Delivery Of Anticancer Drug Doxorubicin Research Articles

A Self-Skin Permeable Doxorubicin Loaded Nanogel Composite as a Transdermal Device for Breast Cancer Therapy.

Modern drug delivery research focuses on developing biodegradable nanopolymer systems. The present study proposed a polymer-based composite nanogel as a transdermal drug delivery system for the pH-responsive targeted and controlled delivery of anticancer drug doxorubicin (DOX). Nanogels have properties of both hydrogels and nanomaterials. The β-cyclodextrin-based nanogels can enhance the loading capacity of poorly soluble drugs and promote a sustained drug release. The β-cyclodextrin-grafted methacrylic acid conjugated hyaluronic acid composite nanogel was successfully synthesized. β-Cyclodextrin was first grafted onto methacrylic acid. The composite nanogel-based drug carrier was prepared by controlled radical polymerization (CRP) of β-cyclodextrin-grafted methacrylic acid with hyaluronic acid. The doxorubicin-loaded carrier was characterized by Fourier transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, ultraviolet-visible (UV-vis) spectroscopy, zeta potential analysis, dynamic light scattering (DLS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The drug loading and release efficiencies were carried out at different pH levels. The maximum drug loading and encapsulation efficiencies of the synthesized final nanogel composite material at pH 8.0 were 86.44 ± 2.12 and 96.07 ± 2.01%, respectively. The DOX-loaded final material showed a 90.0 ± 2.6% release percentage of DOX at pH 5.5, whereas at pH 7.4, the release percentage of DOX was observed to be only 35.0 ± 0.3%. In vitro swelling, degradation, hemocompatibility, drug release kinetics, cytotoxicity, apoptosis, cell colocalization, skin irritation, and skin permeation studies, along with in vivo pharmacokinetic studies, were performed to prove the efficacy of the synthesized nanogel composite as a transdermal carrier for doxorubicin.

Water-soluble ZnO quantum dots modified by polyglycerol: The pH-sensitive and targeted fluorescent probe for delivery of an anticancer drug

Efficacious specific anticancer drug delivery on the tumor site is the basic title of many investigations. In this paper we reported photoluminescence ZnO quantum dots (ZnO QDs) as a pH-responsive platform for delivery of anticancer drug doxorubicin (DOX). Biocompatible ZnO QDs was synthesized using zinc acetate in the alkaline medium. To improve the nanoparticles aqueous dispersion, ZnO QDs are directly functionalized with polyglycerol (PG) through ring-opening polymerization of glycidol. Moreover, folic acid was conjugated to the end of polyglycerol chains through esterification reaction to target the nanoparticles for cancer cells (ZnO QD-PG-FA). These nanocarriers were characterized by different techniques. The HRTEM images confirmed a final size of about 10 nm for ZnO QD-PG-FA. Doxorubicin was loaded on the ZnO QD-PG-FA in a different carrier: drug weight ratios. The photoluminescence property of ZnO QDs was remained after surface modification with PG, FA, and drug loading. The results showed that the drug was immediately released in acidic intracellular environments of tumor cells, while at neutral pH the complex was stable. Cell cytotoxicity assay confirmed the antitumor activity of DOX-ZnO QDs-PG-FA. Therefore, ZnO QD-PG-FA provides a valuable platform that can use as a diagnostic, targeting, and pH-responsive delivery of anticancer drug for tumor therapy.

Tumor-Microenvironment-Activated NIR-II Nanotheranostic Platform for Precise Diagnosis and Treatment of Colon Cancer.

Rational design of tumor-microenvironment (TME)-activated nanoformulation for precisely targeted cancer treatment has recently attracted an enormous attention. However, the all-in-one TME-activated theranostic nanosystems with a simple preparation and high biocompatibility are still rarely reported. Herein, catalase nanocrystals (CatCry) are first introduced as a tumor microenvironment activatable nanoplatform for selective theranostics of colon cancer. They are engaged as (i) a "nanoreactor" for silver nanoparticles (AgNP) synthesis, (ii) a nanovehicle for tumor delivery of anticancer drug doxorubicin (DOX), and (iii) an in situ O2 generator to relief tumor hypoxia. When CatCry-AgNP-DOX nanoformulation is within a tumor, the intratumoral H2S turns AgNP into Ag2S nanoparticles, inducing a photothermal effect and NIR-II emission under 808 nm laser irradiation and also triggering DOX release. Simultaneously, CatCry catalyzes intratumoral H2O2 into O2, relieving hypoxia and enhancing chemotherapy. In contrast, when delivered to healthy tissue without increased concentration of H2S, the developed nanoformulation remains in the "off" state and no theranostic action takes place. Studies with colon cancer cells in vitro and a murine colon cancer model in vivo demonstrated that CatCry-AgNP-DOX delivered a synergistic combination of PTT and enhanced chemotherapy, enabling complete eradication of tumor with minimal side effects. This work not only introduces nanoplatform for theranostics of H2S-rich tumors but also suggests a general strategy for protein-crystal-based nanomedicine.

Nanocomposites: - A Recent Overview

Nanocomposites are substances that incorporate nanoparticles (0.5-5% by weight) into a matrix of standard material, which enhances the mechanical strength, toughness including thermal or electrical conductivity and other properties. Nanocomposites are versatile in terms of their applications such as anti-corrosive, healing of bones, sensors, environmental protection, packaging, wastewater treatment, and diagnosis of tumors and other diverse uses. They may be fabricated by blending nanofillers with a polymer to produce a composite. The current trend of processing is by polymerizing monomers. Nanocomposites serve as sustainable solutions to curb global issues. Evaluation is performed on properties such as mechanical, thermal, dispersion, and toxicological. Some marketed products of nanocomposites include In Mat (coating), FiltekZ350 XT by 3M (tooth fillers), chitosan/organic rectorite nanocomposite films (bactericidal activity), graphene oxide/Carboxymethylcellulose (targeted drug delivery of anti-cancer drug doxorubicin), MD1 Flex, Nano Clean MD1, Plactive TM (Antimicrobial nanocomposites) and NovaProTM(Tooth fillers). This article discusses about Nanocomposites–their types, preparation methods, recent research and applications.

Stable sub-100 nm PDMS nanoparticles as an intracellular drug delivery vehicle

For the past few decades, polydimethylsiloxane (PDMS) elastomer has been used in plethora of biomedical applications. However, PDMS has not much been explored for intracellular drug delivery since the preparation of sub-100 nm particles, preferred for such kind of applications is extremely difficult owing to its innate nature to form a film. In this work, we have performed molecular dynamics (MD) simulation for developing a strategy to restrict the inherent film-forming tendency of PDMS for obtaining stable sub-100 nm PDMS nanoparticles. MD simulation results suggest that introduction of hydroxyl groups on the surface of PDMS improves its stability in the form of nanoparticles. Based on the MD simulation results, for the first time, sub-100 nm PDMS nanoparticles are prepared via in situ surface modification of PDMS with sodium hydroxide inside nanoemulsion droplets. The synthesized nanoparticles are 30–40 nm in size, extremely soft in nature, moderately hydrophobic and stable in phosphate buffered saline. In vitro results demonstrate the synthesized PDMS nanoparticles to possess excellent biocompatibility and an intrinsic capability of selective localization in mitochondria of cancer cells. Furthermore, efficient mitochondrial delivery of anticancer drug doxorubicin through PDMS nanoparticles advocates for their suitability as a potential candidate for developing advanced nanomedicine.

Multivalent Aptamer-modified DNA Origami as Drug Delivery System for Targeted Cancer Therapy

In spite of great development in nanoparticle-based drug delivery systems(DDSs) for improved therapeutic efficacy, it remains challenging for effective delivery of chemotherapeutic drugs to targeted tumor cells. In this work, we report a triangle DNA origami as targeted DDS for cancer therapy. DNA origami shows excellent biocompatibility and stability in cell culture medium for 24 h. In addition, the DNA origami structures conjugated with multivalent aptamers enable for efficient delivery of anticancer drug doxorubicin(Dox) into targeted cancer cell due to their targeting function, reducing side effects associated with nonspecific distribution. Moreover, we also demonstrated that the multivalent aptamer-modified DNA origami loading Dox exhibits prominent therapeutic efficacy in vitro. Accordingly, this work provides a good paradigm for the development of DNA origami nanostructure-based targeted DDS for cancer therapy.

PH dependent drug release from drug conjugated PEGylated CdSe/ZnS nanoparticles

Stimuli-responsive nanoparticles (NPs) are very useful for drug delivery applications. This manuscript presents PEGylated CdSe/ZnS core/shell NPs (PEGylated NPs) for the pH-dependent delivery of anticancer drug doxorubicin (DOX). DOX is conjugated chemically to end group of PEGylated NPs (‒NH2) by an acid cleavable hydrogen bond. DOX is conjugated to PEGylated NPs by two methods (i) without crosslinker and (ii) with crosslinker. TEM studies showed increase in size of NPs (from 25 to 40 nm) on DOX conjugation which is later confirmed by dynamic light scattering (100–260 nm). Zeta studies revealed that NPs exhibits neutral (~0 mV) surface charge. Shifts of peaks in FT‒IR, a shift towards longer wavelength region in UV–vis absorption spectra and quenching of fluorescence intensity in emission spectra confirms the conjugation of DOX to PEGylated NPs. Conjugation of DOX to PEGylated NPs and release profiles are strongly affected by the pH conditions. In vitro, drug release profiles showed maximum release of DOX from PEGylated NPs at acidic pH ~41% for DOX conjugated PEGylated NPs with crosslinker, whereas for DOX conjugated PEGylated NPs without crosslinker the maximum release is ~22%. The approach of conjugating DOX to PEGylated NPs has been proven useful for targeting cancerous cells and controlled release at the target site.

Fabrication and characterization of gold nanospheres‐cored pH‐sensitive thiol‐ended triblock copolymer: A smart drug delivery system for cancer therapy

Conventional chemotherapy suffers lack of multidrug resistance (MDR), lack of bioavailability, and selectivity. Nano‐sized drug delivery systems (DDS) are developing aimed to solve several limitations of conventional DDS. These systems have been offered for targeting tumor tissue owing to enhanced long circulation time, drug solubility, their retention effect, and improved permeability. As a result, the aim of this project was the design and development of DDS for biomedical applications. For this purpose, gold nanospheres (GNSs) covered by pH‐sensitive thiol‐ended triblock copolymer [poly(methacrylic acid) ‐b‐poly(acrylamide) ‐b‐poly(ε‐caprolactone)‐SH; PMAA‐b‐PAM‐b‐PCL‐SH] for delivery of anticancer drug doxorubicin (DOX). The chemical structures of triblock copolymer were investigated by proton nuclear magnetic resonance (1H NMR) and Fourier transform infrared (FTIR) spectroscopies. 1H NMR spectroscopy and gel permeation chromatography (GPC) were used for calculating the molecular weights of each part in the nanocarrier. The success of coating, GNSs with triblock copolymer was considered by means of dynamic light scattering (DLS), FTIR, ultraviolet‐visible (UV‐Vis), and transmission electron microscopy (TEM) measurement. The pH‐responsive drug release ability, (DOX)‐loading capacity, biocompatibility, and in vitro cytotoxicity effects of the nanocarriers were also studied. As a result, it is expected that the synthesized GNSs@polymer‐DOX considered as a potential application in nanomedicine demand like smart drug delivery, imaging, and chemo‐photothermal therapy.

A Self-Targeting, Dual ROS/pH-Responsive Apoferritin Nanocage for Spatiotemporally Controlled Drug Delivery to Breast Cancer

In this study, an intelligent pH and ROS dual-responsive drug delivery system based on an apoferritin (AFt) nanocage was prepared. This therapeutic system can specifically self-target 4T1 breast cancer cells by exploiting L-apoferritin receptor SCARA 5, avoiding the nonspecific binding or aggregation of nanoparticles due to the chemical functionalization for targeting. The characteristics of AFt were utilized for the simultaneous delivery of anticancer drug doxorubicin (DOX) and photosensitizer rose bengal (RB). RB exhibited efficient reactive oxygen species (ROS) generation, which can be applied to photodynamic therapy. Meanwhile, the AFt nanocage was prone to undergoing peptide backbone cleavage when oxidized by ROS. Therefore, by combining the intrinsic pH-responsive property of AFt, the dual ROS/pH-responsive system was developed. The time and location of drug release can be controlled by the combination of internal and external stimulus, which avoids the incomplete drug release under single stimulus response. The drug release rate increased significantly (from 26.1% to 92.0%) under low-pH condition (pH 5.0) and laser irradiation. More DOX from AFt entered the nucleus and killed the tumor cells, and the cell inhibition rate was up to ∼83% (DOX concentration: 5 μg/mL) after 48 h incubation. In addition, the biodistribution and the in vivo antitumor efficacy (within 14 d treatment) of the nanosystem were investigated in 4T1 breast cancer BALB/c mice. The results indicated that the system is a promising therapeutic agent involving ROS/pH dual response, self-targeting, and chemo-photodynamic therapy.

RAFT derived fatty acid based stimuli responsive fluorescent block copolymers as DNA sensor and cargo delivery agent

Novel capric acid-tryptophan based block copolymers with unique self-assembled feature and fluorescence property have been synthesized via reversible addition fragmentation chain transfer polymerization (RAFT) polymerization. For employing the copolymerization, at first the fatty acid based methacrylate monomer has been efficiently polymerized in presence of 4-cyano-4-(thiobenzylthio)pentanoic acid (CTP) as chain transfer agent (CTA) via RAFT polymerization. The polymerization has been preceded in a controlled fashion as confirmed by their narrow polydispersity and molecular weight determination from several methods. The capric acid based polymer then exploited as macro-CTA to synthesize the copolymers of poly(2-(methacryloyloxy)ethyl caprylate)-block-poly(tert-butyloxycarbonyl tryptophan methacryloyloxyethyl ester) (PCRMA-b-P(Boc-Trp-HEMA)) with variable block length of amino acid segment. Removal of Boc group from the amino acid block results in formation of pH responsive cationic polymers soluble in water depending on their block length. The amphiphilic polymer self-assemble in water forming higher ordered structure is then utilized as a scaffold to encapsulate and delivery of anticancer drug doxorubicin. Finally we provide a fatty acid based polymeric DNA sensor that can bind with DNA followed by significant fluorescence quenching.

Multiresponsive Nanogels for Targeted Anticancer Drug Delivery.

Nanogels with a biomolecular coating (biocoating) were shown to be capable of triggered delivery of anticancer drug Doxorubicin. The biocoating was formed utilizing binding between glycogen and the tetra-functional lectin Concanavalin A, which can be triggered to disassemble (and release) upon exposure to glucose and changes in solution pH. We also show the nanogel's thermoresponsivity can be used to accelerate Doxorubicin release. Moreover, we showed that transferrin immobilized on the nanogel surface could accelerate nanogel uptake by cancer cells. In these experiments, we showed that Doxorubicin was able to be released to the nucleus of human liver cancer cell line (HepG2) within 3 h. Doxorubicin-loaded nanogels exhibit a strong growth inhibition ability toward HepG2. This investigation showcases how nanogel design and chemistry can be tuned to achieve useful biomedical applications.

Somatostatin Receptor-Mediated Tumor-Targeting Nanocarriers Based on Octreotide-PEG Conjugated Nanographene Oxide for Combined Chemo and Photothermal Therapy.

Nano-sized in vivo active targeting drug delivery systems have been developed to a high anti-tumor efficacy strategy against certain cancer-cells-specific. Graphene based nanocarriers with unique physical and chemical properties have shown significant potentials in this aspect. Here, octreotide (OCT), an efficient biotarget molecule, is conjugated to PEGylated nanographene oxide (NGO) drug carriers for the first time. The obtained NGO-PEG-OCT complex shows low toxicity and excellent stability in vivo and is able to achieve somatostatin receptor-mediated tumor-specific targeting delivery. Owing to the high loading efficiency and accurate targeting delivery of anti-cancer drug doxorubicin (DOX), our DOX loaded NGO-PEG-OCT complex offers a remarkably improved cancer-cell-specific cellular uptake, chemo-cytotoxicity, and decreased systemic toxicity compared to free DOX or NGO-PEG. More importantly, due to its strong near-infrared absorption, the NGO-PEG-OCT complex further enhances efficient photothermal ablation of tumors, delivering combined chemo and photothermal therapeutic effect against cancer cells.

Cellular environmental stimuli-responsive hyaluronan nanocapsules for delivery of anticancer drugs

Event Abstract Back to Event Cellular environmental stimuli-responsive hyaluronan nanocapsules for delivery of anticancer drugs Qiangying Yi1, Jin Ma1 and Zhongwei Gu1 1 Sichuan University, National Engineering Research Center for Biomaterials, China Introduction: Owing to the widely existence in extracellular matrix and specific binding affinity for cancer cell over-expressed HA receptor CD 44, hyaluronan (HA) has been extensively studied for potential applications in drug delivery. In this work we propose using of this biocompatible polymer to build up novel anti-cancer drug DOX (Doxorubicin) delivery system possessing environmental stimuli responsive properties. In general, folic acid (FA) terminated hydrophilic zwitterionic tentacles was designed for “stealthy” transportation and targeted delivery of the carriers; specific tumor environmental signals were applied as triggering stimuli to achieve rapid swell up and burst of the carriers, and thereby to realize fast release of encapsulated anti-cancer drugs. For cellular activation, chemical modification is conducted to functionalize the hyaluronan, GSH sensitive crosslinking sites and pH sensitive expansion points are introduced specifically. When the DOX encapsulated nanocapsules arriving at tumor sites, cellular environmental signals would activate exploding of these nanocapsules, generate pulsatile release of the payloads. This drug release pattern could greatly overcome drug resistance of tumor cells and promisingly achieve a better tumor inhibitory effect. Materials and Methods: Photoinitiator 2,2-dimethoxy-2-phenylaceto-phenone (DPAP) was used to initiate free radical thiol-ene coupling reaction of the thiolated HA and Di-ipr-galactopyranose-ene. Poly(carboxybetaine methacrylate) (pCBMA) was introduced to the side chain of thiolated HA via ATRP reaction. Encapsulation of anticancer drug DOX was carried out using the oil-in-water emulsion approach, and formed HA nanocapsules were simultaneously stabilized through ultrasound-mediated thiol to disulfide bond transition. External stimuli activated size change and DOX release from HA nanocapsules were investigated in aqueous buffer solutions with varied pH values and GSH concentrations. The anticancer activity of the DOX-encapsulated HA nanocapules (DOX/HA-NCs) was evaluated both in vitro and in vivo. Results and Discussion: Anticancer drug was successful encapsulated into HA nanocapsules with the DOX content of 6.5% (w/w). Prepared DOX/HA-NCs were observed as shrunk black dots in TEM (~100 nm), while their hydrodynamic diameter of was determined to be 195±53 nm in water. Significant different pH and GSH conditions between tumor and adjacent normal tissue were applied to trigger HA nanocapsule disassembly and thus to promote drug release. In the buffer mimicking tumor cellular environments (pH 5, GSH 10 mM), HA nanocapsules exhibited a 10-fold size swelling in 2 hours and nearly disassembly within 24 hours, whereas these nanocapsules in PBS (pH 7.4, GSH 0) and tumor microenvironment (pH 6.8, GSH 2.8 μM) showed quite better stability. Drug release profiles revealed that release of the encapsulated DOX molecules could be accelerated remarkably (6~10 times) in tumor cellular environment than that in tumor microenvironments and PBS, indicating great potential to fast release vast majority of drugs in tumor tissue. In vivo evaluation showed that zwitterionic tentacles could help the carriers’ safe transportation in circulation and large accumulation in liver tumor sites; DOX-encapsulated nanocapsules exhibited comparable antitumor efficiency and greatly reduced side effect as compared with the free drug DOX. Conclusions: We fabricated HA nanocapsules for delivery of anticancer drug DOX. Prepared nanocapsules demonstrated good stability in storage and also body circulation. Tumor cellular environmental stimuli (pH and GSH) could be applied to stimulate nanocapsule disassembly and drug release. DOX encapsulated HA nanocapsules performed high inhibition efficiency against HepG2 cells. More importantly, in vivo study revealed their comparable antitumor activity and reduced side effect of free DOX. National Natural Science Foundation of China (81471775); Fundamental Research Funds for the Central Universities (2015SCU04A31)

Dendrimer-Functionalized Laponite Nanodisks as a Platform for Anticancer Drug Delivery.

In this study, we synthesized dendrimer-functionalized laponite (LAP) nanodisks for loading and delivery of anticancer drug doxorubicin (DOX). Firstly, LAP was modified with silane coupling agents and succinic anhydride to render abundant carboxyl groups on the surface of LAP. Then, poly(amidoamine) (PAMAM) dendrimer of generation 2 (G2) were conjugated to form LM-G2 nanodisks. Anticancer drug DOX was then loaded on the LM-G2 with an impressively high drug loading efficiency of 98.4% and could be released in a pH-sensitive and sustained manner. Moreover, cell viability assay results indicate that LM-G2/DOX complexes could more effectively inhibit the proliferation of KB cells (a human epithelial carcinoma cell line) than free DOX at the same drug concentration. Flow cytometry analysis and confocal laser scanning microscope demonstrated that LM-G2/DOX could be uptaken by KB cells more effectively than free DOX. Considering the exceptional high drug loading efficiency and the abundant dendrimer amine groups on the surface that can be further modified, the developed LM-G2 nanodisks may hold a great promise to be used as a novel platform for anticancer drug delivery.

Multifunctional dextran micelles as drug delivery carriers and magnetic resonance imaging probes

Multifunctional nanoparticles combining diagnostic and therapeutic agents into a single platform make cancer theranostics possible and have attracted wide interests in the field. In this study, a multifunctional nanocomposite based on dextran and superparamagnetic iron oxide nanoparticles (SPIO) was prepared for drug delivery and magnetic resonance imaging (MRI). Amphiphilic dextran was synthesized by grafting stearyl acid onto the carbohydrate backbone, and micelle was formed by the resulted amphiphilic dextran with low critical micelle concentration at 1.8mg L−1. Doxorubicin (DOX) and a cluster of the manganese-doped iron oxide nanoparticles (Mn-SPIO) nanocrystals were then coencapsulated successfully inside the core of dextran micelles, resulting in nanocomposites with diameter at about 100nm. Cell culture experiments demonstrated the potential of these Mn-SPIO/DOX nanocomposites as an effective multifunctional nanoplatform for the delivery of anticancer drug DOX with a loading content (DLC) of 16%. Confocal laser scanning microscopy reveals that the Mn-SPIO/DOX had excellent internalization ability against MCF-7/Adr cells after 2-h labeling compared with free DOX·HCl. Under a 3.0-T MRI scanner, Mn-SPIO/DOX nanocomposite-labeled cells in gelatin phantom show much darker images than the control. Their transverse relaxation (T2) rate is also significantly higher than that of the control cells (33.9 versus 2.3s−1). Our result offers an effective strategy to treat MCF-7/Adr at optimized low dosages with imaging capability.

Application of C60 Fullerene-Doxorubicin Complex for Tumor Cell Treatment In Vitro and In Vivo.

Development of nanocarriers for effective drug delivery to molecular targets in tumor cells is a real problem in modern pharmaceutical chemistry. In the present work we used pristine C60 fullerene as a platform for delivery of anticancer drug doxorubicin (Dox) to its biological targets. The formation of a complex of C60 fullerene with Dox (C60 + Dox) is described and physico-chemical characteristics of such complex are presented. It was found that Dox conjugation with C60 fullerene leads to 1.5-2-fold increase in Dox toxicity towards various human tumor cell lines, compared with such effect when the drug is used alone. Cytotoxic activity of C60 + Dox complex is accompanied by an increased level of cell produced hydrogen peroxide at early time point (3 h) after its addition to cultured cells. At the same time, cellular production of superoxide radicals does not change in comparison with the effect of Dox alone. Cytomorphological studies have demonstrated that C60 + Dox complexes kill tumor cells by apoptosis induction. The results of in vivo experiments using Lewis lung carcinoma in mice confirmed the enhancement of the Dox toxicity towards tumor cells after drug complexation with C60 fullerene. The effect of such complex towards tumor-bearing mice was even more pronounced than that in the in vitro experiment with targeting human tumor cells. The tumor volume decreased by 2.5 times compared with the control, and an average life span of treated animals increased by 63% compared with control. The obtained results suggest a great perspective of application of C60 + Dox complexes for chemotherapy of malignant tumors.

Simple synthesis of biocompatible biotinylated porous hexagonal ZnO nanodisc for targeted doxorubicin delivery against breast cancer cell: In vitro and in vivo cytotoxic potential

Targeted drug delivery with porous materials features great promise as improved therapeutic potential for treatment of various diseases. In the present study we have attempted a microwave synthesis of porous hexagonal nanodisc of zinc oxide (PZHD) for the first time and its subsequent targeted delivery to breast cancer cells, MCF7. PZHD has been fabricated suitably with 3-aminopropyltriethoxysilane to impart additional stability and surface amines to anchor site directing ligand NHS-biotin. Biotinylated scaffold showed targeted delivery of anticancer drug doxorubicin and pH triggered release to MCF 7 cells with preferential distribution on specified domain. A detailed in vitro cytotoxicity study was associated with it to evaluate the mode of action of Dox loaded PZHD on MCF-7 cells by means of cell cycle analysis, apoptosis assays, Western blot and immuno-fluorescence image analysis. The efficacy of the Dox loaded PZHD was further validated from our in vivo tumor regression studies. Finally, the whole study has been supported by in vitro and in vivo bio-safety studies which also signified its biocompatibility with real time applications. To the best of our knowledge this is the first effort to use biotinylated PZHD for targeted delivery of doxorubicin within MCF 7 cells with a detailed study of its mechanistic application. This study might thus hold future prospects for therapeutic intervention for treatment of cancer.

Nanoparticles generated by PEG-Chrysin conjugates for efficient anticancer drug delivery

Nanoparticle-based drug delivery systems promise the safety and efficacy of anticancer drugs. Herein, we presented a facile approach to fabricate novel nanoparticles generated by PEG-Chrysin conjugates for the delivery of anticancer drug doxorubicin. Chrysin was immobilized on the terminal group of methoxy poly(ethylene glycol) (mPEG) to form mPEG-Chrysin conjugate. The conjugates were self-assembled into nanoparticles. Doxorubicin (DOX) was loaded in the nanoparticles. The self-assembly, drug release profiles, interactions between nanoparticle and drug, cellular uptake and in vitro anticancer activity of the DOX loaded nanoparticles were investigated. The results showed that the mean diameters of drug loaded nanoparticles were below 200nm. Strong π–π stacking interaction was tested within the drug loaded nanoparticles. The drug release rate was closely related to the chain length of PEG, shorter PEG chain resulted faster release. The mPEG-Chrysin conjugate was non-toxic to both 3T3 fibroblasts and HepG2 cancer cells. The cellular uptake measurements demonstrated that the mPEG1000-Chrysin nanoparticles exhibited higher capability in endocytosis. The IC50 of drug loaded mPEG1000-Chrysin nanoparticles was 4.4μg/mL, which was much lower than that of drug loaded mPEG2000-Chrysin nanoparticles (6.8μg/mL). These nanoparticles provided a new strategy for fabricating antitumor drug delivery systems.

Sheddable, degradable, cationic micelles enabling drug and gene delivery

In this work, sheddable, degradable, cationic micelles were designed and developed based on intermediate disulfide-linked poly(e-caprolactone)-b-poly(N,N-dimethylamino-2-ethylmethacrylate) (PCL-SS-PDMA) diblock copolymers, for glutathione (GSH)-mediated intracellular delivery of anticancer drug doxorubicin (DOX) and gene. The PCL-SS-PDMA diblock polymers with different PDMA block lengths were prepared by a combination of ring opening polymerization (ROP) and atom transfer radical polymerization (ATRP). Driven by hydrophobic interaction, these polymers self-assembled into nanoscaled micelles with size ranging from 70 to 200 nm, and positive surface charges from +24 to +37 mV. The PDMA length was found to determine the surface charge and in turn affect the physiochemical properties and cumulative drug release. More importantly, glutathione mediated intracellular drug release was observed by intracellular fluorescence arising from DOX for the GSH treated cells. The accelerated drug release was induced by the structural disassembly after disulfide cleavage. The PCL-SS-PDMA block polymers exhibited high DNA binding affinity and cellular uptake efficiency. The gene transfection efficiency of PCL-SS-PDMA/DNA complex showed relatively low transfection efficiency in 293 T and HeLa cells, compared to PEI 25K. However, the transfection efficacy dramatically outperformed PEI 25K in human oral carcinoma cell lines (KB and CAL-27 cells). A ten-fold population of the transfected cells was found for the PS-SS-PDMA polymer, compared with PEI. The experimental results show the great potential of the new micelles in gene and drug delivery for cancer therapy.

A pH-Sensitive, Biobased Calcium Carbonate Aragonite Nanocrystal as a Novel Anticancer Delivery System

The synthesised biobased calcium carbonate nanocrystals had demonstrated to be an effective carrier for delivery of anticancer drug doxorubicin (DOX). The use of these nanocrystals displayed high levels of selectivity and specificity in achieving effective cancer cell death without nonspecific toxicity. These results confirmed that DOX was intercalated into calcium carbonate nanocrystals at high loading and encapsulation efficiency (4.8 and 96%, resp.). The CaCO3/DOX nanocrystals are relatively stable at neutral pH (7.4), resulting in slow release, but the nanocrystals progressively dissociated in acidic pH (4.8) regimes, triggering faster release of DOX. The CaCO3/DOX nanocrystals exhibited high uptake by MDA MB231 breast cancer cells and a promising potential delivery of DOX to target cells. In vitro chemosensitivity using MTT, modified neutral red/trypan blue assay, and LDH on MDA MB231 breast cancer cells revealed that CaCO3/DOX nanocrystals are more sensitive and gave a greater reduction in cell growth than free DOX. Our findings suggest that CaCO3 nanocrystals hold tremendous promise in the areas of controlled drug delivery and targeted cancer therapy.