Doxorubicin Nanoparticles Research Articles

TPGS-Galactose-Modified Polydopamine Co-delivery Nanoparticles of Nitric Oxide Donor and Doxorubicin for Targeted Chemo-Photothermal Therapy against Drug-Resistant Hepatocellular Carcinoma.

The lack of cancer cell specificity and the occurrence of multidrug resistance (MDR) are two major obstacles in the treatment of hepatocellular carcinoma (HCC). To tackle these challenges, a novel nanoparticle (NP)-based drug delivery system (DDS) with a core/shell structure consisted of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)-galactose (Gal)/polydopamine (PDA) is fabricated. The NP is loaded with doxorubicin (DOX) and a nitric oxide (NO) donor N,N'-di-sec-butyl-N,N'-dinitroso-1,4-phenylenediamine (BNN) sensitive to heat to afford NO-DOX@PDA-TPGS-Gal. The unique binding of Gal to asialoglycoprotein receptor (ASGPR) and the pH-sensitive degradation of NP ensure the targeted transportation of NP into liver cells and the release of DOX in HCC cells. The near-infrared (NIR) light further facilitates DOX release and initiates NO generation from BNN due to the photothermal property of PDA. In addition to the cytotoxicity contributed by DOX, NO, and heat, TPGS and NO act as MDR reversal agents to inhibit P-glycoprotein (P-gp)-related efflux of DOX by HepG2/ADR cells. The combined chemo-photothermal therapy (chemo-PTT) by NO-DOX@PDA-TPGS-Gal thus shows potent anti-cancer activity against drug-resistant HCC cells in vitro and in vivo and significantly prolongs the life span of drug-resistant tumor-bearing mice. The present work provides a useful strategy for highly targeted and MDR reversal treatment of HCC.

The Multifunctionally Graded System for a Controlled Size Effect on Iron Oxide-Gold Based Core-Shell Nanoparticles.

We report that Fe3O4@Au core-shell nanoparticles (NPs) serve as a multifunctional molecule delivery platform. This platform is also suitable for sensing the doxorubicin (DOX) through DNA hybridization, and the amount of carried DOX molecules was determined by size-dependent Fe3O4@Au NPs. The limits of detection (LODs) for DOX was found to be 1.839 nM. In our approach, an Au nano-shell coating was coupled with a specially designed DNA sequence using thiol bonding. By means of a high-frequency magnetic field (HFMF), a high release percentage of such a molecule could be efficiently achieved in a relatively short period of time. Furthermore, the thickness increase of the Au nano-shell affords Fe3O4@Au NPs with a larger surface area and a smaller temperature increment due to shielding effects from magnetic field. The change of magnetic property may enable the developed Fe3O4@Au-dsDNA/DOX NPs to be used as future nanocarrier material. More importantly, the core-shell NP structures were demonstrated to act as a controllable and efficient factor for molecule delivery.

A New Water-Soluble Thermosensitive Star-Like Copolymer as a Promising Carrier of the Chemotherapeutic Drug Doxorubicin.

A new water-soluble thermosensitive star-like copolymer, dextran-graft-poly-N-iso-propilacrylamide (D-g-PNIPAM), was created and characterized by various techniques (size-exclusion chromatography, differential scanning calorimetry, Fourier-transform infrared (FTIR) spectroscopy, and dynamic light scattering (DLS) spectroscopy). The viability of cancer cell lines (human transformed cervix epithelial cells, HeLa) as a model for cancer cells was studied using MTT and Live/Dead assays after incubation with a D-g-PNIPAM copolymer as a carrier for the drug doxorubicin (Dox) as well as a D-g-PNIPAM + Dox mixture as a function of the concentration. FTIR spectroscopy clearly indicated the complex formation of Dox with the D-g-PNIPAM copolymer. The size distribution of particles in Hank’s solution was determined by the DLS technique at different temperatures. The in vitro uptake of the studied D-g-PNIPAM + Dox nanoparticles into cancer cells was demonstrated by confocal laser scanning microscopy. It was found that D-g-PNIPAM + Dox nanoparticles in contrast to Dox alone showed higher toxicity toward cancer cells. All of the aforementioned facts indicate a possibility of further preclinical studies of the water-soluble D-g-PNIPAM particles’ behavior in animal tumor models in vivo as promising carriers of anticancer agents.

Preparation of doxorubicin-loaded metallic organic nanoparticles and their effect for enhancing efficacy of high-intensity focused ultrasound therapy in tumor-bearing mice

To prepare metallic organic nanoparticles that produce synergistic effect in high-intensity focused ultrasound (HIFU) therapy of tumors. Glucose oxidase (GOD), MnO2, ferric iron (Fe3+) and doxorubicin (DOX) were self-assembled by physical adsorption with previously prepared manganese dioxide (MnO2) nanoparticles to obtain GOD-MnO2-Fe3+-DOX nanoparticles (GMFD NPs). HepG2 tumor-bearing nude mouse models were given intravenous injections of normal saline or GMFD NPs followed 4 h later by HIFU at the acoustic power of 90 W with a total treatment time of 3 s. The changes of tumor gray value before and after HIFU irradiation were observed and 24 h after HIFU irradiation, coagulation necrosis in the tumor tissues was examined; the histological changes of the tumor tissues were observed with HE staining. We successfully prepared GMFD NPs, which had an average particle size of 131.23±0.84 nm with a surface potential of 21.87±1.72 mV. GMFD NPs, with a drug loading rate of 40.18%, was capable of releasing more than 77.2% of the loaded DOX within 4 h in acidic environment. In the tumor-bearing mouse models, HIFU irradiation following GMFD NP injection, as compared with saline injection, resulted in significantly enhanced gray value of the tumor (25.5±4.5 vs 18.7±3.9, P=0.04) and greater volume of coagulation necrosis (105.80 ± 1.21 mm3 vs 38.02 ± 0.34 mm3). The energy efficiency factor (EEF) was significantly lower in GMFD NPs group than in saline group (1.79 vs 4.97, P < 0.001). GMFD NPs prepared in this study can enhance tumor ablation efficacy of HIFU and release DOX for further treatment of the residual tumor tissue in mice.

Targeted polymeric nanoparticle for anthracycline delivery in hypoxia-induced drug resistance in metastatic breast cancer cells.

Poly lactic-co-glycolic acid (PLGA) nanoparticles are intensively studied nanocarriers in drug delivery because of their biodegradability and biochemical characteristics. Polyethylene glycol (PEG) coating for nanocarriers gives them long circulation time in blood and makes them invisible to the reticuloendothelial system. Breast cancer cells have greater uptake of hyaluronic acid compared to normal cells as it binds to their overexpressed CD44 receptors. Since hypoxia plays an important role in cancer metastasis; we formulated PEG-PLGA nanoparticles coated with hyaluronic acid as targeted delivery system for doxorubicin (DOX) using nanoprecipitation method, and characterized them for chemical composition, size, surface charge, shape, and encapsulation efficiency. Then we tested them in vitro on hypoxia-optimized metastatic breast cancer cells. The nanoparticles were spherical with an average size of about 106 ± 53 nm, a negative surface charge (-15 ± 3 mV), and high encapsulation efficiency (73.3 ± 4.1%). In vitro investigation with hypoxia-elevated CD44 MDA-MB-231 cells showed that hyaluronic acid-targeted nanoparticles maintained their efficacy despite hypoxia-induced drug resistance unlike free DOX and nontargeted nanoparticles. In conclusion, this study revealed a simple third generation nanoparticle formulation for targeted treatment of hypoxia-induced drug resistance in breast cancer metastatic cells. Further, optimization is needed including In vivo efficacy and nanoparticle-specific pharmacokinetic studies.

Tumor‐Activated Photosensitization and Size Transformation of Nanodrugs

AbstractEffective intratumoral distribution of anticancer agents with good tumor penetration is of practical importance for photo‐chemotherapy. Herein, a metal‐organic framework (MOF) assisted strategy is reported for smart delivery of aggregation‐induced emission photosensitizer (AIE PS) and chemodrug for deep tumor penetration to realize effective image‐guided photo‐chemotherapy. A newly designed AIE PS is loaded inside an iron(III) carboxylate‐based MOF, MIL‐100, to produce PS@MIL‐100, which is encapsulated by doxorubicin (Dox) conjugated poly(ethylene glycol) methyl ether (PEG) to yield Dox‐PEG‐PS@MIL nanoparticles (NPs) with a diameter of 120 nm. After Dox‐PEG‐PS@MIL NPs reached the tumor site, intratumoral H2O2 can cause the release of the loaded PS at the tumor surface for activatable photodynamic therapy (PDT). The Dox‐PEG segment is simultaneously triggered to self‐assemble into ultrasmall Dox NPs. Under light irradiation, PDT is activated at the tumor surface, synergistically enhancing the tumor penetration of Dox NPs along with their ultrasmall size. After endocytosis of Dox NPs, free Dox is released from Dox NPs under low pH to enter cell nuclei for effective chemotherapy. Accompanied by bright far‐red/near‐infrared emission from the PS, image‐guided photo‐chemotherapy with enhanced efficacy is achieved.

Phase pure synthesis of lanthanum doped bismuth ferrite nanostructures for the adsorption of doxorubicin

The improper disposal of pharmaceutical effluents, hospital sewage, wastes, and domestic drugs are the typical sources of emerging organic contamination (EOC). The untreated doxorubicin (DOX) effluent being released into the environment has harmful influence on human health. In this study, the lanthanum substituted bismuth ferrite nanoparticles with pure rhombohedral phase were prepared via facile co-precipitation technique, wherein the influence of La3+ ion substitution on structural, optical, and electrical properties of BiFeO3 (BFO) nanoparticles was investigated. Lanthanum content increment did not widely impact the structural properties but a systematic decrease in bandgap with increasing concentration of La3+ ion content was observed. DOX was treated with Bi1−xLaxFeO3 to investigate adsorption activity, where the kinetic modelling of isotherms and intraparticle diffusion showed that the adsorption of DOX followed the multi-layered heterogeneous adsorption mechanism. The BFO nanoparticles exhibited the highest adsorption efficiency of about 93% for DOX in the aqueous solution. The electrostatic interaction between DOX and BFO nanoparticles along with substantial diffusion at porous sites was the probable degradation mechanism of DOX. To assess the reusability merit, BFO were reused up to 4 times as an absorbent for DOX adsorption. Phase pure BFO can efficiently remove the DOX from aqueous medium and provide a cost-effective and eco-friendly solution to deal with EOC of water.

Polymer Pro-Drug Nanoparticles for Sustained Release of Cytotoxic Drugs Evaluated in Patient-Derived Glioblastoma Cell Lines and In Situ Gelling Formulations.

Glioblastoma (GBM) is the most common, malignant and aggressive brain tumour in adults. Despite the use of multimodal treatments, involving surgery, followed by concomitant radiotherapy and chemotherapy, the median survival for patients remains less than 15 months from diagnosis. Low penetration of drugs across the blood-brain barrier (BBB) is a dose-limiting factor for systemic GBM therapies, and as a result, post-surgical intracranial drug delivery strategies are being developed to ensure local delivery of drugs within the brain. Here we describe the effects of PEGylated poly(lactide)-poly(carbonate)-doxorubicin (DOX) nanoparticles (NPs) on the metabolic activity of primary cancer cell lines derived from adult patients following neurosurgical resection, and the commercially available GBM cell line, U87. The results showed that non-drug-loaded NPs were well tolerated at concentrations of up to 100 µg/mL while tumour cell-killing effects were observed for the DOX-NPs at the same concentrations. Further experiments evaluated the release of DOX from polymer-DOX conjugate NPs when incorporated in a thermosensitive in situ gelling poly(DL-lactic-co-glycolic acid) and poly(ethylene glycol) (PLGA/PEG) matrix paste, in order to simulate the clinical setting of a locally injected formulation for GBM following surgical tumour resection. These assays demonstrated drug release from the polymer pro-drugs, when in PLGA/PEG matrices of two formulations, over clinically relevant time scales. These findings encourage future in vivo assessment of the potential capability of polymer–drug conjugate NPs to penetrate brain parenchyma efficaciously, when released from existing interstitial delivery systems.

Precise engineering of dual drug-loaded polymeric nanoparticles system to improve the treatment of glioma-specific targeting therapy

We have fabricated a novel method to achieve therapy- triggered changes in tumor cells by using promising effects concerning dual chemotherapeutic drugs. Dual-drug conveyance of Salinomycin (SAL) and Doxorubicin (DOX) exhibits a great anti-tumor ability, as SAL improves the impact of DOX management of glioma cells by supplying stability of the microenvironment. Nevertheless, encapsulations of SAL and DOX fanatical by (lactic-co-glycolic acid (PLGA) and polyethylene glycol (PEG)- based nanoparticles (NPs) is incompetents due to inappropriateness between the dual drug SAL and DOX polymeric framework. At the present, we show DOX and SAL can be formulated with dioleoylphosphatide acid (DOPA) through the hydrophobic covering of drug centers. In PEG-PLGA NPs, the DOPA- enclosed DOX can be co-incorporating in addition to SAL to encourage superior cancer activities. The DOX revealed seductively that the SAL encapsulations in PEG-PLGA NPs (SAL-DOX NPs) were improved. The transmission microscopy (TEM) studied the morphology of SAL NPs, DOX NPs, SAL-DOX NPs, and nanoparticle size. SAL-DOX NPs also induced major apoptosis in vitro human glioma cells such as LN229 and U251. Different biochemical trials such as AO-EB, Hoechst staining, and annexin V-FITC have confirmed morphological observations and apoptosis. The findings indicate that the SAL-DOX NPs is one of the promising caregivers of therapeutic candidates for human glioma cancer worth further study.

In situ injection of dual-delivery PEG based MMP-2 sensitive hydrogels for enhanced tumor penetration and chemo-immune combination therapy.

Improving the deep penetration of nanoparticles and realizing the combination of chemotherapy and immunotherapy have become a promising strategy for cancer treatment. Herein, a nuclear-targeted tetrahedral DNA nanostructure (NLS-TDNs, NT) was synthesized to construct matrix metalloproteinase (MMP-2) sensitive hydrogels as delivery vehicles with co-loaded disulfide cross-linked polyethyleneimine (PSP)/nuclear-targeted tetrahedral DNA (NLS-TDNs, NT)/doxorubicin (DOX) nanoparticles (NPs) (PSP/NT/DOX NPs and PNT/DOX NPs) and an immune adjuvant imiquimod (R837) to realize a combination of chemotherapy and immunization for metastatic breast cancer. Due to the membrane-breaking ability of the PNT/DOX NPs, the nanoparticles could effectively achieve deep penetration into tumor tissues, and the in situ generation of tumor-associated antigens by PNT/DOX elicited a strong immune response in the presence of R837, achieving a chemo-immune combination therapy of breast cancer, inducing the maturation of dendritic cells (DCs) and secretion of related cytokines, such as interleukin-6 (IL-6), interleukin-12 (IL-12p70) and tumor necrosis factor (TNF-α) in vitro. The combination significantly promoted the proportions of cytotoxic T cells (CD8+ CTL) and cytotoxic T cells/regulatory T cells (CD8+ CTL/Treg) (5.52% and 11.46%, respectively) and the secretion of cytokines, which cooperatively eradicated primary tumor growth (the tumor growth inhibition (TGI) value was 78.3%) and inhibited the tumor from metastasizing effectively in vivo. Our study provided the basis for activating the antitumor immune system to realize chemo-immunotherapy and tumor metastasis therapy.

Modified biomimetic core–shell nanostructures enable long circulation and targeted delivery for cancer therapy

A “Trojan horse” strategy realizes long circulation and precise targeting of Bio-RBCm@MSN–DOX nanoparticles to efficiently kill tumor cells.

Functional Doxorubicin-Loaded Omega-3 Unsaturated Fatty Acids Nanoparticles in Reversing Hepatocellular Carcinoma Multidrug Resistance.

BackgroundThis study investigated a nanoparticle drug delivery system to reverse multidrug resistance (MDR) and assessed its anticancer efficacy in hepatocellular carcinoma (HCC).Material/MethodsDocosahexaenoic acid (DHA) was used as the functional excipient and doxorubicin (DOX) as the chemotherapeutic drug to synthesize DOX nanoparticles (DOX-nano). The human HCC cell line HepG2 was used for experiments. HepG2/DOX, HepG2+DOX, HepG2+DOX-nano, HepG2/DOX+DOX, and HepG2/DOX+DOX-nano groups cells were treated with DOX or DOX-nano (5 μg/mL). Nude mice bearing a HepG2/DOX xenograft were divided into model, DOX, vector-nano, and DOX-nano groups and injected with saline, DOX reagent, vector-nano, and DOX-nano (2 mg/kg), respectively. Next, cytotoxicity, cellular uptake, cell apoptosis and migration, fluorescence imaging, TUNEL assay, and tumor inhibition effects were assessed in vitro and in vivo. Furthermore, expression of MDR-related proteins was also detected using western blotting.ResultsFluorescence imaging showed that the DOX uptake in the DOX-nano-treated group was the strongest in the HCC cells or tumors. Cell apoptosis was significantly increased in DOX-nano-treated HepG2/DOX cells and tumors, and cell migration was significantly inhibited in the DOX-nano-treated HepG2/DOX cells compared with the other groups. The tumor inhibitory rate in DOX-nano-injected tumors was also significantly higher than in other groups. The expression of breast cancer resistance protein, B-cell lymphoma 2, lung resistance protein, multidrug resistance protein, and protein kinase C alpha was significantly decreased in DOX-nano-treated HepG2/DOX cells and xenograft tumors. Significantly better antitumor and MDR-reversing effects were also observed in the HepG2+DOX group compared with the HepG2/DOX group.ConclusionsThis study revealed the potential efficacy of a DOX-nano drug delivery system for the treatment of HCC, using HepG2/DOX cells and nude mice bearing HepG2/DOX xenografts.

Tumor microenvironment-activated therapeutic peptide-conjugated prodrug nanoparticles for enhanced tumor penetration and local T cell activation in the tumor microenvironment

Nanomedicine-based chemoimmunotherapy has shown a great potential for cancer therapies application in recent years. However, most nanoparticles still face a problem of low accumulation and limited penetration of chemotherapeutic drugs and immunotherapeutic drugs into solid tumors. Here, we developed a tumor microenvironment (TME)-activable therapeutic peptide-conjugated prodrug nanoparticle for enhanced tumor penetration and synergistic antitumor effects of chemotherapy and immune checkpoint blockade therapy. The prodrug nanoparticle is composed of a short D-peptide antagonist of PD-L1 (DPPA) conjugated doxorubicin (DOX) prodrug and a PEGylated DOX prodrug, which can dissociate into small DOX nanoparticles (<30 nm) and release DPPA antagonist in TME. The prodrug nanoparticles could co-deliver DOX and DPPA antagonist by one nanocarrier and improve tumor accumulation and penetration of the prodrug nanoparticels via a transcytosis process. It is demonstrated that co-delivery of DOX and DPPA antagonist directly killed tumor cells, promoted the tumor-infiltrating cytotoxic T lymphocytes, reduced the tumor-infiltrating regulatory T cells, and elicited a long-term immune memory effect to prevent tumor recurrence and metastasis. This TME-activable prodrug nanoparticle holds promise as a co-delivery nanoplatform for the improved chemoimmunotherapy of solid tumors.

Chemical Architecture of Block Copolymers Differentially Abrogate Cardiotoxicity and Maintain the Anticancer Efficacy of Doxorubicin.

The molecular architecture of pH-responsive amphiphilic block copolymers, their self-assembly behavior to form nanoparticles (NPs), and doxorubicin (DOX)-loading technique govern the extent of DOX-induced cardiotoxicity. We observed that the choice of pH-sensitive tertiary amines, surface charge, and DOX-loading techniques within the self-assembled NPs strongly influence the release and stimulation of DOX-induced cardiotoxicity in primary cardiomyocytes. However, covalent conjugation of DOX to a pH-sensitive nanocarrier through a "conditionally unstable amide" linkage (PCPY-cDOX; PC = polycarbonate and PY = 2-pyrrolidine-1-yl-ethyl-amine) significantly reduced the cardiotoxicity of DOX in cardiomyocytes as compared to noncovalently encapsulated DOX NPs (PCPY-eDOX). When these formulations were tested for drug release in serum-containing media, the PCPY-cDOX systems showed prolonged control over drug release (for ∼72 h) at acidic pH compared to DOX-encapsulated nanocarriers, as expected. We found that DOX-encapsulated nanoformulations triggered cardiotoxicity in primary cardiomyocytes more acutely, while conjugated systems such as PCPY-cDOX prevented cardiotoxicity by disabling the nuclear entry of the drug. Using 2D and 3D (spheroid) cultures of an ER + breast cancer cell line (MCF-7) and a triple-negative breast cancer cell line (MDA-MB-231), we unravel that, similar to encapsulated systems (PCPY-eDOX-type) as reported earlier, the PCPY-cDOX system suppresses cellular proliferation in both cell lines and enhances trafficking through 3D spheroids of MDA-MB-231 cells. Collectively, our studies indicate that PCPY-cDOX is less cardiotoxic as compared to noncovalently encapsulated variants without compromising the chemotherapeutic properties of the drug. Thus, our studies suggest that the appropriate selection of the nanocarrier for DOX delivery may prove fruitful in shifting the balance between low cardiotoxicity and triggering the chemotherapeutic potency of DOX.

Preparation and characterization of amphiphilic nanoparticles based on chondroitin sulfate A conjugated with hydrophobic drug for enhanced doxorubicin delivery

Novel chondroitin sulfate A conjugated doxorubicin (CSA-DOX) was synthesized and characterized. The mean diameter of CSA-DOX was 152 nm analyzed by dynamic light scattering (DLS). Further, DOX was physically encapsulated into the CSA-DOX nanoparticles. Total amounts of DOX in three kinds of DOX-loaded CSA-DOX (CSA-DOX/DOX) nanoparticles were from 21.8 to 24.2%. The mean diameters of three CSA-DOX/DOX nanoparticles were in the range of 167–177 nm. The shape of CSA-DOX/DOX nanoparticles was almost spherical. DOX released from DOX-loaded nanoparticles exhibited a biphasic way in phosphate buffered saline (PBS, pH 7.4). Cellular uptake studies exhibited that CSA-DOX and CSA-DOX/DOX nanoparticles could enhance the uptake of DOX into CD44 receptor-positive A549 cells. Moreover, the cytotoxicity of CSA-DOX/DOX nanoparticles against A549 cells significantly improved in contrast with free DOX and CSA-DOX nanoparticles. These results suggested that CSA-DOX copolymer could be a potential carrier for antitumor drug delivery.

Poly(3-Hydroxybutyrate)-Based Nanoparticles for Sorafenib and Doxorubicin Anticancer Drug Delivery.

Dual drug-loaded nanotherapeutics can play an important role against the drug resistance and side effects of the single drugs. Doxorubicin and sorafenib were efficiently co-encapsulated by tailor-made poly([R,S]-3-hydroxybutyrate) (PHB) using an emulsion–solvent evaporation method. Subsequent poly(ethylene glycol) (PEG) conjugation onto nanoparticles was applied to make the nanocarriers stealth and to improve their drug release characteristics. Monodisperse PHB–sorafenib–doxorubicin nanoparticles had an average size of 199.3 nm, which was increased to 250.5 nm after PEGylation. The nanoparticle yield and encapsulation efficiencies of drugs decreased slightly in consequence of PEG conjugation. The drug release of the doxorubicin was beneficial, since it was liberated faster in a tumor-specific acidic environment than in blood plasma. The PEG attachment decelerated the release of both the doxorubicin and the sorafenib, however, the release of the latter drug remained still significantly faster with increased initial burst compared to doxorubicin. Nevertheless, the PEG–PHB copolymer showed more beneficial drug release kinetics in vitro in comparison with our recently developed PEGylated poly(lactic-co-glycolic acid) nanoparticles loaded with the same drugs.

Tumor targeted combination therapy mediated by functional macrophages under fluorescence imaging guidance

Imaging-guiding and targeted drug delivery to tumors are essential for precision cancer therapy, which is a challenging goal to achieve extraordinary therapeutic efficacy. Functional live cells-based delivery systems are expected to play an important role in imaging-guiding and targeted drug delivery. Herein, we fabricated a delivery system mediated by IR-820 conjugated macrophages for tumor targeted combination therapy under fluorescence imaging guidance. The functional macrophages by nature could cross the barriers and recruit into tumors, and serve as host cells to targeted deliver drugs to tumors. The pH-sensitive doxorubicin nanoparticles were engulfed by the macrophages to enhance the drug loading and decrease the damage on host cells. IR-820 was anchored into macrophages cytoplasm to achieve the dual function of photothermal therapy and fluorescence imaging guidance. With Balb/C mice bearing murine breast tumor (4 T1) as models, the functional macrophages for their innate tumor tropism could targeted transport these therapeutic drugs into tumor site to exert efficient chemo-photothermal combination therapy. Moreover, fluorescence imaging-guided drug delivery was employed as the visible strategy to provide the optimized therapeutic window based on the fluorescence of IR-820. The multi-functional macrophages-mediated delivery system would provide a potential for precise and targeted delivery of combination therapy.

Cancer-specific drug-drug nanoparticles of pro-apoptotic and cathepsin B-cleavable peptide-conjugated doxorubicin for drug-resistant cancer therapy

Chemotherapy has shown remarkable therapeutic efficacy for various types of cancer. However, drug resistance reduces the effectiveness and sensitivity of chemotherapy, leading treatment failure and cancer relapse in many clinical indications. Herein, we propose cancer-specific drug-drug nanoparticles (DD-NPs) that improve the therapeutic efficacy of chemotherapy against drug-resistant cancer. Cancer-specific and pro-apoptotic drug-drug conjugate was prepared by conjugating the pro-apoptotic peptide drug (SMAC; Ala-Val-Pro-Ile-Ala-Gln, AVPIAQ) and cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly, FRRG) to a doxorubicin (DOX), resulting in SMAC-FRRG-DOX that allows self-assembled into nanoparticles. The resulting DD-NPs were specifically cleaved to pro-apoptotic SMAC and cytotoxic DOX only in cathepsin B-overexpressing cancer cells, inducing a synergy of the pro-apoptotic activity with the chemotherapy. In MCF-7 breast tumor-bearing mice, intravenously injected DD-NPs highly accumulated at targeted tumor tissues via enhanced permeability and retention (EPR) effect, releasing SMAC and DOX, which showed a synergetic pro-apoptotic/chemotherapy. Furthermore, DD-NPs greatly suppressed tumor growth and improved overall survival in a metastatic lung cancer model. Collectively, these cancer-specific drug-drug nanoparticles may be a promising strategy to treat drug-resistant cancers with high cancer cell-specificity.

Function of gold nanoparticles in oral cancer beyond drug delivery: Implications in cell apoptosis

Gold nanoparticles (AuNPs) are used to deliver drugs and therapeutic small molecule inhibitors to cancer cells. Evidence shows that AuNPs coated with nuclear localization sequence can cross the nuclear membrane and induce cellular apoptosis. To determine the therapeutic role of AuNPs, we compared two nanoconstructs conjugated to doxorubicin (DOX) through pH-sensitive and pH-resistant linkers. We tested DOX nanoconjugates' cytotoxicity, cellular and nuclear uptake in oral squamous cell carcinoma cell line. Furthermore, we evaluated the therapeutic effect of pH-sensitive and pH-resistant DOX bioconjugates in hamster buccal pouch carcinoma model. Our data indicate that pH-resistant and pH-sensitive DOX-nanoconjugates were equally localized in cancer cells, but the pH-resistant DOX nanoparticles were more localized in the nuclei inducing a 2-fold increase in the apoptotic effect compared with the pH-sensitive DOX nanoparticles. Our in vivo results show significantly higher tumor shrinkage and survival rates in animals treated with DOX pH-resistant AuNPs compared with pH-sensitive ones. Our findings suggest that AuNPs enhance the cytotoxic effect against cancer cells in addition to acting as drug carriers. DOX pH-resistant AuNPs enhanced accumulation of AuNPs in cancer cells' nuclei inducing a significant cellular apoptosis which was confirmed using in vitro and in vivo experiments without deleterious effects on blood cell count.

Effect of co-treatment with doxorubicin and verapamil loaded into chitosan nanoparticles on diethylnitrosamine-induced hepatocellular carcinoma in mice.

This study aimed to investigate the potential role of co-treatment with doxorubicin (DOX) and verapamil (VRP) nanoparticles in experimentally induced hepatocellular carcinoma in mice and to investigate the possible mechanisms behind the potential favorable effect of the co-treatment. DOX and VRP were loaded into chitosan nanoparticles (CHNPs), and cytotoxicity of loaded and unloaded drugs against HepG2 cells was evaluated. Male albino mice were divided into eight groups (n = 15): (1) normal control, (2) diethylnitrosamine, (3) CHNPs, (4) free DOX, (5) CHNPs DOX, (6) free VRP, (7) CHNPs VRP, and (8) CHNPs DOX + CHNPs VRP. Either VRP or DOX loaded into CHNPs showed stronger growth inhibition of HepG2 cells than their free forms. DOX or VRP nanoparticles displayed pronounced anticancer activity in vivo through the decline of vascular endothelial growth factor and B cell lymphoma-2 contents in liver tissues, upregulation of antioxidant enzymes, and downregulation of multidrug resistance 1. Moreover, reduced cardiotoxicity was evident from decreased level of tumor necrosis factor-α and malondialdehyde in heart tissues coupled with decreased serum activity of creatine kinase-myocardial band and lactate dehydrogenase. Co-treatment with CHNPs DOX and CHNPs VRP showed superior results versus other treatments. Liver sections from the co-treatment group revealed the absence of necrosis, enhanced apoptosis, and nearly normal hepatic lobule architecture. Co-treatment with CHNPs DOX and CHNPs VRP revealed enhanced anticancer activity and decreased cardiotoxicity versus the corresponding free forms.