PAMAM Dendritic Nanoparticle-Incorporated Hydrogel to Enhance the Immunogenic Cell Death and Immune Response of Immunochemotherapy.

The efficiency of chemotherapy is frequently affected by its multidrug resistance, immune suppression, and severe side effects. Its combination with immunotherapy to reverse immune suppression and enhance immunogenic cell death (ICD) has emerged as a new strategy to overcome the aforementioned issues. Herein, we construct a pH-responsive PAMAM dendritic nanocarrier-incorporated hydrogel for the co-delivery of immunochemotherapeutic drugs. The stepwise conjugation of moieties and drug load was confirmed by various techniques. In vitro experimental results demonstrated that PAMAM dendritic nanoparticles loaded with a combination of drugs exhibited spherical nanosized particles, facilitated the sustained release of drugs, enhanced cellular uptake, mitigated cell viability, and induced apoptosis. The incorporation of PAB-DOX/IND nanoparticles into thermosensitive hydrogels also revealed the formation of a gel state at a physiological temperature and further a robust sustained release of drugs at the tumor microenvironment. Local injection of this formulation into HeLa cell-grafted mice significantly suppressed tumor growth, induced immunogenic cell death-associated cytokines, reduced cancer cell proliferation, and triggered a CD8+ T-cell-mediated immune response without obvious systemic toxicity, which indicates a synergistic ICD effect and reverse of immunosuppression. Hence, the localized delivery of immunochemotherapeutic drugs by a PAMAM dendritic nanoparticle-incorporated hydrogel could provide a promising strategy to enhance antitumor activity in cancer therapy.

Combination of ovalbumin-coated iron oxide nanoparticles and poly(amidoamine) dendrimer-cisplatin nanocomplex for enhanced anticancer efficacy.

Enhancement of drug efficacy is essential in cancer treatment. The immune stimulator ovalbumin (Ova)-coated citric acid (AC-)-stabilized iron oxide nanoparticles (AC-IO-Ova NPs) and enhanced permeability and retention (EPR)-based tumor targeted 4.5 generation poly(amidoamine) dendrimer(4.5GDP)-cisplatin (Cis-pt) nanocomplex (NC) (4.5GDP-Cis-pt NC) were used for enhanced anticancer efficiency. The formations of 4.5GDP-Cis-pt NC, AC-IO, and AC-IO-Ova NPs were examined via FTIR spectroscopy, X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy. The conjugation of Cis-pt with 4.5GDP was confirmed using carbon NMR spectroscopy. The tumor-specific 4.5GDP-Cis-pt NC provided 45%and 28% cumulative cisplatin release in 72 h at pH 6.5 and 7.4, respectively. A significant immune response with high TNF-α and IL-6 cytokine secretion was confirmed for the co-incubation of AC-IO-Ova with RAW 264.7 or HaCaT cells. AC-IO-Ova NPs were biocompatible with different cell lines, even at a high concentration (200 µg mL-1). However, AC-IO-Ova NPs mixed with 4.5GDP-Cis-pt NC (Cis-pt at 15 µg mL-1) significantly increased the cytotoxicity against the cancer cells in a dose-dependent manner with the increasing AC-IO-Ova NPs concentrations. The increased anticancer effects may be attributed to the generation of reactive oxygen species (ROS). Moreover, AC-IO-Ova NPs might assist the efficiency of anticancer cells, inducing an innate immune response via M1 macrophage polarization. We provide a novel synergistic chemoimmunotherapeutic strategy to enhance the anticancer efficacy of cisplatin via a chemotherapeutic agent 4.5GDP-Cis-pt NC and induce proinflammatory cytokines stimulating innate immunity through AC-IO-Ova NPs against tumors.

Development of hydrogels with thermal-healing properties using a network of polyvinyl alcohol and boron nitride composites.

The biocompatibility, flexibility, and tissue-like mechanical properties of hydrogels suggest they are promising materials for wearable devices. However, the production of smart, self-healing hydrogels is limited by the unstable structure of load-bearing stressors and the need for long-term healing capacity. An important goal when developing such hydrogels is to improve their mechanical characteristics and rapid ability to self-repair in physiological environments. In this study, we aimed to create a thermo-responsive hydrogel that possessed thermal-healing and enhanced mechanical properties, without losing its self-healing capabilities, by employing two interpenetrating cross-linked networks of polyvinyl alcohol (PVA) and boron nitride nanosheets (BNNSs). We observed that addition of BNNSs significantly increased the glass transition temperature (Tg) and temperature-dependent swelling of PVA hydrogels, indicating a high compatibility between these two materials and a high thermal response to external stimuli. Our results suggest that PVA hydrogels combined with BNNSs outperform single-network PVA hydrogels in terms of thermal-healing capacity. As above Tg, the thermal energy gained during moisture loss leads to an increase in the thermal mobility of the polymer chains and in the free volume available for new hydrogen bonds at the fracture surface. This unique structure increases water content and confers better mechanical properties. Interestingly, this structure of the second network benefits the first PVA network during deformation by effectively dissipating energy and bearing force, and contrarily to single-network PVA hydrogels. Taken together, our results show that combining PVA and BNNSs to create a hybrid structure, exerts a synergistic effect and successfully improves the thermal-healing performance of wet hydrogels.

Bioinspired Composite, pH-Responsive Sodium Deoxycholate Hydrogel and Generation 4.5 Poly(amidoamine) Dendrimer Improves Cancer Treatment Efficacy via Doxorubicin and Resveratrol Co-Delivery.

Maximizing the antitumor efficacy of doxorubicin (DOX) with a new drug delivery strategy is always desired in the field of biomedical science. Because the clinical applications of DOX in the treatment of cancer is limited by the side effects related to the dose. Herein, we report the co-loading of DOX and resveratrol (RESV) using an injectable in situ formed sodium deoxycholate hydrogel (Na-DOC-hyd) at the pH of the tumor extracellular microenvironment. The sequential, controlled, and sustained release of RESV and DOX for synergistic antitumor effects was confirmed by entrapping G4.5-DOX in the RESV-loaded Na-DOC hydrogel (Na-DOC-hyd-RESV). The synergistic antitumor activity of Na-DOC-hyd-RESV+G4.5-DOX was assessed on HeLa cell xenograft tumor in BALB/c nude mice. In the MTT biocompatibility assay, both the G4.5 PAMAM dendrimer and Na-DOC-hyd exhibited negligible cytotoxicity up to the highest dose of 2.0 mg mL-1 in HeLa, MDA-MB-231, and HaCaT cells. The release profiles of DOX and RESV from the Na-DOC-hyd-RESV+G4.5-DOX confirmed the relatively rapid release of RESV (70.43 ± 1.39%), followed by that of DOX (54.58 ± 0.62%) at pH 6.5 in the 7 days of drug release studies. A single intratumoral injection of Na-DOC-hyd-RESV+G4.5-DOX maximally suppressed tumor growth during the 28 days of the treatment period. Na-DOC-hyd-RESV+G4.5-DOX did not cause any histological damage in the major visceral organs. Therefore, this Na-DOC-hydrogel for dual drugs (DOX and RESV) delivery at the pH of the tumor extracellular microenvironment is a promising, safe, and effective combination for antitumor chemotherapy.

Ibuprofen-Loaded Heparin Modified Thermosensitive Hydrogel for Inhibiting Excessive Inflammation and Promoting Wound Healing.

Hydrogels have been investigated as ideal biomaterials for wound treatment owing to their ability to form a highly moist environment which accelerates cell migration and tissue regeneration for prompt wound healing. They can also be used as a drug carrier for local delivery, and are able to activate immune cells to enhance wound healing. Here, we developed heparin-conjugated poly(N-isopropylacrylamide), an injectable, in situ gel-forming polymer, and evaluated its use in wound healing. Ibuprofen was encapsulated into the hydrogel to help reduce pain and excessive inflammation during healing. In addition to in vitro studies, a BALB/c mice model was used to evaluate its effect on would healing and the secretion of inflammatory mediators. The in vitro assay confirmed that the ibuprofen released from the hydrogel dramatically reduced lipopolysaccharide-induced inflammation by suppressing the production of NO, PGE2 and TNF-α in RAW264.7 macrophages. Moreover, an in vivo wound healing assay was conducted by applying hydrogels to wounds on the backs of mice. The results showed that the ibuprofen-loaded hydrogel improved healing relative to the phosphate buffered saline group. This study indicates that ibuprofen loaded in an injectable hydrogel is a promising candidate for wound healing therapy.

Design of an Interpenetrating Polymeric Network Hydrogel Made of Calcium-Alginate from a Thermos-Sensitive Pluronic Template as a Thermal-Ionic Reversible Wound Dressing.

Polymer-based hydrogels demonstrate superior performance when used as wound dressing. An ideal dressing should possess an active healing function, absorb wound exudates, and provide a moist interface on the wound for rapid injury repair and the prevention of pain and injury during replacement of the dressing. Thus, the aim of this study was to develop a novel, reversible, smart, interpenetrating polymeric network (IPN) by utilizing the thermosensitive network of pluronic F127 (PF127) as a template to regulate the conformation of calcium-ion-crosslinked alginate. We found that the IPN hydrogels formed soft and elastic thermosensitive networks, retaining their form even after absorbing a large amount of wound exudate. The exterior of the hydrogels was made up of a rigid calcium alginate network that supported the entire hydrogel, promoting the stability of the vascular endothelial growth factor (VEGF) payload and controlling its release when the hydrogel was applied topically to wounds. Raman spectroscopy confirmed the layered structure of the hydrogel, which was found to easily disintegrate even after moderate rinsing of the wound with cold phosphate-buffered saline. Taken together, these results show that the IPN hydrogel developed in this study could be a promising delivery platform for growth factors to accelerate wound healing.

Fabrication of Core Crosslinked Polymeric Micelles as Nanocarriers for Doxorubicin Delivery: Self-Assembly, In Situ Diselenide Metathesis and Redox-Responsive Drug Release.

Polymeric micelles (PMs) have been used to improve the poor aqueous solubility, slow absorption and non-selective biodistribution of chemotherapeutic agents (CAs), albeit, they suffer from disassembly and premature release of payloads in the bloodstream. To alleviate the thermodynamic instability of PMs, different core crosslinking approaches were employed. Herein, we synthesized the poly(ethylene oxide)-b-poly((2-aminoethyl)diselanyl)ethyl l-aspartamide)-b-polycaprolactone (mPEG-P(LA-DSeDEA)-PCL) copolymer which self-assembled into monodispersed nanoscale, 156.57 ± 4.42 nm, core crosslinked micelles (CCMs) through visible light-induced diselenide metathesis reaction between the pendant selenocystamine moieties. The CCMs demonstrated desirable doxorubicin (DOX)-loading content (7.31%) and encapsulation efficiency (42.73%). Both blank and DOX-loaded CCMs (DOX@CCMs) established appreciable colloidal stability in the presence of bovine serum albumin (BSA). The DOX@CCMs showed redox-responsive drug releasing behavior when treated with 5 and 10 mM reduced glutathione (GSH) and 0.1% H2O2. Unlike the DOX-loaded non-crosslinked micelles (DOX@NCMs) which exhibited initial burst release, DOX@CCMs demonstrated a sustained release profile in vitro where 71.7% of the encapsulated DOX was released within 72 h. In addition, the in vitro fluorescent microscope images and flow cytometry analysis confirmed the efficient cellular internalization of DOX@CCMs. The in vitro cytotoxicity test on HaCaT, MDCK, and HeLa cell lines reiterated the cytocompatibility (≥82% cell viability) of the mPEG-P(LA-DSeDEA)-PCL copolymer and DOX@CCMs selectively inhibit the viabilities of 48.85% of HeLa cells as compared to 15.75% of HaCaT and 7.85% of MDCK cells at a maximum dose of 10 µg/mL. Overall, all these appealing attributes make CCMs desirable as nanocarriers for the delivery and controlled release of DOX in tumor cells.

Biotin-Decorated PAMAM G4.5 Dendrimer Nanoparticles to Enhance the Delivery, Anti-Proliferative, and Apoptotic Effects of Chemotherapeutic Drug in Cancer Cells.

Biotin receptors are overexpressed by various types of solid cancer cells and play a significant role in tumor metabolism, growth, and metastasis. Thus, targeting the biotin receptors on tumor cells may enhance the efficiency and reduce the side-effects of chemotherapy. The aim of this study was to develop a biotin-coupled poly(amido)amine (PAMAM) (PG4.5) dendrimer nanoparticle to enhance the tumor-specific delivery and intracellular uptake of anticancer drugs via receptor-mediated endocytosis. We modified PG4.5 with diethylenetriamine (DETA) followed by biotin via an amide bond and characterized the resulting PG4.5-DETA-biotin nanoparticles by 1H NMR, FTIR, and Raman spectroscopy. Loading and releasing of gemcitabine (GEM) from PG4.5-DETA-biotin were evaluated by UV-Visible spectrophotometry. Cell viability and cellular uptake were examined by MTT assay and flow cytometry to assess the biocompatibility, cellular internalization efficiency and antiproliferative activity of PG4.5-DETA-biotin/GEM. Gemcitabine-loaded PG4.5-DETA-biotin nanoparticles were spherical with a particle size of 81.6 ± 6.08 nm and zeta potential of 0.47 ± 1.25 mV. Maximum drug-loading content and encapsulation efficiency were 10.84 ± 0.16% and 47.01 ± 0.71%, respectively. Nearly 60.54 ± 1.99% and 73.96 ± 1.14% of gemcitabine was released from PG4.5-DETA-biotin/GEM nanoparticles after 48 h at the acidic pH values of 6.5 and 5, respectively. Flow cytometry and fluorescence microscopy of cellular uptake results revealed PG4.5-DETA-biotin/GEM nanoparticles selectively targeted cancer cells in vitro. Cytotoxicity assays demonstrated gemcitabine-loaded PG4.5-DETA-biotin significantly reduced cell viability and induced apoptosis in HeLa cells. Thus, biotin-coupled PG4.5-DETA nanocarrier could provide an effective, targeted drug delivery system and selectively convey gemcitabine into tumor cells.

Radioprotective effect of self-assembled low molecular weight Fucoidan-Chitosan nanoparticles.

Fucoidan, a sulphated polysaccharide, plays a vital role in reducing cellular oxidative damage by exerting potential antioxidant activity. However, because of the negative surface charges of oligofucoidan, it shows poor oral intestinal absorption. To overcome this drawback, the oligofucoidan polysaccharides self-assembled with opposite charge based polysaccharides (chitosan) to form the chitosan-fucoidan polysaccharides (C1-F3P) nanoparticles (NPs) of 190-230 nm in size. The oligofucoidan and C1-F3P NPs were studied for their radioprotective property using mice exposed to 5 Gy radiation. The C1-F3P NPs prevents radiation induced lipid peroxidation and restores intestinal enzymatic and non-enzymatic antioxidants (p < 0.05) status. In addition, hematoxylin-eosin staining revealed the radioprotective effect of oligofucoidan and C1-F3P NPs by mitigating the loss of crypt and villi in the small intestine. Thus, the present study demonstrated that C1-F3P NPs can be considered as a radioprotective agent that can be used for the prevention and treatment of Gy-radiation-induced intestine injury.

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.

In vitro siRNA delivery via diethylenetriamine- and tetraethylenepentamine-modified carboxyl group-terminated Poly(amido)amine generation 4.5 dendrimers.

The recent discovery of small interfering RNAs (siRNAs) has opened new avenues for designing personalized treatment options for various diseases. However, the therapeutic application of siRNAs has been confronted with many challenges because of short half-life in circulation, poor membrane penetration, difficulty in escaping from endosomes, and insufficient release into the cytosol. To overcome these challenges, we designed a diethylenetriamine (DETA)- and tetraethylenepentamine (TEPA)-modified polyamidoamine dendrimer generation 4.5 (PDG4.5), and characterized it using 1H nuclear magnetic resonance (NMR), 13C NMR, correlation spectroscopy (COSY), heteronuclear single-quantum correlation spectroscopy (HSQC), and Fourier transform infrared (FTIR) spectroscopy followed by conjugation with siRNA. The PDG4.5-DETA and PDG4.5-TEPA polyplexes exhibited spherical nanosize, ideal zeta potential, and effective siRNA binding ability, protected the siRNA from nuclease attack, and revealed less cytotoxicity of PDG4.5-DETA and PDG4.5-TEPA in HeLa cells. More importantly, the polyplexes also revealed good cellular internalization and facilitated translocation of the siRNA into the cytosol. Thus, PDG4.5-DETA and PDG4.5-TEPA can act as potential siRNA carriers in future medical and pharmaceutical applications.

Localized controlled release of bevacizumab and doxorubicin by thermo-sensitive hydrogel for normalization of tumor vasculature and to enhance the efficacy of chemotherapy.

In a malignant tumor, overexpression of pro-angiogenic factors like vascular endothelial growth factor (VEGF) provokes the production of pathologic vascular networks characterized by leaky, chaotically organized, immature, thin-walled, and ill-perfused. As a result, hostile tumor environment would be developed and profoundly hinders anti-cancer drug activities and fuels tumor progression. In this study, we develop a strategy of sequential sustain release of anti-angiogenic drug, Bevacizumab (BVZ), and anti-cancer drug, Doxorubicin (DOX), using poly (d, l-Lactide)- Poly (ethylene glycol) -Poly (d, l-Lactide) (PDLLA-PEG-PDLLA) hydrogel as a local delivery system. The release profiles of the drugs from the hydrogel were investigated in vitro which confirmed that relatively rapid release of BVZ (73.56 ±â€¯1.39%) followed by Dox (61.21 ±â€¯0.62%) at pH 6.5 for prolonged period. The in vitro cytotoxicity test revealed that the copolymer exhibited negligible cytotoxicity up to 2.5 mg ml-1 concentration on HaCaT and HeLa cells. Likeways, the in vitro degradation of the copolymer showed 41.63 ±â€¯2.62% and 73.25 ±â€¯4.36% weight loss within 6 weeks at pH 7.4 and 6.5, respectively. After a single intratumoral injection of the drug-encapsulated hydrogel on Hela xenograft nude, hydrogel co-loaded with BVZ and Dox displayed the highest tumor suppression efficacy for up to 36 days with no noticeable damage on vital organs. Therefore, localized co-delivery of anti-angiogenic drug and anti-cancer drug by hydrogel system may be a promising approach for enhanced chemotherapeutic efficacy in cancer treatment.

Encapsulation of gadolinium ferrite nanoparticle in generation 4.5 poly(amidoamine) dendrimer for cancer theranostics applications using low frequency alternating magnetic field.

Iron oxide-based magnetic resonance imaging (MRI) contrast agents have negative contrast limitations in cancer diagnosis. Gadolinium (Gd)-based contrast agents show toxicity. To overcome these limitations, Gd-doped ferrite (Gd:Fe3O4 (GdIO) nanoparticles (NPs) were synthesized as T1-T2 dual-modal contrast agents for MRI-traced drug delivery. A theranostics GdIO encapsulated in a Generation 4.5 PAMAM dendrimer (G4.5-GdIO) was developed by alkaline coprecipitation. The drug-loading efficiency of the NPs was ∼24%. In the presence of a low-frequency alternating magnetic field (LFAMF), a maximum cumulative doxorubicin (DOX) release of ∼77.47% was achieved in a mildly acidic (pH = 5.0) simulated endosomal microenvironment. Relaxometric measurements indicated superior r1 (5.19 mM-1s-1) and r2 (26.13 mM-1s-1) for G4.5-GdIO relative to commercially available Gd-DTPA. Thus, G4.5-GdIO is promising as an alternative noninvasive MRI-traced cancer drug delivery system.

Preparation of Immunotherapy Liposomal-Loaded Thermal-Responsive Hydrogel Carrier in the Local Treatment of Breast Cancer.

To reduce the side effects of immune drugs and the sustainable release of immune drugs on local parts, we have designed an injectable thermal-sensitive hydrogel containing an imiquimod-loaded liposome system. In the extracellular environment of tumor tissues (pH 6.4), 50% of the drug was released from the carrier, which could be a result of the morphological changes of the liposomal microstructure in the acidic environment. According to the results in animals, the drug-containing liposomes combined with hydrogel can be effectively applied in breast cancer therapy to delay the growth of tumors as well as to dramatically reduce the death rate of mice.

Diselenide linkage containing triblock copolymer nanoparticles based on Bi(methoxyl poly(ethylene glycol))-poly(ε-carprolactone): Selective intracellular drug delivery in cancer cells.

Redox-responsive diselenide bond containing triblock copolymer Bi(mPEG-SeSe)-PCL,Bi(mPEG-SeSe)-PCL was developed for specific drug release in cancer cells. Initially, ditosylated polycaprolactone was prepared via the reaction between polycaprolactone diol (PCL-diol) and tosyl chloride (TsCl). Next, Bi(mPEG-SeSe)-PCL was synthesized via the reaction between ditosylated polycaprolactone and sodium diselenide initiated poly (ethylene glycol) methyl ether tosylate. The synthesized amphiphilic triblock copolymer could self-assemble into uniform nanoparticles in aqueous medium and disassemble upon redox stimuli. The Bi(mPEG-SeSe)-PCL nanoparticles showed a DOX loading content of 5.1 wt% and a loading efficiency of 49%. In vitro drug release studies showed that about 62.4% and 56% of DOX was released from the nanoparticles during 72 h at 37 °C in PBS containing 2 mg/mL (6 mM) GSH and 0.1% H2O2, respectively, whereas only about 30% of DOX was released in PBS under the same conditions. The cell viability (MTT assays) results showed that the synthesized material was biocompatible with above 90% cell viability, and that the DOX-loaded Bi(mPEG-SeSe)-PCL nanoparticles had a high antitumor activity against HeLa cells and low antitumor activity against HaCaT cells, following a 24-h incubation period. Three-dimensional (3D) spheroids of HeLa cells were established for the evaluation of localization of the DOX-loaded nanoparticles into spheroids cells and the successfully inhibition of 3D tumor spheroid growth. The results indicated that the synthesized material Bi(mPEG-SeSe)-PCL was biocompatible and it could be a potential candidate for anticancer drug delivery system.

Fabrication of redox-responsive Bi(mPEG-PLGA)-Se2 micelles for doxorubicin delivery.

Stimuli-responsive polymeric nanostructures have emerged as potential drug carriers for cancer therapy. Herein, we synthesized redox-responsive diselenide bond containing amphiphilic polymer, Bi(mPEG-PLGA)-Se2 from mPEG-PLGA and 3,3'-diselanediyldipropanoic acid (DSeDPA) using DCC/DMAP as coupling agents. Due to its amphiphilic nature, Bi(mPEG-PLGA)-Se2 self-assembled in to stable micelles in aqueous solution with a hydrodynamic size of 123.9 ±â€¯0.85 nm. The Bi(mPEG-PLGA)-Se2 micelles exhibited DOX-loading content (DLC) of 6.61 wt% and encapsulation efficiency (EE) of 54.9%. The DOX-loaded Bi(mPEG-PLGA)-Se2 micelles released 73.94% and 69.54% of their cargo within 72 h upon treatment with 6 mM GSH and 0.1% H2O2, respectively, at pH 7.4 and 37 °C. The MTT assay results demonstrated that Bi(mPEG-PLGA)-Se2 was devoid of any inherent toxicity and the DOX-loaded micelles showed pronounced antitumor activities against HeLa cells, 44.46% of cells were viable at maximum dose of 7.5 µg/mL. The cellular uptake experiment further confirmed the internalization of DOX-loaded Bi(mPEG-PLGA)-Se2 micelles and endowed redox stimuli triggered drug release in cytosol and nuclei of cancer cells. Overall, the results suggested that the smart, biocompatible Bi(mPEG-PLGA)-Se2 copolymer could serve as potential drug delivery biomaterial for the controlled release of hydrophobic drugs in cancer cells.

Mixed Lanthanide Oxide Nanoparticles Coated with Alginate-Polydopamine as Multifunctional Nanovehicles for Dual Modality: Targeted Imaging and Chemotherapy.

Integrating anticancer drugs and diagnostic agents in a polymer nanosystem is an emerging and promising strategy for improving cancer treatment. However, the development of multifunctional nanoparticles (NPs) for an "all-in-one" platform characterized by specific targeting, therapeutic efficiency, and imaging feedback remains an unmet clinical need. In this study, pH-responsive mixed-lanthanide-based multifunctional NPs were fabricated based on simple metal-ligand interactions for simultaneous cancer cell imaging and drug delivery. We investigated two new systems of alginate-polydopamine complexed with either terbium/europium or dysprosium/erbium oxide NPs (Tb/Eu@AlgPDA or Dy/Er@AlgPDA NPs). Tb/Eu@AlgPDA NPs were then functionalized with the tumor-targeting ligand folic acid (FA) and loaded with the anticancer drug doxorubicin (DOX) to form FA-Tb/Eu@AlgPDA-DOX NPs. Using such systems, the mussel-inspired property of PDA was introduced to improve tumor targetability and penetration, in addition to active targeting (via FA-folate receptor interactions). Determining the photoluminescence efficiency showed that the Tb/Eu@AlgPDA system was superior to the Dy/Er@AlgPDA system, presenting intense and sharp emission peaks on the fluorescence spectra. In addition, compared to Dy/Er@AlgPDA NPs (82.4%), Tb/Eu@AlgPDA NPs exhibited negligible cytotoxicity with >93.3% HeLa cell viability found in MTT assays at NP concentrations of up to 0.50 mg/mL and high biocompatibility when incubated with zebrafish (Danio rerio) embryos and larvae. The FA-Tb/Eu@AlgPDA-DOX system exhibited a pH-responsive and sustained drug-release pattern. In a spheroid model of HeLa cells, the FA-Tb/Eu@AlgPDA-DOX system showed a better penetration efficiency and spheroid growth-inhibitory effect than free DOX. After incubation with zebrafish embryos, the FA-Tb/Eu@AlgPDA-DOX system also showed improved antitumor efficacies versus the other experimental groups in HeLa tumor cell xenografted zebrafish. Therefore, our results suggested that FA-Tb/Eu@AlgPDA-DOX NPs are promising multifunctional nanocarriers with therapeutic capacity for tumor targeting and penetration.

Redox-Responsive Heparin-Chlorambucil Conjugate Polymeric Prodrug for Improved Anti-Tumor Activity.

Polymeric prodrug-based delivery systems have been extensively studied to find a better solution for the limitations of a single drug and to improve the therapeutic and pharmacodynamics properties of chemotherapeutic agents, which can lead to efficient therapy. In this study, redox-responsive disulfide bond-containing amphiphilic heparin-chlorambucil conjugated polymeric prodrugs were designed and synthesized to enhance anti-tumor activities of chlorambucil. The conjugated prodrug could be self-assembled to form spherical vesicles with 61.33% chlorambucil grafting efficiency. The cell viability test results showed that the prodrug was biocompatible with normal cells (HaCaT) and that it selectively killed tumor cells (HeLa cells). The uptake of prodrugs by HeLa cells increased with time. Therefore, the designed prodrugs can be a better alternative as delivery vehicles for the chlorambucil controlled release in cancer cells.

Radiation-Sensitive Dendrimer-Based Drug Delivery System.

Combination of chemotherapy and radiotherapy is used to enhance local drug delivery while reducing off-target tissue effects. Anticancer drug doxorubicin (DOX) is loaded into l-cysteine modified G4.5 dendrimer (GC/DOX) and released at different pH values in the presence and absence of γ-radiation. Presence of γ-radiation significantly improves DOX release from the GC/DOX under acidic pH conditions, suggesting that GC dendrimer is a radiation-sensitive drug delivery system. GC/DOX is further evaluated by determining cytotoxicity in uterine cervical carcinoma HeLa cells. GC/DOX shows high affinity for cancer cells and effective drug release following an external stimulus (radiation exposure), whereas an in vivo zebrafish study confirms that l-cysteine acts as a radiosensitizer. GC/DOX treatment combined with radiotherapy synergistically and successfully inhibits cancer cell growth.

Potential fluorescence and magnetic resonance imaging modality using mixed lanthanide oxide nanoparticles.

Imaging is a very important technique in the diagnosis and treatment of cancer diseases. This study developed a dual modality (fluorescence/MR) imaging technique for cancer cell lines (HeLa) and T2-weighted phantom imaging by using a mixed lanthanide (Dy/Er/Tb) oxide nanoparticles. To further enhance the solubility, stability and biocompatibility of mixed lanthanide oxide, the nanoparticles were coated with folic acid as well as G4.5 PAMAM dendrimer. The coated nanoparticles were then compared, the later with results demonstrating pronounced effects in both T2 weighted phantom MR and fluorescence imaging of the cancer cell lines. Imaging enhancement was attributed to a synergistic effect of the fluorescent properties and higher water solubility of the PAMAM dendrimer when compared to the folic acid. Besides, mixed lanthanides of Dy and Tb were used for T2 weighted MR imaging, while mixed lanthanides of Er and Tb were used for fluorescence imaging in the near infrared and visible regions, and were synthesized in the facile composition control. Hence, the mixed lanthanide oxides are packed together, and stable, which is used to facilitate biomedical imaging in vitro. To conclude, the G4.5 PAMAM dendrimer coated mixed lanthanide oxide nanoparticles will be used for dual-modality (fluorescence/MR imaging) cancer cell line detection in both in vitro and in vivo study.