Multi-responsive albumin-lonidamine conjugated hybridized gold nanoparticle as a combined photothermal-chemotherapy for synergistic tumor ablation.

Herein, we developed a multifunctional nanoplatform based on the nanoassembly of gold nanoparticles (GNP) conjugated with lonidamine (LND) and aptamer AS1411 (AS-LAGN) as an effective cancer treatment. Conjugating AS1411 aptamer on the surface of the nanoparticle significantly improved particle accumulation in cancer cells via specific affinity toward the nucleolin receptors. In vitro study clearly revealed that laser irradiation-based hyperthermia effect enhanced the chemotherapeutic effects of LND. Combinational treatment modalities revealed significant apoptosis with higher cell killing effect due to increased ROS production and inhibition of cell migration. GNP's ability to convert the excited state photon energy into thermal heat enabled synergistic photothermal/chemotherapy with improved therapeutic efficacy in animal models. Moreover, immunohistochemistry staining assays confirmed the ability of AS-LAGN to induce cellular apoptosis/necrosis and ablation in tumor tissues, without causing evident damages to the surrounding healthy tissues. Altogether, this AS-LAGN nanoplatform could be a promising strategy for mitochondria-based cancer treatment. STATEMENT OF SIGNIFICANCE: We have designed a facile biodegradable multifunctional nanocarrier system to target the mitochondria, the major "power house" of the cancer cells. We have constructed a multifunctional nanoassembly of protein coronated gold nanoparticles (GNP) conjugated with lonidamine (LND) and aptamer AS1411 (AS-LAGN) as an effective combination of phototherapy with chemotherapy for cancer treatment. The LND was conjugated with albumin which was in turn conjugated to GNP via redox-liable disulfide linkage to generate oxidative stress and ROS to kill cancer cells. GNP's ability to convert the excited state photon energy into thermal heat enabled synergistic photothermal/chemotherapy with improved therapeutic efficacy in animal models. Consistently, AS-LAGN showed enhanced antitumor efficacy in xenograft tumor model with remarkable tumor regression property.

Tailored Black Phosphorus for Erythrocyte Membrane Nanocloaking with Interleukin-1α siRNA and Paclitaxel for Targeted, Durable, and Mild Combination Cancer Therapy.

Several therapeutic nanosystems have been engineered to remedy the shortcomings of cancer monotherapies, including immunotherapy (stimulating the host immune system to eradicate cancer), to improve therapeutic efficacy with minimizing off-target effects and tumor-induced immunosuppression. Light-activated components in nanosystems confer additional phototherapeutic effects as combinatorial modalities; however, systemic and thermal toxicities with unfavorable accumulation and excretion of nanoystem components now hamper their practical applications. Thus, there remains a need for optimal multifunctional nanosystems to enhance targeted, durable, and mild combination therapies for efficient cancer treatment without notable side effects. Methods: A nanosystem constructed with a base core (poly-L-histidine [H]-grafted black phosphorus [BP]) and a shell (erythrocyte membrane [EM]) is developed to offer a mild photoresponsive (near-infrared) activity with erythrocyte mimicry. In-flight electrostatic tailoring to extract uniform BP nanoparticles maintains a hydrodynamic size of <200 nm (enabling enhanced permeability and retention) after EM cloaking and enhances their biocompatibility. Results: Ephrin-A2 receptor-specific peptide (YSA, targeting cancer cells), interleukin-1α silencing small interfering RNA (ILsi, restricting regulatory T cell trafficking), and paclitaxel (X, inducing durable chemotherapeutics) are incorporated within the base core@shell constructs to create BP-H-ILsi-X@EM-YSA architectures, which provide a more intelligent nanosystem for combination cancer therapies. Conclusion: The in-flight tailoring of BP particles provides a promising base core for fabricating <200 nm EM-mimicking multifunctional nanosystems, which could be beneficial for constructing smarter nanoarchitectures to use in combination cancer therapies.

Plug-and-Play Continuous Gas Flow Assembly of Cysteine-Inserted AuCu Nanobimetals for Folate-Receptor-Targeted Chemo-Phototherapy.

Conjugatable nanobimetals exhibiting broadband light absorption for use as phototherapeutic platforms were assembled via a plug-and-play continuous gas flow route. Electrically produced AuCu nanobunches (NBs) under nitrogen gas flow were directly injected into cysteine (cys) solution through gas pressurization to mechanically spray the solution (AuCu into cys droplets). The sprayed droplets were then exposed to 185 nm UV light (higher photon energy [6.2 eV] than the work functions of Au [5.1 eV] and Cu [4.7 eV]) to initiate photoionization of AuCu NBs for subsequent electrostatic reaction with the SH- group of cys to form cys-inserted AuCu (AuCu-cys) platforms in a single-pass gas stream. These platforms exhibited broadband light absorption spectra because of hybridized interparticle plasmonic coupling and could be conjugated to folic acid (FA) when dispersed in FA solution to form highly dispersible, biocompatible, and cancer-targetable AuCu-cys-FA. This material was suitable for use in targeted phototherapy of folate-receptor (FR)-rich cancers via FR-mediated endocytosis, and loading doxorubicin (DOX) into AuCu-cys-FA (i.e., AuCu-cys-DOXFA) facilitated chemo-phototherapy because of photoresponsive anticancer drug release upon induction of hyperthermia.

Aerosol technique-based carbon-encapsulated hollow mesoporous silica nanoparticles for synergistic chemo-photothermal therapy.

Near-infrared (NIR)-responsive drug delivery systems have enhanced tumor ablative efficiency through permeation and retention effects. Graphene oxide (GO) has shown great potential both in photothermal therapy and in drug delivery. Thus, in this study, we designed an ambient spark-generated GO, wrapped on topotecan (TPT)-loaded hollow mesoporous silica nanoparticles (HMSN-NH2-TPT-CGO), to function as an efficient platform for pH-dependent sustained release of TPT. HMSN-NH2-TPT-CGO also exhibited a combined chemo-photothermal effect within a single carrier system. This developed system was stable with a uniform particle size (∼190 nm) and was demonstrated to possess a sufficient heat-absorbing capacity to induce tumor cell ablation. We performed the ablation of tumor cells both in vitro and in vivo in combination with photothermal therapy and chemotherapy using the spark-generated functional GO and HMSN. The prepared nanocarriers demonstrated high cellular uptake, apoptosis, and G0/G1 cell cycle arrest. In vivo study using the MDA-MB-231 xenograft model revealed the ultraefficient tumor ablative performance of HMSN-NH2-TPT-CGO compared with that of free TPT, with no toxic effect on vital organs. Altogether, the optimized nanocarriers presented a significant potential to act as a vehicle for cancer treatment. STATEMENT OF SIGNIFICANCE: This is the first study that uses spark-generated graphene oxide nanoflakes to cover the topotecan (TPT)-loaded hollow mesoporous silica nanoparticles (HMSNs) to treat breast cancer. Dense silica was used as a hard template to prepare the HMSNs attributing to a high drug payload. The concentration of Na2CO3 was precisely controlled to minimize the silica etching time within 70 min. The use of the nanographene flakes served a dual purpose, first, by acting as a capping agent to prevent the premature release of drug and, second, by serving as a nano heater that significantly ablates the tumor cells. The prepared nanocarriers (NCs) exhibited effective and enhanced in vitro and in vivo apoptosis, as well as significant tumor growth inhibition even after 15 days of treatment time, with no toxic effect to the vital organs. The NCs enhanced in vitro tumor cell killing effects and served as an effective carrier for in vivo tumor regression, thereby highlighting the enormous potential of this system for breast cancer therapy.

Folate-targeted nanostructured chitosan/chondroitin sulfate complex carriers for enhanced delivery of bortezomib to colorectal cancer cells.

Folate-targeting self-assembled nanoparticles (NPs) using biocompatible and biodegradable natural polymers chitosan (Cs) and chondroitin sulfate (Chs) were developed to address the major challenge in cancer treatment, the selective delivery of nanoparticles to the target site. In this study, we successfully incorporated a hydrophobic drug, bortezomib (Bor), into folic acid (FA)-conjugated Cs/Chs self-assembled NPs (Bor/Cs/Chs-FA) for colorectal cancer therapy. The particle size and polydispersity index of Bor/Cs/Chs-FA were ∼196.5 ±â€¯1.2 nm and ∼0.21 ±â€¯0.5, respectively. A pH-dependent release profile was observed, facilitating cancer cell-targeted drug release under an acidic tumor microenvironment. Moreover, in vitro data revealed enhanced cellular uptake and apoptosis in folate receptor-expressing colorectal cancer cells (HCT-116 and HT-29) as compared to that in lung cancer cells (A549), which do not express folate receptors. Furthermore, intravenous administration of Bor/Cs/Chs-FA in a HCT-116 bearing xenograft mouse model showed that the NPs were a safe and effective drug delivery system. The results suggest that folate-targeted nanoparticle can be effectively applied for efficient chemotherapy of colorectal cancer.

Hyaluronic acid-capped compact silica-supported mesoporous titania nanoparticles for ligand-directed delivery of doxorubicin.

Mesoporous titania nanoparticles (MTN), owing to their high surface area to volume ratio and tunable pore sizes, appear capable of delivering sizable amounts of drug payloads, and hence, show considerable promise as drug delivery candidates in cancer therapy. We designed silica-supported MTN (MTNst) coated with hyaluronic acid (HA) to effectively deliver doxorubicin (DOX) for breast cancer therapy. The HA coating served a dual purpose of stabilizing the payload in the carriers as well as actively targeting the nanodevices to CD44 receptors. The so-formed HA-coated MTNst carrying DOX (HA/DOX-MTNst) had spheroid particles with a considerable drug-loading capacity and showed significantly superior in vitro cytotoxicity against MDA-MB-231 cells as compared to free DOX. HA/DOX-MTNst markedly improved the cellular uptake of DOX in an apparently CD44 receptor-dependent manner, and increased the number of apoptotic cells as compared to free DOX. These nanoplatforms accumulated in large quantities in the tumors of MDA-MB-231 xenograft tumor-bearing mice, where they significantly enhanced the inhibition of tumor growth compared to that observed with free DOX with no signs of acute toxicity. Based on these excellent results, we deduced that HA/DOX-MTNst could be successfully used for targeted breast cancer therapy. STATEMENT OF SIGNIFICANCE: This is the first study to use silica-supported mesoporous titania nanoparticles (MTNst) for doxorubicin (DOX) delivery to treat breast cancer, which exhibited effective and enhanced in vitro and in vivo apoptosis and tumor growth inhibition. Solid silica was used to support the mesoporous TiO2 resulting in MTNst, which efficiently incorporated a high DOX payload. The hyaluronic acid (HA) coating over the MTNst surface served a dual purpose of first, stabilizing DOX inside the MTNst (capping agent), and second, directing the nanoplatform device to CD44 receptors that are highly expressed in MDA-MB-231 cells (targeting ligand). The NPs exhibited highly efficacious in vitro tumor-cell killing and excellent in vivo tumor regression, highlighting the enormous promise of this system for breast cancer therapy.

Polyamino Acid Layer-by-Layer (LbL) Constructed Silica-Supported Mesoporous Titania Nanocarriers for Stimuli-Responsive Delivery of microRNA 708 and Paclitaxel for Combined Chemotherapy.

Cellular Fas-associated protein with death domain-like interleukin-1ß-converting enzyme-inhibitory protein (c-FLIP), often strongly expressed in numerous cancers, plays a pivotal role in thwarting apoptosis and inducing chemotherapy resistance in cancer. An integrated approach combining chemotherapy with suppression of c-FLIP levels could prove paramount in the treatment of cancers with c-FLIP overexpression. In this study, we utilized a polymeric layer-by-layer (LbL) assembly of silica-supported mesoporous titania nanoparticles (MTNst) to co-deliver paclitaxel (PTX) and microRNA 708 (miR708) for simultaneous chemotherapy and c-FLIP suppression in colorectal carcinoma. The resulting LbL miR708/PTX-MTNst showed dose-dependent cytotoxicity in HCT-116 and DLD-1 colorectal carcinoma cell lines, which was remarkably superior to that of free PTX or LbL PTX-MTNst. LbL miR708/PTX-MTNst strongly inhibited c-FLIP expression and resulted in increased expression of proapoptotic proteins. In DLD-1 xenograft tumor-bearing mice, the nanoparticles accumulated in the tumor, resulting in remarkable tumor regression, with the PTX and miR708-loaded nanoparticles showing significantly greater inhibitory effects than the free PTX or PTX-loaded nanoparticles. Immunohistochemical analyses of the tumors further confirmed the remarkable apoptotic and antiproliferative effects of the nanoparticles, whereas organ histology reinforced the biocompatibility of the system. Therefore, the LbL miR708/PTX-MTNst system, owing to its ability to deliver both chemotherapeutic drug and inhibitory miRNA to the tumor site, shows great potential to treat colorectal carcinoma in clinical settings.

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.

Paclitaxel and Erlotinib-co-loaded Solid Lipid Core Nanocapsules: Assessment of Physicochemical Characteristics and Cytotoxicity in Non-small Cell Lung Cancer.

PURPOSE: Lung cancer is the leading cause of cancer-related deaths. The aim of this study was to design solid lipid core nanocapsules (SLCN) comprising a solid lipid core and a PEGylated polymeric corona for paclitaxel (PTX) and erlotinib (ERL) co-delivery to non-small cell lung cancer (NSCLC), and evaluate their physicochemical characteristics and in vitro activity in NCI-H23 cells. METHODS: PTX/ERL-SLCN were prepared by nanoprecipitation and sonication and physicochemically characterized by dynamic light scattering, transmission electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier-transform infrared spectroscopy. In vitro release profiles at pH 7.4 and pH 5.0 were studied and analyzed. In vitro cytotoxicity and cellular uptake and apoptosis assays were performed in NCI-H23 cells. RESULTS: PTX/ERL-SLCN exhibited appropriately-sized spherical particles with a high payload. Both PTX and ERL showed pH-dependent and sustained release in vitro profiles. PTX/ERL-SLCN demonstrated concentration- and time-dependent uptake by NCI-H23 cells and caused dose-dependent cytotoxicity in the cells, which was remarkably greater than that of not only the free individual drugs but also the free drug cocktail. Moreover, well-defined early and late apoptosis were observed with clearly visible signs of apoptotic nuclei. CONCLUSION: PTX/ERL-SLCN could be employed as an optimal approach for combination chemotherapy of NSCLC.

Photoinduced Rapid Transformation from Au Nanoagglomerates to Drug-Conjugated Au Nanovesicles.

Gold (Au) agglomerates (AGs) are reassembled using Triton X-100 (T) and doxorubicin (D) dissolved in ethanol under 185 nm photoirradiation to form TAuD nanovesicles (NVs) under ambient gas flow conditions. The positively charged Au particles are then electrostatically conjugated with the anionic chains of TD components via a flowing drop (FD) reaction. Photoirradiation of the droplets in a tubular reactor continues the photophysicochemical reactions, resulting in the reassembly of Au AGs and TD into TAuD NVs. The fabricated NVs are electrostatically collected onto a polished aluminum rod in a single-pass configuration. The dispersion of NVs is employed for bioassays to confirm uptake by cells and accumulation in tumors. The chemo-photothermal activity is determined both in vitro and in vivo. Different combinations of components are also used to fabricate NVs using the FD reaction, and these NVs are suitable for gene delivery as well. This newly designed gaseous single-pass process results in the reassembly of Au AGs for incorporation with TD without the need of batch wet chemical reactions, modifications, separations, or purifications. Thus, this process offers an efficient platform for preparing biofunctional Au nanostructures that requires neither complex physicochemical steps nor special storage techniques.

Direct fluorescent labeling for efficient biological assessment of inhalable particles.

Labeling of aerosol particles with a radioactive, magnetic, or optical tracer has been employed to confirm particle localization in cell compartments, which has provided useful evidence for correlating toxic effects of inhaled particles. However, labeling requires several physicochemical steps to identify functionalities of the inner or outer surfaces of particles, and moreover, these steps can cause changes in size, surface charge, and bioactivity of the particles, resulting in misinterpretations regarding their toxic effects. This study addresses this challenging issue with a goal of introducing an efficient strategy for constantly supplying labeled aerosol particles in a single-pass configuration without any pre- or post-physicochemical batch treatments of aerosol particles. Carbon black (CB, simulating combustion-generated soot) or calcium carbonate (CC, simulating brake-wear fragments) particles were constantly produced via spark ablation or bubble bursting, respectively. These minute particles were incorporated with fluorescein isothiocyanate-poly(ethylene glycol) 2-aminoethyl ether acetic acid solution at the orifice of a collison atomizer to fabricate hybrid droplets. The droplets successively entered a diffusion dryer containing 254-nm UV irradiation; therefore, the droplets were dynamically stiffened by UV to form fluorescent probes on particles during solvent extraction in the dryer. Particle size distributions, morphologies, and surface charges before and after labeling were measured to confirm fluorescence labeling without significant changes in the properties. In vitro assays, including confocal imaging, were conducted to confirm the feasibility of the labeling approach without inducing significant differences in bioactivity compared with untreated CB or CC particles.

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.

In vitro exposure of simulated meat-cooking fumes to assess adverse biological effects.

The heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is considered as a human carcinogenic or mutagenic compound that is produced from the co-condensation of creatinine and amino acids as meats cook at high temperatures. The cooking of meats at high temperatures produces fumes, and these fumes can be suspended as aerosols via the vapor-to-particle (or -droplet) process in a temperature gradient field. Size distributions of the aerosols included a significant portion of nano- and submicron-sized particles, and these can be directly deposited in the lungs and on skin by particle transport phenomena near cooking areas. In this study, for the first time, PhIP-incorporated oleic acid (OA, simulating cooking oil) (PhIP@OA) particles, including individual particulate PhIP as simulated fumes from meat cooking, were constantly produced via collison atomization and subsequent drying processes. The aerosol particles were then dispersed in phosphate-buffered saline for cytotoxicity and senescence-associated ß-galactosidase assays, which were compared with dissolved PhIP in dimethyl sulfoxide. PhIP and PhIP@OA did not show significant cytotoxic effects on SHSY5Y, MRC5, and human dermal fibroblast cells compared with the dissolved PhIP but clearly induced premature senescence activities that may be caused by a limited release of PhIP molecules from the particulate PhIP.

Smart chemistry-based nanosized drug delivery systems for systemic applications: A comprehensive review.

This review focuses on the smart chemistry that has been utilized in developing polymer-based drug delivery systems over the past 10years. We provide a comprehensive overview of the different functional moieties and reducible linkages exploited in these systems, and outline their design, synthesis, and application from a therapeutic efficacy viewpoint. Furthermore, we highlight the next generation nanomedicine strategies based on this novel chemistry.

Folate receptor-targeted hybrid lipid-core nanocapsules for sequential delivery of doxorubicin and tanespimycin.

When exposed to cancer cells, cytotoxic drugs such as doxorubicin (DOX) can lead to the induction of heat shock protein 90 (Hsp90), a molecular chaperone associated with a number of cancer-related client proteins, and result in cell survival. Co-administration of DOX with tanespimycin (TNP), an Hsp90 inhibitor, can sensitize the cancer cells to the cytotoxic effects of DOX. The effect of such a combination has been found to depend on the schedule of administration. Sequential administration of DOX and TNP has been linked to highly synergistic combination effects. Therefore, we aimed to develop folate-receptor targeted hybrid lipid-core nanocapsules comprising a hybrid lipid core lodging TNP and a polymeric corona lodging DOX (F-DTN). These nanocarriers were capable of delivering DOX and TNP sequentially, which was well demonstrated by an in vitro release study. The in vitro release profiles displayed pH-dependent and sustained release features. F-DTN exhibited excellent morphological characteristics with highly monodispersed particles. In vitro tests with F-DTN in MCF-7 cell line demonstrated exceptional cytotoxicity, with high cellular uptake and apoptosis. These findings were appreciably more assertive than tests with free individual drugs (DOX, TNP), free drug combination (DOX/TNP), or non-folate receptor-targeted hybrid lipid-core nanocapsules (DTN). In vivo pharmacokinetic study revealed noticeable enhancement of bioavailability and plasma circulation time of the drugs when encapsulated in the carrier system. Therefore, hybrid lipid-core nanocapsules have the potential to be utilized for application in folate receptor-targeted combination chemotherapy.

On-Demand Gas-to-Liquid Process To Fabricate Thermoresponsive Antimicrobial Nanocomposites and Coatings.

Antimicrobial material is emerging as a major component of the mitigation strategy against microbial growth on abiotic surfaces. In this work, a newly designed process is proposed to fabricate thermoresponsive antimicrobial nanocomposites (TANs) and coatings (TACs) as an on-demand system. Thermoresponsive polymer (TRP)-incorporated silver (Ag) nanocomposites with silica nanoparticles (SNPs) or carbon nanotubes (CNTs; Ag-SNP@TRP or Ag-CNT@TRP) were produced by a single-pass gas-to-liquid process. The SNPs or CNTs were first produced by spark ablation and successively injected for dispersal in a liquid cell containing polydimethylsiloxane, poly(N-isopropylacrylamide), and silver nitrate under ultrasound irradiation. Suspensions of Ag-SNP@TRP or Ag-CNT@TRP nanocomposites were then deposited on a touch screen panel (TSP) protection film via electrohydrodynamic spray to form transparent antibacterial coatings. Fundamental antibacterial activities of TANs were evaluated against Escherichia coli and Staphylococcus epidermidis. The TANs showed stronger antibacterial activities at the higher temperature for all testing conditions. Lower minimum inhibitory concentrations of Ag-SNP@TRP and Ag-CNT@TRP nanocomposites were required against the two bacteria at 37 °C compared to those at 27 °C. The TACs on display showed elevated antimicrobial activity when the panel was turned on (38.1 °C) compared with when the panel was turned off (23.8 °C). This work provides a utilizable concept to continuously fabricate TANs and TACs, and it specifically offers stimuli-sensitive control of antimicrobial activity on TSPs, including other frequently touched surfaces.

Development of Bioactive PEGylated Nanostructured Platforms for Sequential Delivery of Doxorubicin and Imatinib to Overcome Drug Resistance in Metastatic Tumors.

Metastasis of cancers accounts for almost all cancer-related deaths. In this study, we report a PEGylated nanostructured platform for coadministration of doxorubicin (DOX) and imatinib (IMT) intended to effectively inhibit metastatic tumors. The DOX and IMT coloaded nanostructured system (DOX/IMT-N) is characterized by an excellent encapsulation potential for both drugs and shows sequential and sustained drug release in vitro. DOX/IMT-N significantly inhibited the in vitro proliferation of MDA-MB-231 and SK-MEL-28 cells. The inhibitory effect on in vitro proliferation of the cells was significantly greater than the effect of free DOX, DOX/IMT cocktail, or the nanostructured system housing DOX only (DOX-N). DOX/IMT-N remarkably enhanced cellular drug uptake, resulting in enhanced apoptosis, caused by significant increases in the expression levels of apoptotic marker proteins. Intravenous administration of DOX/IMT-N to MBA-MB-231 xenograft tumor-bearing mice resulted in significantly improved inhibition of tumor progression compared to that with DOX, DOX/IMT, or DOX-N. Therefore, the nanostructured DOX/IMT-N system could potentially aid in overcoming drug resistance in metastatic tumors and improve the effectiveness of metastatic tumor therapeutics.

Development of polymeric irinotecan nanoparticles using a novel lactone preservation strategy.

Irinotecan (IRT) is an important part of the first- and second-line regimen for metastatic colorectal and some other cancers. However, IRT suffers the constraints of pH-dependent conversion of active lactone form to inactive carboxylate form, burst release owing to its aqueous solubility, short half-life and dose-dependent side effects. In this study, we developed polymeric nanoparticles (NPs) that not only deliver IRT to tumor sites, but also overcome its drawbacks by preserving active lactone conformation, prolonging the plasma circulation time, and by providing sustained release. IRT complex was rendered hydrophobic by ion-pairing with anions (docusate sodium, sodium lauryl sulfate, and sodium tripolyphosphate), and loaded in PEG-PLGA NPs via water/oil/water double emulsification method. The NPs were spherical, ∼60nm, monodispersed, and had shell-core morphology. They retained >80% lactone form for more than 1 month of storage and exhibited sustained release characteristics. In addition, sub -100nm size of NPs offered elevated cellular internalization. Owing to the presence of hydrophilic PEG outer layer and drug-loaded hydrophobic PLGA core, NPs conferred excellent plasma stability and prolonged the retention time of IRT by more than 10-fold as compared to free IRT. Therefore, this system could provide an excellent platform for efficient and sustained delivery of IRT and similar labile drugs to the tumor site, while maintaining their chemical integrity.

Liquid crystalline nanoparticles encapsulating cisplatin and docetaxel combination for targeted therapy of breast cancer.

Cancer remains a leading cause of death. A combination of anticancer agents can effectively kill cancer through multiple pathways; however, improvements to their delivery are needed. Hence, docetaxel and cisplatin-loaded liquid crystalline nanoparticles with folic acid were prepared for effective and targeted anticancer therapy. Notably, hydroxypropyl-ß-cyclodextrin/cisplatin complexes in 0.9% NaCl solution were used for the prevention of possible aquation of cisplatin, which would otherwise lead to severe adverse effects. The optimized nanoparticles exhibited small particle size, high drug loading capacity (>90%), and controlled drug release profiles. In vitro cell cytotoxicity assays demonstrated that the optimized nanoparticles were taken up by folate receptor-expressing cells to a greater extent than non-folate expressing cells, which is attributable to folate-specific endocytosis of the optimized nanoparticles. Enhanced expression of apoptotic markers (Bax, p21, and cleaved caspase-3) along with enhanced anti-migration effects in MDA-MB-231 cells following treatment suggests that the optimized nanoparticles provide an effective treatment for metastatic breast cancer. These results were further supported by in vivo findings obtained for a MDA-MB-231 tumor xenograft model. Altogether, the optimized nanoparticles may potentially be developed as an effective treatment modality for folate-targeted metastatic breast cancer treatment.

Receptor-targeted, drug-loaded, functionalized graphene oxides for chemotherapy and photothermal therapy.

Cancer is one of the leading causes of death worldwide. Although different chemotherapeutic agents have been developed to treat cancers, their use can be limited by low cellular uptake, drug resistance, and side effects. Hence, targeted drug delivery systems are continually being developed in order to improve the efficacy of chemotherapeutic agents. The main aim of this study was to prepare folic acid (FA)-conjugated polyvinyl pyrrolidone-functionalized graphene oxides (GO) (FA-GO) for targeted delivery of sorafenib (SF). GO were prepared using a modified Hummer's method and subsequently altered to prepare FA-GO and SF-loaded FA-GO (FA-GO/SF). Characterization of GO derivatives was done using ultraviolet/visible spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction, atomic force microscopy, zeta potential measurements, and determination of in vitro drug release. Hemolytic toxicity, in vitro cytotoxicity, cellular uptake, and apoptotic effects of FA-GO/SF were also investigated. The results revealed that GO was successfully synthesized and that further transformation to FA-GO improved the stability and SF drug-loading capacity. In addition, the enhanced SF release under acidic conditions suggested possible benefits for cancer treatment. Conjugation of FA within the FA-GO/SF delivery system enabled targeted delivery of SF to cancer cells expressing high levels of FA receptors, thus increasing the cellular uptake and apoptotic effects of SF. Furthermore, the photothermal effect achieved by exposure of GO to near-infrared irradiation enhanced the anticancer effects of FA-GO/SF. Taken together, FA-GO/SF is a potential carrier for targeted delivery of chemotherapeutic agents in cancer.