Oral administration of ginseng berry concentrate improves lactate metabolism and increases endurance performance in mice.

In the present study, to determine the efficacy of oral supplementation of ginseng berry extracts in augmenting exercise performance and exercise-associated metabolism, male mice were given orally 200 and 400 mg/kg of body weight (BW) of GBC for nine weeks. Although there are no differences in pre-exercise blood lactate levels among (1) the control group that received neither exercise nor GBC, (2) the group that performed only twice-weekly endurance exercise, and (3) and (4) the groups that combined twice-weekly endurance exercise with either 200 or 400 mg/kg GBC, statistically significant reductions in post-exercise blood lactate levels were observed in the groups that combined twice-weekly endurance exercise with oral administration of either 200 or 400 mg/kg GBC. Histological analysis showed no muscle hypertrophy, but transcriptome analysis revealed changes in gene sets related to lactate metabolism and mitochondrial function. GBC intake increased nicotinamide adenine dinucleotide levels in the gastrocnemius, possibly enhancing the mitochondrial electron transport system and lactate metabolism. Further molecular mechanisms are needed to confirm this hypothesis. [BMB Reports 2023; 56(6): 353-358].

Eudesmane and Eremophilane Sesquiterpenes from the Fruits of Alpinia oxyphylla with Protective Effects against Oxidative Stress in Adipose-Derived Mesenchymal Stem Cells.

Alpinia oxyphylla Miquel (Zingiberaceae) has been reported to show antioxidant, anti-inflammatory, and neuroprotective effects. In this study, two new eudesmane sesquiterpenes, 7α-hydroperoxy eudesma-3,11-diene-2-one (1) and 7ß-hydroperoxy eudesma-3,11-diene-2-one (2), and a new eremophilane sesquiterpene, 3α-hydroxynootkatone (3), were isolated from the MeOH extract of dried fruits of A. oxyphylla along with eleven known sesquiterpenes (4-14). The structures were elucidated by the analysis of 1D/2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and optical rotation data. Compounds (1-3, 5-14) were evaluated for their protective effects against tert-butyl hydroperoxide (tBHP)-induced oxidative stress in adipose-derived mesenchymal stem cells (ADMSCs). As a result, treatment with isolated compounds, especially compounds 11 and 12, effectively reverted the damage of tBHP on ADMSCs in a dose-dependent manner. In particular, 11 and 12 at 50 µM improved the viability of tBHP-toxified ADMSCs by 1.69 ± 0.05-fold and 1.61 ± 0.03-fold, respectively.

Redox/photo dual-responsive, self-targeted, and photosensitizer-laden bismuth sulfide nanourchins for combination therapy in cancer.

Targeted and stimuli-sensitive nanobombs for the release of therapeutic agents after laser irradiation of the tumor site are gaining widespread attention as personalized anticancer regimens. In this study, redox and photo dual-responsive, folate receptor-targeted nanourchin carriers for chemo-, photodynamic, and photothermal therapy were constructed by the amalgamation of an outer layer of polyethylene glycol (PEG)-S-S-methotrexate (MTX) and an inner core of indocyanine green (ICG)-loaded bismuth sulfide (Bi2S3) nanoparticles for cancer treatment. MTX introduces the carrier to folate receptors resulting in the internalization of nanoparticles into cancer cells, specifically and increasingly. In the reducing environment inside cancer cells, MTX was cleaved, resulting in a burst release that effectively inhibited tumor growth. Simultaneously, the fusion of Bi2S3 and ICG in the inner core absorbed energy from a near-infrared radiation (NIR) laser to generate heat and reactive oxygen species, which further ablated the tumors and synergistically enhanced the anticancer activity of MTX. These results indicate the successful preparation of combined nanourchins (NUs) showing GSH-induced and laser-responsive release of MTX and ICG, accompanied by hyperthermia via Bi2S3 and ICG. Effective in vitro cellular internalization, cellular cytotoxicity, and pro-apoptotic behavior of the nanosystem were achieved through a targeting, redox, and NIR-responsive combination strategy. In vivo biodistribution and photothermal imaging also revealed tumor-selective and -retentive, as well as thermally responsive attributes. Ultimately, this in vivo antitumor study shows an effective tumor ablation by these nanourchins without affecting the vital organs. Our findings indicate that using these targeted redox- and laser-responsive combination therapeutic carriers can be a promising strategy in folate receptor-expressing tumors.

Localized therapy using anti-PD-L1 anchored and NIR-responsive hollow gold nanoshell (HGNS) loaded with doxorubicin (DOX) for the treatment of locally advanced melanoma.

Drug resistance and inefficient localization of chemotherapeutic agent limit the current treatment strategy in locally advanced melanoma (MEL), accounting to the 10-year survival rate from 24% to 68%. In this study we constructed anti-PD-L1 conjugated and doxorubicin loaded hollow gold nanoshell (T-HGNS-DOX) for targeted and localized chemo-photothermal therapy of MEL by the conjugation of LA-PEG-anti-PD-L1 antibody and short PEG chain on the surface of HGNS-DOX. Near infrared (NIR) as well as pH dependent drug release profile was observed. Significant uptake of DOX following NIR due to high PD-L1 receptors resulted in pronounced anticancer effect of T-HGNS-DOX. Following intratumoral administration, maximum nanoparticles retention with the significant reduction in tumor growth was observed as a result of elevated apoptosis marker (cleaved caspase-3, cleaved PARP) as well as downregulation of proliferative (Ki-67) and angiogenesis marker (CD31). Cumulatively, our system avoids the systemic toxicities of the nanosystem thereby providing maximum chemotherapeutic retention in tumor.

Hyaluronic acid wreathed, trio-stimuli receptive and on-demand triggerable nanoconstruct for anchored combinatorial cancer therapy.

Hyaluronic acid (HA) assisted effective internalization into CD44 receptor-overexpressing cancer cells, which could offer an excellent cytotoxic profile and tumor alterations. In this study, duo-photothermal agents (copper sulfide (CuS) and graphene oxide (GO)), chemotherapeutic drug (doxorubicin (DOX)), and targeting moiety (HA) were incorporated into a complexed nanoconstruct for trio-responsive chemo-phototherapy. The nanosystem (CuS(DOX)-GO-HA) was demonstrating its responsive drug release and escalated photothermal behavior. The hyperthermia and photodynamic effect were observed along with efficient ROS generation in the presence of dual photosensitizers. The in vivo biodistribution and photothermal profile reflected a high accumulation and retention of the nanoconstruct in the tumor. Importantly, nanoconstructs effectively inhibit tumor growth based on tumor volume analysis and the altered expression of apoptosis, cell proliferation, and angiogenesis markers. Collectively, these findings suggest that this nanoconstruct has excellent antitumor effects in CD44 overexpressed cells showing the potential for clinical translation in the future.

Immunoadjuvants for cancer immunotherapy: A review of recent developments.

Cancer immunotherapy evolved as a new treatment modality to eradicate tumor cells and has gained in popularity after its successful clinical transition. By activating antigen-presenting cells (APCs), and thus, inducing innate or adaptive immune responses, immunoadjuvants have become promising tools for cancer immunotherapy. Different types of immunoadjuvants such as toll-like receptor (TLR) agonists, exosomes, and metallic and plant-derived immunoadjuvants have been studied for their immunological effects. However, the clinical use of immunoadjuvants is limited by short response rates and various side-effects. The rapid progress made in the development of nanoparticle systems as immunoadjuvant carrier vehicles has provided potential carriers for cancer immunotherapy. In this review article, we describe different types of immunoadjuvants, their limitations, modes of action, and the reasons for their clinical adoption. In addition, we review recent progress made in the nanoparticle-based immunoadjuvant field and on the combined use of nanoparticle-based immunoadjuvants and chemotherapy, phototherapy, radiation therapy, and immune checkpoint inhibitor-based therapy. STATEMENT OF SIGNIFICANCE: Cancer immunotherapy emerged as a new hope for treating malignant tumors. Different types of immunoadjuvants serve as an important tool for cancer immunotherapy by activating an innate or adaptive immune response. Limitation of free immunoadjuvant has paved the path for the development of nanoparticle-based immunoadjuvant therapy with the hope of prolonging the therapeutic efficacy. This review highlights the recent advancement made in nanoparticle-based immunoadjuvant therapy in modulating the adaptive and innate immune system. The application of the combinatorial approach of chemotherapy, phototherapy, radiation therapy adds synergy in nanoparticle-based immunoadjuvant therapy. It will broaden the reader's understanding on the recent progress made in immunotherapy with the aid of immunoadjuvant-based nanosystem.

Stealth Polymer-Coated Graphene Oxide Decorated Mesoporous Titania Nanoplatforms for In Vivo Chemo-Photodynamic Cancer Therapy.

PURPOSE: The goal of this study was to develop chemotherapeutic drug-loaded photoactivable stealth polymer-coated silica based- mesoporous titania nanoplatforms for enhanced antitumor activity. METHODS: Both in vitro and in vivo models of solvothermal treated photoactivable nanoplatforms were evaluated for efficient chemo-photothermal activity. A versatile nanocomposite that combined silica based- mesoporous titania nanocarriers (S-MTN) with the promising photoactivable agent, graphene oxide (G) modified with a stealth polymer (P) was fabricated to deliver chemotherapeutic agent, imatinib (I), (referred as S-MTN@IG-P) for near-infrared (NIR)-triggered drug delivery and enhanced chemo-photothermal therapy. RESULTS: The fabricated S-MTN@IG-P nanoplatform showed higher drug loading (~20%) and increased drug release (~60%) in response to light in acidic condition (pH 5.0). As prepared nanoplatform significantly converted NIR light into thermal energy (43.2°C) to produce reactive oxygen species (ROS). The pronounced cytotoxic effect was seen in both colon cancer cells (HCT-116 and HT-29) that was mediated through the chemotherapeutic effect of imatinib and the photothermal and ROS generation effects of graphene oxide. In vivo study also showed that S-MTN@IG-P could significantly accumulate into the tumor area and suppress the tumor growth under NIR irradiation without any biocompatibility issues. CONCLUSION: Cumulatively, the above results showed promising effects of S-MTN@IG-P for effective chemo-phototherapy of colon cancer.

Polydopamine-tailored paclitaxel-loaded polymeric microspheres with adhered NIR-controllable gold nanoparticles for chemo-phototherapy of pancreatic cancer.

Chemotherapeutic drugs often used as a first-line treatment of pancreatic cancer (PC) exhibit challenges due to resistance development, lack of selectivity, and tumor heterogeneity. Currently, combination chemo-photothermal therapy is known to enhance the therapeutic efficacy of chemotherapeutic drugs in PC. In this study, we develop adherent gold nanoparticles (GNPs) and paclitaxel (PTX)-loaded PLGA microspheres for the treatment of PC. Polydopamine (pD) was used as a linker to adhere GNPs to the surface of PLGA-Ms and characterized using TEM. Short-term cytotoxicity of GNPs-pD-PTX-PLGA-Ms with or without NIR treatment was evaluated using CCK-8 assays. ROS and western blot assay were performed to determine the intensity of ROS following the treatment of GNPs-pD-PTX-PLGA-Ms with or without NIR in Panc-1 cell line. Successful adhesion of GNPs on the microspheres was confirmed by TEM. CCK-8 assay revealed that GNPs-pD-PTX-PLGA-Ms with NIR showed three-fold higher cytotoxicity, compared to the group without NIR. Furthermore, ROS and western blot assay suggest that GNPs-pD-PTX-PLGA-Ms with NIR showed more ROS generation, followed by downregulation of the expression levels of antioxidant enzyme (SOD2 and CATALASE). These results suggest that the GNPs-pD-PTX-PLGA-Ms in combination with NIR irradiation can provide a synergistic chemo-photothermal therapy for the treatment of PC.

Multifaceted NIR-responsive polymer-peptide-enveloped drug-loaded copper sulfide nanoplatform for chemo-phototherapy against highly tumorigenic prostate cancer.

Targeted, biocompatible, and synergistic "all in one" systems should be designed to combat the heterogeneity of cancer. In this study, we constructed a dual function nanosystem, copper sulfide nanoplatform loaded with the chemotherapeutic drug docetaxel wrapped by a conjugated polymer-peptide for targeted chemo-phototherapy. The nanoconstruct has been successfully designed with a size of 186.1 ±â€¯5.2 nm, a polydispersity index of 0.18 ±â€¯0.01, and zeta potential of -16.4 ±â€¯0.1 mV. The enhanced uptake and near-infrared-responsive behavior of the nanosystem resulted in efficient drug release, photothermal ablation, effective cytotoxic activity, and potentiated reactive oxygen species generation. The induction of apoptotic markers, enhanced accumulation in the tumor site, and maximum tumor growth inhibition were seen during in vivo studies compared to non-targeted nanoformulations and free drug. Cumulatively, our results indicate that, with low systemic toxicity and better biocompatibility, this nanoconstruct could provide a promising strategy for treating prostate cancer.

Mesenchymal Stem Cell Capping on ECM-Anchored Caspase Inhibitor-Loaded PLGA Microspheres for Intraperitoneal Injection in DSS-Induced Murine Colitis.

Mesenchymal stem cells (MSCs) are considered as a promising alternative for the treatment of various inflammatory disorders. However, poor viability and engraftment of MSCs after transplantation are major hurdles in mesenchymal stem cell therapy. Extracellular matrix (ECM)-coated scaffolds provide better cell attachment and mechanical support for MSCs after transplantation. A single-step method for ECM functionalization on poly(lactic-co-glycolic acid) (PLGA) microspheres using a novel compound, dopamine-conjugated poly(ethylene-alt-maleic acid), as a stabilizer during the preparation of microspheres is reported. The dopamine molecules on the surface of microspheres provide active sites for the conjugation of ECM in an aqueous solution. The results reveal that the viability of MSCs improves when they are coated over the ECM-functionalized PLGA microspheres (eMs). In addition, the incorporation of a broad-spectrum caspase inhibitor (IDN6556) into the eMs synergistically increases the viability of MSCs under in vitro conditions. Intraperitoneal injection of the MSC-microsphere hybrid alleviates experimental colitis in a murine model via inhibiting Th1 and Th17 differentiation of CD4+ T cells in colon-draining mesenteric lymph nodes. Therefore, drug-loaded ECM-coated surfaces may be considered as attractive tools for improving viability, proliferation, and functionality of MSCs following transplantation.

Transferrin-conjugated pH-sensitive platform for effective delivery of porous palladium nanoparticles and paclitaxel in cancer treatment.

Porous palladium (Pd) nanoparticles have garnered great research attention due to their potential anticancer activity and photothermal effect. In this study, a transferrin-conjugated pH-sensitive platform (Tf-PPP), comprising porous Pd nanoparticles (PdNPs) and paclitaxel (PTX), was successfully developed for combined chemo-phototherapy. Tf-PPPs have a small size of 164.6 ± 8.7 nm, PDI of 0.278 ± 0.029, and negative charge (-13.2 ± 1.8 mV). Poly(acrylic acid)-poly(ethylene oxide) (PAA-PEO), a pH sensitive polymer, was used to achieve pH-dependent drug release from nanoparticles. Transferrin (Tf) conjugated on the surface of nanoplatforms could enhance the cellular uptake and prolong nanoparticle accumulation in the tumor site. The combination of phototherapy induced by PdNPs and chemotherapeutic agent (PTX) could exhibit synergistic anticancer activities. Consistent findings were observed in both in vitro experiments including cytotoxicity, live/dead assay, and assessment of apoptotic protein levels, and in vivo antitumor study in MCF-7 tumor-bearing mice, with results decreasing in the following order: Tf-PPPs + NIR > Tf-PPPs > PPPs + NIR > PPPs > PTX > PdNPs. These findings suggest that the administration of Tf-PPPs, followed by NIR irradiation could be a promising strategy in the treatment of cancer.

In situ fabrication of mesoporous silica-coated silver-gold hollow nanoshell for remotely controllable chemo-photothermal therapy via phase-change molecule as gatekeepers.

This study reports a new strategy for in situ fabrication of plasmonic hollow silver-gold nanoshell (with resonance tuned to NIR region) encased in the hollow mesoporous silica as an efficient platform to efficiently and precisely regulate the release of 5-fluorouracil (anticancer drug) for prostate cancer therapy and photothermal therapy. The mesopores were capped with thermosensitive phase-change material lauric acid, which allowed for remote, precise, and spatiotemporal control of drug release via external heating or photothermal heating of plasmonic silver-gold nanoshell via NIR laser irradiation. The system was nanometric, monodispersed, and showed negative surface charge. The nanocarrier showed better pH stability and thermodynamic stability compared to dense silica-coated gold nanoshells. The drug release could be triggered remotely by applying low powered continuous wave NIR laser (λ = 808 nm). The nanocarrier showed improved internalization by cancer cells, which was further enhanced by laser irradiation. High powered laser directly killed the cancer cells via photothermal effect in the region irradiated. Thus, this system fabricated by novel synthetic strategy provided efficient chemo- and phototherapy.

PEGylated polyaminoacid-capped mesoporous silica nanoparticles for mitochondria-targeted delivery of celastrol in solid tumors.

The major goal of cancer chemotherapy is to maximize the therapeutic efficacy of anticancer drugs, while minimizing their associated side effects. Celastrol (CST), which is extracted from the traditional Chinese medicinal plant Tripterygium wilfordii, has been reported to exhibit significant anticancer effects in various in vitro and in vivo cancer models. Nanoparticulate drug delivery systems could be employed to preserve and enhance the pharmacological effects of CST in cancer cells. Among these, mesoporous silica nanoparticles (MSNs) are one of the most promising drug delivery systems. MSNs possess the capability of passive accumulation within solid tumors, and could efficiently transport anticancer drugs to such tumors in a site-specific manner. In this study, PEGylated polyaminoacid-capped CST-loaded MSN (CMSN-PEG) showed controlled in vitro drug release behavior, and exhibited high in vitro cytotoxicity in different cancer cells. Compared to treatment with free CST, treatment with CMSN-PEG resulted in the increased expression of the apoptosis protein HIF-1α and proteins corresponding to mitochondrial apoptosis pathway. Importantly, CMSN-PEG remarkably reduced tumor burden with no toxicity to healthy cells in the SCC7 tumor-bearing xenograft model. Our results clearly demonstrate a promising potential of CMSN-PEG for the treatment of solid tumors.

Multifunctional nanoparticles as somatostatin receptor-targeting delivery system of polyaniline and methotrexate for combined chemo-photothermal therapy.

Lanreotide (LT), a synthetic analog of somatostatin, has been demonstrated to specifically bind to somatostatin receptors (SSTRs), which are widely overexpressed in several types of cancer cells. In this study, we incorporated a chemotherapeutic agent, methotrexate (MTX), and a photosensitizer material, polyaniline (PANI), into hybrid polymer nanoparticles (NPs), which could target cancer cells after conjugation with LT (LT-MTX/PANI NPs). The successful preparation of LT-MTX/PANI NPs was confirmed by a small particle size (187.9 ±â€¯3.2 nm), a polydispersity index of 0.232 ±â€¯0.011, and a negative ζ potential of -14.6 ±â€¯1.0 mV. Notably, LT-MTX/PANI NPs showed a greater uptake into SSTR-positive cancer cells and thereby better inhibited cell viability and induced higher levels of apoptosis than MTX, PANI NP, and MTX/PANI NP treatments did. In addition, the heat associated with the burst drug release induced by near-infrared (NIR) irradiation resulted in remarkably enhanced cell apoptosis, which was confirmed by an increase in the expression levels of apoptotic marker proteins. In agreement with the in vitro results, the administration of the SSTR-targeting NPs, followed by NIR exposure, to xenograft tumor-bearing mice resulted in an improved suppression of tumor development compared to that shown by MTX, PANI NPs, and MTX/PANI NPs, as well as by LT-MTX/PANI NPs without photothermal therapy. Thus, the SSTR-targeting NPs could be a promising delivery system for the effective treatment of SSTR-positive cancers. STATEMENT OF SIGNIFICANCE: Somatostatin receptors are widely overexpressed in several types of cancer cells. In this study, we designed nanoparticles for targeted delivery of chemotherapeutic agents to tumor sites by conjugating hybrid polymers with a synthetic analog of somatostatin, specifically binding to somatostatin receptors. In addition, a photosensitizer material, polyaniline, was incorporated into the nanoparticles for combined chemo-photothermal therapy. The results demonstrated clear advantages of the newly designed targeted nanoparticles over their non-targeted counterparts or a free chemotherapeutic drug in inhibiting the viability of cancer cells in vitro and targeting/suppressing the tumor growth in an animal xenograft model. The study suggests that the designed nanoparticles are a promising delivery system for the effective treatment of somatostatin receptor-positive cancers.

PEGylated thermosensitive lipid-coated hollow gold nanoshells for effective combinational chemo-photothermal therapy of pancreatic cancer.

Pancreatic cancer has extremely poor prognosis with an 85% mortality rate that results from aggressive and asymptomatic growth, high metastatic potential, and rapid development of resistance to already ineffective chemotherapy. In this study, plasmonic hollow gold nanoshells (GNS) coated with PEGylated thermosensitive lipids were prepared as an efficient platform to ratiometrically co-deliver two drugs, bortezomib and gemcitabine (GNS-L/GB), for combinational chemotherapy and photothermal therapy of pancreatic cancer. Bortezomib was loaded within the lipid bilayers, while gemcitabine was loaded into the hydrophilic interior of the porous GNS via an ammonium sulfate-driven pH gradient method. Physicochemical characterizations and biological studies of GNS-L/GB were performed, with the latter using cytotoxicity assays, cellular uptake and apoptosis assays, live/dead assays, and western blot analysis of pancreatic cancer cell lines (MIA PaCa-2 and PANC-1). The nanoshells showed remotely controllable drug release when exposed to near-infrared laser for site-specific delivery. GNS-L/GB showed synergistic cytotoxicity and improved internalization by cancer cells. High-powered near-infrared continuous wave laser (λ=808nm) effectively killed cancer cells via the photothermal effect of GNS-L/GB, irrespective of cell type in a power density-, time-, and GNS dose-dependent manner. These results suggest that this method can provide a novel approach to achieve synergistic combinational chemotherapy and photothermal therapy, even with resistant pancreatic cancer.

Combined photothermal and photodynamic therapy by hyaluronic acid-decorated polypyrrole nanoparticles.

AIM: To develop a nanoparticle-based platform using polypyrrole and IR-780 for effective combined photothermal and photodynamic therapy. MATERIALS & METHODS: IR-780 was loaded in a poly(lactic-co-glycolic acid) core, decorated with polypyrrole shells and hyaluronic acid (IPPH). Physicochemical properties and in vitro and in vivo anticancer effects of these nanoparticles were evaluated. RESULTS: The resulting IPPHs were spherical, small and negatively charged. Under near-infrared laser irradiation, the IPPHs generated reactive oxygen species and heat and synergistically improved therapeutic efficacy. The antitumor effects were confirmed by in vitro cellular reactive oxygen species detection and cytotoxicity assays, and in vivo in a xenograft tumor model, with no damage to body organs. CONCLUSION: Our results indicate the potential of applying IPPH in oncology nanomedicine.

Targeted co-delivery of polypyrrole and rapamycin by trastuzumab-conjugated liposomes for combined chemo-photothermal therapy.

Trastuzumab is a therapeutic monoclonal antibody that selectively recognizes HER2/neu receptor for targeting breast cancers. In this study, we aimed to present a strategy to combine chemo and phototherapy and targeted delivery via monoclonal antibody for enhanced anticancer effects. We co-loaded a chemotherapeutic agent, rapamycin, and a photosensitizer, polypyrrole, in trastuzumab-conjugated liposomes (LRPmAb) for combined chemo-photothermal therapy. LRPmAb had small size (172.2±9.6nm), narrow distribution, and negative ζ-potential (-12.0±0.3mV). In addition, LRPmAb showed pH- and temperature-dependent release profiles. LRPmAb showed significantly enhanced uptake in BT-474 cells, a natural HER2/neu expressing cell line. We found that these LRPmAb were effective in delivering rapamycin and showed higher therapeutic efficacy in breast cancer cells overexpressing HER2/neu receptors compared with cells that did not overexpress these receptors. Furthermore, LRPmAb showed synergistic activity against rapamycin-sensitive and resistant cell lines in vitro. These findings indicated that LRPmAb-mediated drug delivery could improve the therapeutic efficacy against breast cancer and overcome drug resistance.

Incorporation of chemotherapeutic agent and photosensitizer in a low temperature-sensitive liposome for effective chemo-hyperthermic anticancer activity.

OBJECTIVES: In this study, we combined chemo- and hyperthermia therapy in a low temperature-sensitive liposome (LTSL) for potential cancer treatment. METHODS: Docetaxel (DOC) and indocyanine green (ICG) as a therapeutic agent and photosensitizer, respectively, were incorporated in a low temperature-sensitive liposome (LTSL/DI). Nanoparticles were evaluated for the physicochemical characterizations, in vitro uptake and cytotoxicity, and furthermore in vivo anticancer activity. RESULTS: The particle size of LTSL/DI was 130.8 ± 2.3 nm, and its drug release profile was pH- and temperature-dependent, which are effective for tumor targeting. The in vitro anticancer activity of LTSL/DI was significantly enhanced compared with free DOC in SCC-7 and MCF-7 cell lines. Interestingly, near-infrared laser irradiation after the treatment resulted in better anticancer activity than in the non-irradiated condition. The in vivo tumor regression effect of LTSL/DI in combination with NIR irradiation was much greater compared with the control group in SCC-7 tumor-bearing mice. After intratumoral injection of LTSL/DI, local heat induced by NIR irradiation and the localized docetaxel burst release could completely ablate the tumor, and inhibit its recurrence. CONCLUSIONS: These results suggest LTSL/DI formulation as a potential therapeutic strategy with effectively localized anti-tumor activity and low risk of side effect to non-target organs.

Folate-Mediated Targeted Delivery of Combination Chemotherapeutics Loaded Reduced Graphene Oxide for Synergistic Chemo-Photothermal Therapy of Cancers.

PURPOSE: Larger surface area for drug incorporation and superior optical activity makes reduced graphene oxide (rGO) a suitable drug carrier for combination chemotherapeutics delivery. And folate receptors are potential mediators for cancer targeted delivery. This study mainly aimed to prepare irinotecan (IRI)- and docetaxel (DOC)-loaded, folate (FA)-conjugated rGO (FA-P407-rGO/ID) for synergistic cancer therapy. METHODS: FA-P407-rGO/ID was prepared as aqueous dispersion. Characterization was performed using high performance liquid chromatography (HPLC), transmission electron microscopy (TEM), atomic force microscopy (AFM), ultraviolet/visible spectroscopy, fourier transform infrared spectroscopy (FTIR) and drug release. In vitro cellular studies were performed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), fluorescence-activated cell sorting (FACS) and western blot analyses. RESULTS: Our results revealed successful preparation of stable FA-P407-rGO/ID formulation with enhanced drug release profiles in acidic microenvironment. In vitro cytotoxicity of the formulation on folate receptor-expressing human mammary carcinoma (MCF-7) cells was higher than that when free IRI/DOC combination (ID) was used; such increased cytotoxicity was not observed in folate receptor-negative hepatocellular carcinoma (HepG2) cells. Cellular uptake of FA-P407-rGO/ID in MCF-7 cells was higher than in HepG2 cells. Further, FACS and western blot analysis revealed better apoptotic effects of the formulation in MCF-7 cells than in HepG2 cells, suggesting the important role of folate receptors for targeted chemotherapy delivery to cancer cells. Near infrared irradiation further enhanced the apoptotic effect in cancer cells, resulting from the photothermal effects of rGO. CONCLUSIONS: Hence, FA-P407-rGO/ID can be considered as a potential formulation for folate-targeted chemo-photothermal therapy in cancer cells.

Modulation of Pharmacokinetic and Cytotoxicity Profile of Imatinib Base by Employing Optimized Nanostructured Lipid Carriers.

PURPOSE: To prepare, optimize and characterize imatinib-loaded nanostructured lipid carriers (IMT-NLC), and evaluate their pharmacokinetic and cytotoxicity characteristics. METHODS: IMT-NLC was prepared by hot homogenization method, and optimized by an approach involving Plackett-Burman design (PBD) and central composite design (CCD). An in vivo pharmacokinetic study was conducted in rats after both oral and intravenous administration. The in vitro cytotoxicity was evaluated by MTT assay on NCI-H727 cell-lines. RESULTS: PBD screening, followed by optimization by CCD and desirability function, yielded an optimized condition of 0.054, 6% w/w, 2.5% w/w and 1.25% w/v for organic-to-aqueous phase ratio (O/A), drug-to-lipid ratio (D/L), amount of lecithin (Lec) and amount of Tween® 20 (Tw20) respectively. The optimized IMT-NLC exhibited a particle size (Sz) of 148.80 ± 1.37 nm, polydispersity index (PDI) 0.191 ± 0.017 of and ζ-potential of -23.0 ± 1.5 mV, with a drug loading (DL) of 5.48 ± 0.01% and encapsulation efficiency (EE) of 97.93 ± 0.03%. IMT-NLC displayed sustained IMT release in vitro, significantly enhanced in vivo bioavailability of IMT after intravenous and oral administration, and greater in vitro cytotoxicity on NCI-H727 cells, compared with free IMT. CONCLUSION: A combined DoE approach enabled accurate optimization and successful preparation of IMT-NLC with enhanced in vivo pharmacokinetic and in vitro cytotoxicity characteristics.