CD44-overexpressing Cancer Cells Research Articles

X-Ray-Triggered CO-Release from Gold Nanocluster: All-in-One Nanoplatforms for Cancer Targeted Gas and Radio Synergistic Therapy.

Glycolysis-dominant metabolic pathway in cancer cells can promote their therapeutic resistance against radiotherapy (RT). Carbon monoxide (CO) as a glycolysis inhibitor can enhance the efficiency of RT. Herein, an X-ray responsive CO-releasing nanocomposite (HA@AuNC@CO) based on strong host-guest interactions between the radiosensitizer and CO donor for enhanced RT is developed. The encapsulated gold nanoclusters (CD-AuNCs) can effectively generate cytotoxic reactive oxygen species (ROS) under X-ray radiation, which not only directly inactivate cancer cells but also induce in situ CO gas generation from adamantane modified metal carbonyl (Ada-CO) for glycolysis inhibition. Both in vitro and in vivo results demonstrate that HA@AuNC@CO exhibits active targeting toward CD44 overexpressed cancer cells, along with excellent inhibition of glycolysis and efficient RT against cancer. This study offers a new strategy for the combination of gas therapy and RT in tumor treatment.

Development of hyaluronate tethered magnetic nanoparticlesfor targeted anti-cancer drug delivery

Despite the tremendous progress in understanding the molecular basis of the disease, cancer still remains one of the leading causes of deaths. Recently, advances in nanotechnology are rapidly enabling the development of novel, multifunctional materials with combined cancer specific targeting, therapeutic and diagnostic functions within a single nanocomplex (NP) that address the shortcomings of traditional disease diagnostic and therapeutic agents. Among the myriad of nanocarriers, magnetic nanoparticles (MNPs) have sparked extensive promise as novel theranostic applications as these MNPs can be directly targeted to the diseased cells with effective therapeutic efficiency. For this, these MNPs should be modified with some highly biocompatible polymers (specially polysaccharides) exhibiting the cancer targeting properties that can strongly interact with receptors expressed on the target cancer to facilitate accurate detection of the specific cancer and enhanced delivery to the target site while reducing unintended tside effects. Over the last few years, many groups have reported hyaluronic acid (HA) as the targeting agent as it directly delivers targeted MNPs to CD44 overexpressed cancer cells. In most of the cases, doxorubicin (DOX) has been used as the anticancer drug as it is largely utilized for treating a broad spectrum of cancers. In our work, we have designed a novel, intravenously injectable, CD44 receptor targeted MNP formulation, where the HA moiety of MNPs facilitate easy detection of cancer cells via receptor specific interactions, DOX can regress the cancer cells with simultaneous imaging efficacy. This theranostic MNPs led to the formation of novel nanoformulation, capable of performing concomitant detection, regression and imaging in in vitro CD44 over expressing cancer cells.

DON encapsulated carbon dot-vesicle conjugate in therapeutic intervention of lung adenocarcinoma by dual targeting of CD44 and SLC1A5.

Lung adenocarcinoma, recognized as one of the most formidable malignancies with a dismal prognosis and low survival rates, poses a significant challenge in its treatment. This article delineates the design and development of a carbon dot-vesicle conjugate (HACD-TMAV) for efficient cytotoxicity towards lung cancer cells by target selective delivery of the glutamine inhibitor 6-diazo-5-oxo-L-norleucine (DON) within CD44-enriched A549 cancer cells. HACD-TMAV is composed of hyaluronic acid-based carbon dots (HACDs) and trimesic acid-based vesicles (TMAV), which are bound via electrostatic interactions. TMAVs are formed by positively charged trimesic acid-based amphiphiles through H-type aggregation in water. HACDs were synthesized through a one-step hydrothermal route. The blue-emitting HACD-TMAV conjugate demonstrated selective bioimaging in CD44-overexpressed A549 lung cancer cells due to specific ligand-receptor interactions between HA and CD44. HACD-TMAV exhibited notably improved DON loading efficiency compared to individual nano-vehicles. HACD-TMAV-DON exhibited remarkable (∼6.0-fold higher) cytotoxicity against CD44-overexpressing A549 cells compared to CD44- HepG2 cells and HEK 293 normal cells. Also, DON-loaded HACD-TMAV showed ∼2.0-fold higher cytotoxicity against A549 cells compared to individual carriers and ∼4.5-fold higher cytotoxicity than by DON. Furthermore, HACD-TMAV-DON induced a ∼3.5-fold reduction in the size of 3D tumor spheroids of A549 cells. The enhanced anticancer effectiveness was attributed to starvation of the A549 cells of glutamine by dual targeting of glutamine metabolism and solute linked carrier family 1 member A5 (SLC1A5) through HA-linked CD44-mediated targeted delivery of DON. This led to over-production of reactive oxygen species (ROS) that induced apoptosis of cancer cells through downregulation of the PI3K/AKT/mTOR signaling cascade.

Surface Engineering of Natural Killer Cells with CD44-targeting Ligands for Augmented Cancer Immunotherapy.

Adoptive immunotherapy utilizing natural killer (NK) cells has demonstrated remarkable efficacy in treating hematologic malignancies. However, its clinical intervention for solid tumors is hindered by the limited expression of tumor-specific antigens. Herein, lipid-PEG conjugated hyaluronic acid (HA) materials (HA-PEG-Lipid) for the simple ex-vivo surface coating of NK cells is developed for 1) lipid-mediated cellular membrane anchoring via hydrophobic interaction and thereby 2) sufficient presentation of the CD44 ligand (i.e., HA) onto NK cells for cancer targeting, without the need for genetic manipulation. Membrane-engineered NK cells can selectively recognize CD44-overexpressing cancer cells through HA-CD44 affinity and subsequently induce in situ activation of NK cells for cancer elimination. Therefore, the surface-engineered NK cells using HA-PEG-Lipid (HANK cells) establish an immune synapse with CD44-overexpressing MIA PaCa-2 pancreatic cancer cells, triggering the "recognition-activation" mechanism, and ultimately eliminating cancer cells. Moreover, in mouse xenograft tumor models, administrated HANK cells demonstrate significant infiltration into solid tumors, resulting in tumor apoptosis/necrosis and effective suppression of tumor progression and metastasis, as compared to NK cells and gemcitabine. Taken together, the HA-PEG-Lipid biomaterials expedite the treatment of solid tumors by facilitating a sequential recognition-activation mechanism of surface-engineered HANK cells, suggesting a promising approach for NK cell-mediated immunotherapy.

Enhanced anticancer activity of siRNA and drug codelivered by anionic biopolymer: overcoming electrostatic repulsion.

Aim: To codeliver an anticancer drug (doxorubicin) and siRNA in the form of nanoparticles into CD44-overexpressing colon cancer cells (HT-29) using an anionic, amphiphilic biopolymer comprisingmodified hyaluronic acid (6-O-[3-hexadecyloxy-2-hydroxypropyl]-hyaluronic acid). Materials & methods: Characterization of nanoparticles was performed using dynamic light scattering, scanning electron microscopy, transmission electron microscopy, molecular docking, in vitro drug release and gel mobility assays. Detailed in vitro experiments, including a gene silencing study and western blot, were also performed. Results: A 69% knockdown of the target gene was observed, and western blot showed 5.7-fold downregulation of the target protein. The repulsive forces between siRNA and 6-O-(3-hexadecyloxy-2-hydroxypropyl)-hyaluronic acid were overcome by hydrogen bonding and hydrophobic interactions. Conclusion: The authors successfully codelivered a drug and siRNA by anionic vector.

Hyaluronic acid-magnetic fluorescent polydopamine/gold-based fluorescent probe for bioimaging of CD44 over-expressed cancer cells

CD44 is a transmembrane glycoprotein (P-glycoprotein) that expressed in a large scale on the surface membrane of breast cancer cells. The CD44 receptor has been employed for various medial aims such as imaging, drug delivery, and etc. In the present work, the surface of citrate-capped gold nanoparticles (cit-AuNPs) was modified with magnetic polydopamine nanoparticles to provide fluorescent nanocomposite and amine groups for attachment to hyaluronic acid (HA) molecules. HA molecules have been bonded to the surface of fluorescent polydopamine nanoparticles (FPNPs) via the formation of amide bonds between carboxyl (COOH) group of HA and amine groups of the FPNPs. Due to the presence of the HA molecules, the MNPs-FPNPs/AuNPs/HA can attach to the CD44-overexpressed MCF-7 cells with high specificity and could be employed for bioimaging aims. Fluorescence microscopy was applied for bioimaging of the MNPs-FPNPs/AuNPs/HA internalized cancer cells. Obtained results offered that the MNPs-FPNPs/AuNPs/HA can especially and efficiently internalize to the cells and differentiate CD44-positive cancer cells and normal cells of HFFF-2 cells. Also, the MNPs-FPNPs/AuNPs/HA has a biocompatible nature with the toxic levels around 250 μg/mL levels. As a conclusion, the MNPs-FPNPs/AuNPs/HA is a good candidate for specific bioimaging applications of CD44−overexpressed MCF-7 cancer cells with high physicochemical stability and advantageous spectral features.

Hyaluronan-coated nanoparticles for active tumor targeting: Influence of polysaccharide molecular weight on cell uptake

Here we aimed to correlate different molecular weights of hyaluronic acid (HA), 200, 800 and 1437 kDa, used to decorate poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs), to their cell uptakes. NP internalization kinetics in CD44-overexpressing breast carcinoma cells were quantified, using healthy fibroblast cells as reference. Actually, NP uptake and selectivity by tumor cells were maximized for NPs HA 800 kDa, while being minimum for NPs HA1400 kDa. This unexpected result could be explained considering that the interaction between NPs and tumor cells is dictated by rearrangement and conformation of that segment of HA chain that actually protrudes from the NPs. Overall, results obtained in this work point at how HA molecular weight, is pivotal project parameter in NP formulation to promote active targeting in the CD44 overexpressing cancer cells.

A Versatile Calcium Phosphate Nanogenerator for Tumor Microenvironment-activated Cancer Synergistic Therapy.

Gas therapy is an emerging "green" cancer treatment strategy; however, its outcome often restricted by the complexity, diversity, and heterogeneity of tumor. Herein, a tumor targeting and tumor microenvironment-activated calcium phosphate nanotheranostic system (denoted as GCAH) is constructed for effective synergistic cancer starvation/gas therapy. GCAH is obtained by a facile biomineralization strategy using glucose oxidase (GOx) as a biotemplate, followed by loading of l-Arginine (L-Arg) and modification of hyaluronic acid (HA) to allow special selectivity for glycoprotien CD44 overexpressed cancer cells. This nanotheranostic system not only exhausts the glucose nutrients in tumor region by the GOx-triggered glucose oxidation, the generated H2 O2 can oxidize L-Arg into NO under acidic tumor microenvironment for enhanced gas therapy. As such, there are significant enhancement effects of starvation therapy and gas therapy through the cascade reactions of GOx and L-Arg, which yields a remarkable synergistic therapeutic effect for 4T1 tumor-bearing mice without discernible toxic side effects.

Targeted delivery of doxorubicin through CD44 aptamer to cancer cells.

Aim: The current investigation is focused on the targeted delivery of doxorubicin through CD44 aptamer-mediated active targeting to the human breast cancer cells. Methods: CD44 aptamer-doxorubicin (Apt-Dox) conjugates were developed by incubating different molar ratios of aptamer and doxorubicin. Cytotoxicity, selective intracellular accumulation and uptake of the Apt-Dox conjugates were analyzed to evaluate the efficacy of Apt-Dox conjugates. Results: Dox was efficiently conjugated with aptamer at 1:2 Apt-Dox molar ratios. Apt-Dox conjugate significantly inhibited the proliferation of CD44-overexpressing breast cancer cells, whereas negligible inhibition of cell proliferation was found in the control cells. Apt-Dox conjugate selectively internalized andaccumulatedin CD44-overexpressing cells. Conclusion: Apt-Dox conjugate selectively delivers doxorubicin to CD44-expressing cancer cells, thereby inhibiting selective cell proliferation and enhancing the targeted therapy.

Tumor-targeting pH/redox dual-responsive nanosystem epigenetically reverses cancer drug resistance by co-delivering doxorubicin and GCN5 siRNA

Multidrug resistance (MDR) is a major cause accounting for chemotherapy failure and recurrence of malignant tumors. A prominent mechanism underlying MDR is overexpression of P-glycoprotein (P-gp, a drug efflux pump). Promoting drug delivery efficacy by targeting tumor and concurrently suppressing drug efflux through down-regulating P-gp emerges as an effective strategy to enhance intracellular drug accumulation for combating MDR tumor. General Control Non-repressed 5 (GCN5), a histone acetyltransferase acting as an epigenetic regulator of multidrug resistance protein 1 (MDR1), positively regulates P-gp levels in drug-resistant cancer cells. Herein, a hyaluronic acid-coated, pH/redox dual-responsive nanosystem (HPMSNs) is fabricated for co-delivering doxorubicin (DOX) and GCN5 siRNA (siGCN5). This nanosystem can effectively encapsulate DOX and siRNA preventing premature leakage and releasing these therapeutics intracellularly via its pH/redox dual responsiveness. Through CD44-mediated targeting, DOX/siGCN5@HPMSNs increases drug internalization in CD44-overexpressing cancer cells, and markedly promotes DOX retention by down-regulating P-gp expression in drug-resistant cancers through silencing GCN5. Of note, in an MDR breast tumor model, DOX and siGCN5 co-delivered HPMSNs inhibits MDR tumor growth by 77%, abolishes P-gp-mediated drug resistance, and eliminates DOX's systemic toxicity. Thus, the tumor-targeting, stimuli-responsive nanosystem is an effective carrier for co-delivering anticancer drug and siRNA for combating cancer drug resistance. Statement of significanceWe designed a tumor-targeting, pH/redox dual-responsive nanosystem (HPMSNs) for chemo-drug and siRNA co-delivery. This nanosystem efficiently co-delivered DOX and siGCN5 into drug-resistant cancer cells and significantly inhibited the tumor growth through: (1) HA shell enhanced the cellular internalization of loaded DOX and siGCN5 via CD44-mediated targeting; (2) the pH/redox dual-responsive nanosystem released the cargos in response to the intracellular environment; (3) the released siGCN5 downregulated P-gp epigenetically. In an MDR breast tumor model (MCF7/ADR), DOX and siGCN5 loaded HPMSNs markedly inhibited tumor growth, almost completely abolished P-gp expression, and minimized systemic toxicity of DOX.

CD44 Promotes Lung Cancer Cell Metastasis through ERK-ZEB1 Signaling.

Simple SummaryLung cancer treatment has always been challenging as its metastasis rate is higher than other cancers. Cancer stemness promotes cancer metastasis, and it is important to understand the mechanism behind the cancer-stemness-mediated metastasis. CD44 is a well-known cancer stem cell marker and plays a role in tumor metastasis in different cancer types. In this study, we investigated the role of CD44 in lung cancer metastasis by using clinical studies as well as in vitro and in vivo studies. We found that CD44 promotes the migration and invasion abilities of lung cancer cells through ERK–ZEB1 signaling. This study provided evidence that CD44 may be a possible therapeutic target to decrease lung cancer metastasis.Lung cancer is a malignancy with high mortality worldwide, and metastasis occurs at a high frequency even when cancer spread is not detectable at primary operation. Cancer stemness plays an important role in malignant cancer behavior, treatment resistance, and cancer metastasis. Therefore, understanding the molecular pathogenesis behind cancer-stemness-mediated metastasis and developing effective approaches to prevent metastasis are key issues for improving cancer treatment. In this study, we investigated the role of CD44 stemness marker in lung cancer using in vitro and clinical studies. Immunohistochemical staining of lung cancer tissue specimens revealed that primary tumors with higher CD44 expression showed increased metastasis to regional lymph nodes. Flow cytometry analysis suggested that CD44 positive cells were enriched in the metastatic lymph nodes compared to the primary tumors. CD44 overexpression significantly increased migration and invasion abilities of lung cancer cells through CD44-induced ERK phosphorylation, ZEB1 upregulation, and Claudin-1 downregulation. Furthermore, ERK inhibition suppressed the migration and invasion abilities of CD44-overexpressing lung cancer cells. In summary, our in vitro and clinical results indicate that CD44 may be a potential prognostic and therapeutic marker for lung cancer patients.

Hyaluronic acid-functionalized halloysite nanotubes for targeted drug delivery to CD44-overexpressing cancer cells

Chemotherapeutic drug has inevitable drawbacks of nonspecific tumor targeting and poor therapeutic efficiency, limiting practical clinical applications. To overcome these challenges, a novel halloysite nanotube-based drug delivery system was designed for efficient CD44-mediated targeting in this study. CD44 molecule, a major receptor for hyaluronic acid (HA), overexpressed in aggressive cancer cells. The successful synthesis of hyaluronic acid modified halloysite (HNTs-NH-HA) complexes were proved by 13C solid state NMR spectroscopy, FT-IR, XPS and TGA. Thereafter, a model anticancer drug doxorubicin (DOX) was loaded into HNTs-NH-HA to from the final drug delivery system (HNTs-NH-HA/DOX). In vitro cytotoxicity assay tests revealed that HNTs-NH-HA/DOX improved therapeutic efficacy of DOX by specific targeting. Furthermore, confocal laser scanning microscopy (CLSM) results showed better uptake of HNTs-NH-HA/DOX nanoparticles in CD44 receptor-positive cells than in CD44 receptor-negative cells. It was expected that HNTs-NH-HA drug delivery systems hold great potential for targeting CD44 over-expressing tumors.

Tumor-Targeting H2O2-Responsive Photosensitizing Nanoparticles with Antiangiogenic and Immunogenic Activities for Maximizing Anticancer Efficacy of Phototherapy.

Phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) uses photosensitizers and light to kill cancer cells and has become a promising therapeutic modality because of advantages such as minimal invasiveness and high cancer selectivity. However, PTT or PDT as a single treatment modality has insufficient therapeutic efficacy. Moreover, oxygen consumption by PDT activates angiogenic factors and leads to cancer recurrence and progression. Therefore, the therapeutic outcomes of phototherapy would be maximized by employing photosensitizers for concurrent PTT and PDT and suppressing angiogenic factors. Therefore, integrating photosensitive agents and antiangiogenic agents in a single nanoplatform would be a promising strategy to maximize the therapeutic efficacy of phototherapy. In this study, we developed hyaluronic acid-coated fluorescent boronated polysaccharide (HA-FBM) nanoparticles as a combination therapeutic agent for phototherapy and antiangiogenic therapy. Upon a single near-infrared laser irradiation, HA-FBM nanoparticles generated heat and singlet oxygen simultaneously to kill cancer cells and also induced immunogenic cancer cell death. Beside their fundamental roles as photosensitizers, HA-FBM nanoparticles exerted antiangiogenic effects by suppressing the vascular endothelial growth factor (VEGF) and cancer cell migration. In a mouse xenograft model, intravenously injected HA-FBM nanoparticles targeted tumors by binding CD44-overexpressing cancer cells and suppressed angiogenic VEGF expression. Upon laser irradiation, HA-FBM nanoparticles remarkably eradicated tumors and increased anticancer immunity. Given their synergistic effects of phototherapy and antiangiogenic therapy from tumor-targeting HA-FBM nanoparticles, we believe that integrating the photosensitizers and antiangiogenic agents into a single nanoplatform presents an attractive strategy to maximize the anticancer therapeutic efficacy of phototherapy.

Tirapazamine encapsulated hyaluronic acid nanomicelles realized targeted and efficient photo-bioreductive cascading cancer therapy

Currently, architecting a rational and efficient nanoplatform combing with multi-therapeutic modalities is highly obligatory for advanced cancer treatment. In order to remedy the self-limiting hypoxic dilemma of photodynamic therapy (PDT), herein, a facile photosensitizer (i.e., chlorin e6, Ce6) and bioreductive prodrug (i.e., tirapazamine, TPZ)-coloaded hyaluronic acid (HA) nanomicelles (denoted as TPZ@HA-Ce6) was developed for the cascading mode of photo-bioreductive cancer therapy. Taking the typical advantage of Ce6 coupled HA conjugate, TPZ was easily and successfully accommodated into the hydrophobic core of HA-Ce6 nanomicelles, yielding TPZ@HA-Ce6. It showed good dispersibility and stability with the hydrodynamic size of ca. 170 nm. It targeted the CD44 overexpressed cancer cells by receptor-mediated endocytosis way and killed them effectively with singlet oxygen and the subsequent TPZ radicals resulting from the oxygen depletion of PDT. The later was further verified by the hypoxia probe in vivo. Using murine mammary carcinoma 4T1 model, TPZ@HA-Ce6 nanomicelles exhibited cascading and synergistic anticancer effect of PDT and TPZ bioreductive therapy compared with each monotherapy. This work suggests the promising prospect of the hybrid hyaluronic nanomicelles for highly efficient cancer combination treatment.

Preparation of hyaluronic acid-decorated mixed nanomicelles for targeted delivery of hydrophobic drugs to CD44-overexpressing cancer cells

Most of the employed methods for preparation of targeted nanoparticles containing hydrophobic herbal drugs have multiple surface modifications with time-consuming steps. The present research was aimed to develop a facile method for preparation of hyaluronic acid (HA)-decorated mixed nanomicelles loaded with curcumin (as a hydrophobic drug model) to provide an efficient drug delivery system for targeted therapy of breast cancer cells with high expression of CD44 receptor. To this end, curcumin was first encapsulated in the hydrophobic core of Pluronic F127/didecyldimethylammonium bromide (PD) mixed nanomicelles using thin-film hydration method. Then, negatively charged HA was coated on the positively charged surface of PD mixed nanomicelles via electrostatic interactions. The drug loading and entrapment efficiency of the targeted nanomicelles were 2.8% and 95.1%, respectively. The average hydrodynamic size of the prepared nanomicelles before and after coating with HA were 19.8 and 35.8 nm, respectively. Moreover, in vitro cytotoxicity analyses showed that, HA-coated PD (HA-PD) mixed nanomicelles can enhance the cytotoxicity of curcumin against MDA-MB-231 cancer cells compared to non-targeted ones (PD mixed nanomicelles), and free curcumin. The IC50 concentrations of free curcumin, curcumin-loaded PD mixed nanomicelles, and curcumin-loaded HA-PD mixed nanomicelles were 4.11, 3.20, and 2.83 μg/mL, respectively, after 48 h incubation with MDA-MB-231 cancer cells. Our results suggest that, curcumin-loaded HA-PD mixed nanomicelles may be considered as a promising targeted anticancer drug delivery system for breast cancer therapy and/or delivering other hydrophobic drugs to different kinds of cancer cells with CD44-receptor overexpression.

Hyaluronic acid-based label-free electrochemical impedance analysis for cancer cell quantification and CD44 expression

In this study, a novel label-free electrochemical impedance spectroscopy (EIS) sensor was developed by successfully conjugating hyaluronic acid (HA) with bovine serum albumin (BSA)-modified gold nanoparticles (GNPs) for cancer cell quantification and CD44 expression analysis. Based on the molecular recognition of HA, the CD44-overexpressing cancer cells can be captured on the nanocomposites (HA-BSA-GNPs) modified electrode, increasing the electron-transfer resistance (Ret). The change of Ret was measured by the EIS to quantify the number of cancer cells and evaluate the CD44 expression level on the cell surface. Under optimal conditions, the change of Ret was proportional to the logarithm of the cell concentration, namely from 2.0 × 102 to 3.0 × 105 cells mL−1 with a detection limit of 128 cells mL−1 for the MDA-MB-231 cells. Moreover, compared to HCT116 and L02 cells, the MDA-MB-231 cells exhibited a distinctly higher expression level of CD44. This indicates that the MDA-MB-231 cells have greater metastatic potential. The proposed sensor may find potential applications in cancer monitoring and research on tumor metastasis.

Heteroatom doped carbon dots with nanoenzyme like properties as theranostic platforms for free radical scavenging, imaging, and chemotherapy

Carbon-based artificial nanoenzymes have gained increasing interest as emerging and promising nanotheranostic agents due to their biocompatibility, low cost, and straightforward production. Herein, a multifunctional Mn, N, and S incorporated carbon dots (MnNS:CDs) nanoenzyme exhibiting scavenging activity against reactive oxygen species (ROS) and reactive nitrogen species (RNS), photoluminescence quantum yield of 17.7%, and magnetic resonance imaging (MRI) contrast was explored. The optical, magnetic, and antioxidant properties of MnNS:CDs were then regulated by control over Mn incorporation to achieve higher photostability and antioxidant properties. Furthermore, conjugation of MnNS:CDs with hyaluronic acid (HA) (denoted as MnNS:CDs@HA) endowed them with high biocompatibility, which is validated by in vivo studies on zebrafish, and the ability to specifically target cluster determinant 44 (CD44)-overexpressing B16F1 cells, as verified by in vitro confocal and MRI studies. The MnNS:CDs@HA probe with therapeutic antioxidant and dual-modal imaging capability was further assessed for non-covalent binding of doxorubicin (DOX) as a model chemotherapeutic cancer drug. Results showed that targeted delivery and pH-dependent release of DOX elicited apparent cell toxicity (90%) toward B16F1 cancer cells when compared to free DOX treatment group (60%). Benefiting from their intrinsic antioxidant properties, and dual-modal imaging ability, the MnNS:CDs@HA nanocarrier is projected to improve non-invasive targeted diagnosis and therapy. Statement of significanceCarbon dots (CDs) have gained increasing interest as emerging and promising artificial functional nanomaterials that mimic the structures and functions of natural enzymes. In this work, Mn, N, and S incorporated CDs (MnNS:CDs) were synthesized using a one-pot microwave hydrothermal method to serve as fluorescent and magnetic resonance imaging probes, and catalase mimics in the reduction of the oxidative-stress related damage. Further conjugation of the probes with hyaluronic acid endows them with a good in vitro and in vivo biocompatibility as well as the capability to selectively target CD44-overexpressing cancer cells, as investigated by in vitro fluorescence, and magnetic resonance imaging. The dual-modal nanoprobe was then used to carry on doxorubicin through a non-covalent association. Favorably, targeted delivery, and pH-responsive release of doxorubicin enhanced cell killing efficiency by 50% as opposed to the free doxorubicin treatment group. The presented theranostic heteroatom doped CDs hold great promise for dual-modal imaging enabling accurate diagnosis coupled with therapeutic effect through free radical scavenging and chemotherapy.

Hyaluronic Acid-Coated Camptothecin Nanocrystals for Targeted Drug Delivery to Enhance Anticancer Efficacy.

Tumor-targeted drug delivery via chemotherapy is very effective on cancer treatment. For potential anticancer agent such as Camptothecin (CPT), high chemotherapeutic efficacy and accurate tumor targeting are equally crucial. Inspired by special CD44 binding capability from hyaluronic acid (HA), in this study, novel HA-coated CPT nanocrystals were successfully prepared by an antisolvent precipitation method for tumor-targeted delivery of hydrophobic drug CPT. These HA-coated CPT nanocrystals demonstrated high drug loading efficiency, improved aqueous dispersion, prolonged circulation, and enhanced stability resulting from their nanoscaled sizes and hydrophilic HA layer. Moreover, as compared to crude CPT and naked CPT nanocrystals, HA-coated CPT nanocrystals displayed dramatically enhanced in vitro anticancer activity, apoptosis-inducing potency against CD44 overexpressed cancer cells, and lower toxic effect toward normal cells due to pH-responsive drug release behavior and specific HA-CD44 mediated endocytosis. Additionally, HA-coated CPT nanocrystals performed fairly better antimigration activity and biocompatibility. The possible molecular mechanism regarding this novel drug formulation might be linked to intrinsic mitochondria-mediated apoptosis by an increase of Bax to Bcl-2 ratio and upregulation of P53. Consequently, HA-coated CPT nanocrystals are expected to be an effective nanoplatform in drug delivery for cancer therapy.

Dual-stimuli responsive mesoporous copper (II) sulfide nanocomposite for chemo-photothermal synergistic therapy

A combination of chemo-photothermal therapy has recently emerged as a great potential cancer treatment due to enhanced therapeutic efficacy. Herein, we present a novel nanocomposite for chemo-photothermal synergistic therapy. The glutathione (GSH)-responsive mesoporous silica-coated copper sulfide (mesoporous CuS) nanocomposite was synthesized by co-condensation using tetraethyl orthosilicate (TEOS) and bis[3-(triethoxysilyl)propyl]tetrasulfide (BTES). Hyaluronic acid (HA) was functionalized on nanocarrier for drug leakage prevention, enzyme-triggered drug release and targeting moiety toward CD44 overexpressing cancer cells. The mesoporous CuS nanocomposite generated the heat for photothermal therapy in response to near-infrared (NIR) irradiation. The release of doxorubicin (Dox) from mesoporous CuS nanocomposite was controlled by dual-stimuli of response. We confirmed that mesoporous CuS nanocomposite was internalized to HeLa cells by CD44 receptor-mediated endocytosis and significantly enhanced anticancer effects due to the combination treatment. Therefore, we developed a tumor targeted dual-stimuli responsive drug delivery system for chemo-photothermal synergistic therapy. • GSH-responsive mesoporous silica coated CuS nanocomposites was prepared by in-situ co-condensation method using TEOS and BTES. • HA was functionalized on nanocarrier as a gate keeper and CD44 receptor targeting moiety. • Mesoporous CuS nanocomposite exhibited good photothermal effect and dual stimuli-responsive durg release property by GSH and HAase. • Mesoporous CuS nanocomposite enhanced therapeutic efficacy against cancer cell by chemo-photothermal combination treatment.

One-pot preparation of hyaluronic acid‐coated iron oxide nanoparticles for magnetic hyperthermia therapy and targeting CD44-overexpressing cancer cells

In the present study, a facile one-pot hydrothermal method is introduced for preparation of hyaluronic acid-coated Fe3O4 nanoparticles (Fe3O4@HA NPs) for theranostic applications. In the proposed method, hyaluronic acid acts simultaneously as a biocompatible coating layer and as a targeting ligand for CD44 receptor overexpressed on the surface of breast cancer cells. The obtained product with narrow hydrodynamic size distribution exhibited a high colloidal stability at physiological pH for more than three months. Cytotoxicity measurements indicated a negligible toxicity of the prepared sample against L929 normal cells. Preferential targeting of Fe3O4@HA NPs to CD44-overexpressing cancer cells was studied by comparing the uptake of the prepared nanoparticles by MDA-MB-231 cancer cells (positive CD44 expression) and L929 normal cells (negative CD44 expression). Uptake of the Fe3O4@HA NPs by MDA-MB-231 cells was found to be 4-fold higher than the normal cells. Also, the in vitro analysis showed that, the uptake of Fe3O4@HA NPs by MDA-MB-231 breast cancer cells is significantly enhanced as compared to non-targeted dextran-coated Fe3O4 NPs. Moreover, the heat generation capability of the Fe3O4@HA NPs for magnetic hyperthermia application was studied by exposing the prepared nanoparticles to different safe alternating magnetic fields (f = 120 kHz, H = 8, 10, and 12 kA/m). The intrinsic loss power obtained for Fe3O4@HA NPs was about 3.5 nHm2/kg, which is about 25-fold larger than that of obtained for commercial available Fe3O4 nanoparticles for biomedical applications. Good colloidal stability, biocompatibility, high heating efficacy, and targeting specificity to CD44 receptor‐overexpressing cancer cells could make the Fe3O4@HA NPs as a promising multifunctional platform for diagnosis and therapeutic applications.