Burst Release Of Doxorubicin Research Articles

Incorporation of CuS nanorods in polyelectrolyte multilayer microcapsules improved cancer cell cytotoxicity and signal intensity in ultrasound imaging

The fabrications of hollow microcapsules (MCs) with new architecture and ability to incorporate different nanomaterials have received great interest for targeted cancer therapy. Recently, CuS based nanomaterials have been demonstrated to possess the ability to mimic Fenton-like activity in tumor environment and inducing cancer cell apoptosis by generating highly reactive oxygen species (ROS). In this study, we have developed poly(allylamine) hydrochloride (PAH)/dextran sulfate (DS) polyelectrolyte MCs capable of carrying doxorubicin (DOX) for targeted cancer therapy and ultrasound imaging. The electron microscopy investigations showed the formation of polymeric MCs of 3 µm in size with incorporated CuS NRs in their interior structure. The surface modification of MCs with folic acid (FA), and encapsulation of model hydrophilic molecules in MCs was studied by UV–Visible (UV–Vis) spectroscopy, Fourier transform infra-red (FTIR) spectroscopy and confocal laser scanning microscopy. The encapsulation efficiency of DOX was found to be 56 % and the release was found to be linear at pH 5.5 and 7.4 in the absence of ultrasound exposure. The ultrasound exposure resulted in sudden rupture of MCs at 1 MHz and 1 W/cm2 and caused burst release of DOX at both pH conditions. The FA decorated PAH/DS/CuS NR MCs exhibited improved anti-cancer activity against MDA-MB-231 cancer cells due to the synergistic effects of ultrasound mediated burst release of chemotherapeutic drug (DOX), glutathione-stimulated ROS and targeted cancer therapy. Further, the capsules showed better echogenicity than that of control PAH/DS MCs when imaged under medical ultrasound-scanning system. Hence, the MCs demonstrated in this study have huge potential for targeted cancer theranostics by offering an option to image the cancer cells during the treatment period.

Implantable 3D Printed Hydrogel Scaffolds Loading Copper-Doxorubicin Complexes for Postoperative Chemo/Chemodynamic Therapy

Biomaterial-based implants hold great potential for postoperative cancer treatment due to the enhanced drug dosage at the disease site and decreased systemic toxicity. However, the elaborate design of implants to avoid complicated chemical modification and burst release remains challenging. Herein, we report a three-dimensional (3D) printed hydrogel scaffold to enable sustained release of drugs for postoperative synergistic cancer therapy. The hydrogel scaffold is composed of Pluronic F127 and sodium alginate (SA) as well as doxorubicin (DOX) and copper ions (F127-SA/Cu-DOX hydrogel scaffold). Benefiting from the coordination of Cu(II) with both SA and DOX, burst release of DOX can be overcome, and prolonged release time can be achieved. The therapeutic efficiency can be adjusted by altering the amount of DOX and Cu(II) in the scaffolds. Moreover, apoptosis and ferroptosis of cancer cells can be induced through the combination of chemotherapy and chemodynamic therapy. In addition, DOX supplies excess hydrogen peroxide to enhance the efficiency of Cu-based chemodynamic therapy. When implanted in the resection site, hydrogel scaffolds effectively inhibit tumor growth. Overall, this study may offer a new strategy for fabricating local implants with synergistic therapeutic performance for preventing postoperative cancer recurrence.

Near‐Infrared Light Triggered Intelligent Nanoplatform for Synergistic Chemo‐Photodynamic Therapy of Tumor

AbstractChemo‐photodynamic therapy nanodelivery systems provide a potential strategy to enhance anticancer effect. However, the treatment efficiency of stimuli‐responsive nanotheranostics remains a challenge owing to off‐target properties, poor tissue penetration, and slow drugs release. Herein, di‐selenide‐bridged mesoporous silica (Se‐Se‐mSiO2) is introduced into a near‐infrared (NIR) light triggered and tumor microenvironment (TME)‐activated intelligent nanoplatform (UCNPs@mSiO2‐Ce6@Se‐Se‐mSiO2(DOX)@HA (UCSSDH)) realizing burst drug release on demand. Typically, the UCSSDH actively targets cancer cells and accumulates in tumor site through hyaluronic acid (HA). Then, under the irradiation of 980 nm NIR light, the upconverted 650 nm emission light activates photosensitizer Ce6 to produce the singlet oxygen (1O2) for photodynamic therapy (PDT). More importantly, 1O2 further cleaves di‐selenide bonds which are sensitive to reactive oxygen species (ROS), driving the rapid degradation of Se‐Se‐mSiO2 accompanied by the burst release of doxorubicin (DOX). Consequently, UCSSDH achieves efficient chemo‐photodynamic therapy of tumors. Last but not least, the upconversion nanoparticles (UCNPs) perform upconversion luminescence (UCL) imaging to monitor the drugs delivery. Collectively, an intelligent drug delivery system integrating therapeutic, monitoring, and targeting is exploited for NIR light‐triggered synergistic tumor therapy. This study broadens fresh vision into the development of controlled drug release and provides a momentous thought for potential clinical cancer therapy.

Targeted drug delivery nanocarriers based on hyaluronic acid-decorated dendrimer encapsulating gold nanoparticles for ovarian cancer therapy

The integration of active targeted drug delivery and stimuli-dependent drug release in one nanocarrier holds great potential for enhancing anticancer efficacy and limiting adverse effects. Herein, we prepared hyaluronic acid (HA)-modified dendrimer encapsulating gold nanoparticles (AuDEN) as active targeted drug delivery nanocarriers for effective treatment of ovarian cancer. Resulting nanocarriers could load doxorubicin (DOX) efficiently with high drug loading content and chemical stability through self-assembly of thiolated DOX on the Au surface of nanocarriers. Surface-exposed HA in these nanocarriers made it possible to deliver the nanodrug (denoted as HA-AuDEN-DOX) to cluster determinant 44-overexpressing cancer cells. DOX was then released in an acidic tumor microenvironment with a high glutathione (GSH) concentration. HA-AuDEN-DOX greatly delayed DOX release under a physiological condition (pH 7.4), whereas a burst release of DOX was observed under an acidic condition (pH 5.6) in the presence of GSH. In comparison with free-DOX, HA-AuDEN-DOX showed enhanced cytotoxicity to cancer cells, demonstrating an enhanced cellular uptake and a superior IC50 value of 2.72 μM. Importantly, cellular internalization pathways of HA-AuDEN-DOX to SK-OV-3 cells were estimated, showing the following quantitative values: receptor-mediated endocytosis, 31.5%; caveolae-mediated endocytosis, 28.7%; macropinocytosis, 26.1%. In vivo anticancer activity and biodistributions of HA-AuDEN-DOX were evaluated with an SK-OV-3 xenograft tumor-bearing mouse model, revealing an outstanding treatment-control (T/C) ratio of 66% (about four times higher than free-DOX treated value of 16.4%) for tumor growth inhibition. Compared to the administration of free-DOX, HA-AuDEN-DOX showed a decreased cardiotoxic effect. Furthermore, immunohistochemical study of Ki67 antigen expression revealed the effective suppression of cell proliferation in xenograft ovarian tumor tissues after HA-AuDEN-DOX treatment. These features highlight a promising application of HA-AuDEN-DOX for the treatment of ovarian cancer with cluster determinant 44 overexpression.

Glycyrrhetinic Acid-Functionalized Mesoporous Silica Nanoparticles for the Co-Delivery of DOX/CPT-PEG for Targeting HepG2 Cells.

A pH-triggered mesoporous silica nanoparticle (MSN)-based nano-vehicle for the dual delivery of doxorubicin (DOX)/camptothecin-PEG (CPT-PEG) has been prepared. To enhance its selectivity, the nanoparticles were decorated with glycyrrhetinic acid (GA) to target HepG2 cells. The highly insoluble CPT was derivatized with a reductive-cleavable PEG chain to improve its loading within the MSN. The preparation of these particles consisted of four steps. First, CPT-PEG was loaded within the pores of the MSN. Then, dihydrazide polyethylene glycol chains were introduced onto the surface of an aldehyde-functionalized MSN by means of a hydrazone bond. Afterwards, DOX was covalently attached to the other end of the dihydrazide polyethylene glycol chains. Finally, the resulting nanoparticles were decorated with GA by formation of an imine bond between the amino group of DOX and a benzaldehyde-GA derivative. The system was stable at physiological conditions and the release of both drugs was negligible. However, at acidic pH, a burst release of DOX and a gradual release of CPT-PEG takes place. GA-decorated drug delivery systems (DDS) selectively internalizes into HepG2. In vitro tests demonstrated that this system shows a great cytotoxicity towards HepG2 cells. Furthermore, glutathione cleavage of CPT prodrug assures the formation of free CPT leading to a synergistic effect in combination with DOX.

Tumor Microenvironment-Activated NIR-II Nanotheranostic System for Precise Diagnosis and Treatment of Peritoneal Metastasis.

Activatable theranostic systems show potential for improved tumor diagnosis and therapy owing to high detection specificities, effective ablation, and minimal side-effects. Herein, a tumor microenvironment (TME)-activated NIR-II nanotheranostic system (FEAD1) for precise diagnosis and treatment of peritoneal metastases is presented. FEAD1 was fabricated by self-assembling the peptide Fmoc-His, mercaptopropionic-functionalized Ag2 S quantum dots (MPA-Ag2 S QDs), the chemodrug doxorubicin (DOX), and NIR absorber A1094 into nanoparticles. We show that in healthy tissue, FEAD1 exists in an NIR-II fluorescence "off" state, because of Ag2 S QDs-A1094 interactions, while DOX remains in stealth mode. Upon delivery of FEAD1 to the tumor, the acidic TME triggers its disassembly through breakage of the Fmoc-His metal coordination and DOX hydrophobic interactions. Release of A1094 switches on Ag2 S fluorescence, illuminating the tumor, accompanied by burst release of DOX within the tumor tissue, thereby achieving precise tumor theranostics. This TME-activated theranostic strategy holds great promise for future clinical applications.

Tumor Microenvironment‐Activated NIR‐II Nanotheranostic System for Precise Diagnosis and Treatment of Peritoneal Metastasis

AbstractActivatable theranostic systems show potential for improved tumor diagnosis and therapy owing to high detection specificities, effective ablation, and minimal side‐effects. Herein, a tumor microenvironment (TME)‐activated NIR‐II nanotheranostic system (FEAD1) for precise diagnosis and treatment of peritoneal metastases is presented. FEAD1 was fabricated by self‐assembling the peptide Fmoc‐His, mercaptopropionic‐functionalized Ag2S quantum dots (MPA‐Ag2S QDs), the chemodrug doxorubicin (DOX), and NIR absorber A1094 into nanoparticles. We show that in healthy tissue, FEAD1 exists in an NIR‐II fluorescence “off” state, because of Ag2S QDs‐A1094 interactions, while DOX remains in stealth mode. Upon delivery of FEAD1 to the tumor, the acidic TME triggers its disassembly through breakage of the Fmoc‐His metal coordination and DOX hydrophobic interactions. Release of A1094 switches on Ag2S fluorescence, illuminating the tumor, accompanied by burst release of DOX within the tumor tissue, thereby achieving precise tumor theranostics. This TME‐activated theranostic strategy holds great promise for future clinical applications.

Polyampholyte-grafted single walled carbon nanotubes prepared via a green process for anticancer drug delivery application

We report a novel process for surface modified single-walled carbon nanotubes (SWCNTs) as drug nanocarriers by using facile and green synthetic methods. Firstly, polyampholytic alternating polymers having furfuryl amine and 3-(dimethylamino)-1-propylamine as functional groups were prepared via one-pot thiol-ene chemistry in sustainable conditions. The obtained polymers were then used to a direct functionalization onto the surface of SWCNTs through Diels-Alder click reaction conducted in aqueous media under ultrasonication. The resulting hybrid was characterized by 1H NMR, FT-IR, TGA and UV–vis measurements. The hybrid improved the drug loading content up to 150 wt%, indicating that they are potential doxorubicin (DOX) delivery nano-vehicles. Furthermore, the in-vitro drug release profiles showed that there was a burst release of DOX at pH 5.5 under an acidic condition in microenvironment of tumor cells, in contrast with a lower release rate at pH 7.4 in the physiological condition. Cell viability assays demonstrated the low cytotoxicity against the normal HEK293 cell of SWCNT hybrids, while they exhibited a high cytotoxic activity towards HeLa cancer cells. These evidences revealed the promising SWCNT-based drug carrier for tumor-targeting chemotherapy release in the cancer therapy.

Quick-Responsive Polymer-Based Thermosensitive Liposomes for Controlled Doxorubicin Release and Chemotherapy.

Thermosensitive liposomes (TSLs) have been widely investigated for controlled drug release at specific pathophysiological sites. Although excellent thermo-sensitivity under hyperthermia (HT) was already realized for TSLs, their in vivo stability under physiological temperature still remains challenging. To overcome this limitation, optimized polymer-based thermosensitive liposomes (P-TSLs) with good thermo-sensitivity as well as satisfactory in vivo stability were developed in this study for tumor-specific controlled delivery of doxorubicin (DOX). In particular, polymers including p(NIPAM-r-HPMA) and p(HPMA-r-APMA) were successfully synthesized based on a reversible addition-fragmentation chain transfer (RAFT) technique. Next, thermosensitive polymer p(NIPAM-r-HPMA) was first proposed to be inserted into the lipid bilayer of TTSL by a postinsertion method. The resulting P-TTSL had a phase transition temperature (Tm) of around 42 °C and displayed excellent thermo-sensitivity under HT: nearly 70% of DOX was released within 1 min when only 1% p(NIPAM-r-HPMA) was incorporated. Moreover, its stability was maintained at 37 °C. Compared with TTSL, significantly higher cellular uptake of DOX under HT was noticed in P-TTSL, indicating a burst release of DOX at 42 °C. In addition, both in vitro tumor spheroid experiments and in vivo tumor slices demonstrated an enhanced DOX deep penetration when treated by P-TTSL under HT. To achieve in vivo imaging and local HT under NIR, p (HPMA-r-APMA) was labeled by Cy7.5 and coinserted into TTSL, and the best drug efficacy was observed in CY-P-TTSL with HT along with prolonged blood circulation time. We have further investigated the biocompatibility of the developed CY-P-TTSL, and reduced cardiotoxicity was observed even under HT in comparison with free DOX, demonstrating it is a reliable thermosensitive drug carrier for improving drug stability and therapeutic efficacy.

PH and reduction dual‐stimuli‐responsive PEGDA/PAMAM injectable network hydrogels via aza‐michael addition for anticancer drug delivery

ABSTRACTA pH and reduction dual‐stimuli‐responsive PEGDA/PAMAM injectable network hydrogel containing “acetals” as pH‐sensitive groups and “disulfides” as reducible linkages was designed and synthesized via aza‐Michael addition reaction between PAMAM and PEGDA diacrylates. The pore size and swelling ratio of hydrogels was varied from 14 ± 3 to 19 ± 4 μm and 214 ± 13 to 300 ± 19 μm, respectively, with varying ethylene glycol repeating units in diacrylates. The swelling ratio of PEGDA/PAMAM network hydrogel increased with increase in the molecular weight of PEG and with decrease in pH. The presence of different cationizable amino‐functionalities in PEGDA/PAMAM network hydrogel helped to enhance the swelling ability of hydrogel under the acidic conditions. The continuous increase in metabolically active live HeLa cells with time in MTT assay implied biocompatibility/noncytotoxicity of the synthesized PEGDA/PAMAM injectable network hydrogel. Furthermore, the prepared PEGDA/PAMAM hydrogel showed higher degradation at lower pH and at higher concentration of DTT. The burst release of doxorubicin from PEGDA/PAMAM hydrogel under the environment of the lower pH and in presence of DTT compared to the release at normal physiological pH and in absence of DTT suggested the potential ability of this model hydrogel system for targeted and selective anticancer drug release at tumor tissues. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 2080–2095

The comparative effect of wrapping solid gold nanoparticles and hollow gold nanoparticles with doxorubicin-loaded thermosensitive liposomes for cancer thermo-chemotherapy.

Since conventional chemotherapy is a systemic treatment that affects the body globally and will not concentrate inside the tumor, it causes adverse side effects to patients. In this study, doxorubicin (DOX) together with solid gold nanoparticles (GNPs) or hollow gold nanoparticles (HGNPs), respectively, is loaded inside thermosensitive liposomes (GNPs&DOX-TLs and HGNPs&DOX-TLs), where the GNPs and HGNPs act as a "nanoswitch" for killing tumor cells directly by hyperthermia and triggering DOX release from TLs in the tumor quickly by near infrared laser (NIR) illumination. In addition, this study investigated the photothermal transformation ability, NIR triggered drug release behavior, and the intracellular uptake and cytotoxicity of breast tumor cells and the thermo-chemotherapy mediated by the co-delivery of GNPs&DOX-TLs and HGNPs&DOX-TLs. GNPs and HGNPs had very different light-to-heat transduction efficiencies, while the hollow HGNPs had the advantage of NIR surface plasmon tunability, resulting in the photothermal ablation of tumors with 800 nm light penetration in tissue. The prepared HGNPs&DOX-TLs exhibited a spherical shape with a diameter of 190 nm and a ξ potential of -29 mV, which were steadily dispersed for at least one month. The co-encapsulated DOX was released under hyperthermia caused by NIR-responsive HGNPs and the local drug concentration increased along with the disintegration of the liposomal membrane. This co-delivery of HGNPs&DOX-TLs produced a synergistic cytotoxicity response, thereby enhancing anticancer efficacy 8-fold and increasing the survival time compared to GNPs&DOX-TLs. This work suggested that the co-delivery of HGNPs&DOX-TLs followed by burst-release of DOX using NIR-responsive HGNPs sensitized cancer cells to the chemotherapeutic compound, which provided a novel concept for the combination strategy of chemotherapy and photothermal therapy. These results suggest that the markedly improved therapeutic efficacy and decreased systemic toxicity of the NPs presented in this study hold significant potential for future cancer treatment.

Preparation of poly(styrene-alt-maleic anhydride) grafted multi-walled carbon nanotubes for pH-responsive release of doxorubicin

ABSTRACTA pH-responsive drug release system based on doxorubicin conjugated poly(styrene-alt-maleic anhydride) grafted multi-walled carbon nanotubes (MWNT/PSMA-DOX) was prepared by the reversible addition-fragmentation chain transfer (RAFT) polymerization and acid-cleavable hydrazone linkages. Firstly, multi-walled carbon nanotubes (MWNTs) were modified with a furfuryl derivative RAFT agent by Diels-Alder reaction. The polymerization of styrene and maleic anhydride was carried out in the presence of functionalized MWNTs to afford MWNT/PSMA. The maleic anhydride ring located along the polymer chains was opened by hydrazine subsequently conjugated with doxorubicin via an acid-sensitive hydrazone bond. The composite materials were characterized by FT-IR, 1H-NMR, TGA and TEM analysis. In vitro experiments showed a burst release of doxorubicin at pH 5.0 whereas slight release at pH 7.4.

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

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

One-Pot Construction of Functional Mesoporous Silica Nanoparticles for the Tumor-Acidity-Activated Synergistic Chemotherapy of Glioblastoma

Mesoporous silica nanoparticles (MSNs) have proved to be an effective carrier for controlled drug release and can be functionalized easily for use as stimuli-responsive vehicles. Here, a novel intelligent drug-delivery system (DDS), camptothecin (CPT)-loaded and doxorubicin (DOX)-conjugated MSN (CPT@MSN-hyd-DOX), is reported via a facile one-pot preparation for use in synergistic chemotherapy of glioblastoma. DOX was conjugated to MSNs via acid-labile hydrazone bonds, and CPT was loaded in the pores of the MSNs. At pH 6.5 (analogous to the pH in tumor tissues), a fast DOX release was observed that was attributed to the hydrolysis of the hydrazone bonds. In addition, a further burst release of DOX was found at pH 5.0 (analogous to the pH in lyso/endosomes of tumor cells), leading to a strong synergistic effect. In all, CPT and DOX could be delivered simultaneously into tumor cells, and this intelligent DDS has great potential for tumor-trigged drug release for use in the synergistic chemotherapy of tumors.