicin (DOX) via hydrophobic and π–π stacking interaction. In this nanomedicine system (mPEG-b-PCPT/DOX), the ratio of the two drugs can be easily modulated by changing the loading content of DOX. The in vitro drug release curves and laser confocal images suggested that the release of CPT and DOX is induced through a “release promotes release strategy”: after internalization into tumor cells, the disulfide bonds in the nanomedicine are cleaved by glutathione (GSH) in the cytoplasm and then lead to the release of CPT. Meanwhile, the disassembly of nanomedicine immediately promotes the co-release of DOX. The optimum dose ratio of CPT and DOX is evaluated via the combination index (CI) value using HepG-2 cells. The results of cell apoptosis and cell viability prove the better synergistic efficiency of the nanomedicine than free drugs at the optimum dose ratio of 1. Consequently, this stimuli-responsive synergistic chemotherapy system provides a direction for the fabrication of nanomedicines possessing promising potential in clinical trials.

In the GSH-responsive doxorubicin loading camptothecin prodrug nanomedicine, easy modulation of the dose ratio and controlled co-release were achieved, and the synergistic effect was significantly improved.     

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.     

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.