Gold-Nanoparticle Hybrid Nanostructures for Multimodal Cancer Therapy.

With the urgent need for bio-nanomaterials to improve the currently available cancer treatments, gold nanoparticle (GNP) hybrid nanostructures are rapidly rising as promising multimodal candidates for cancer therapy. Gold nanoparticles (GNPs) have been hybridized with several nanocarriers, including liposomes and polymers, to achieve chemotherapy, photothermal therapy, radiotherapy, and imaging using a single composite. The GNP nanohybrids used for targeted chemotherapy can be designed to respond to external stimuli such as heat or internal stimuli such as intratumoral pH. Despite their promise for multimodal cancer therapy, there are currently no reviews summarizing the current status of GNP nanohybrid use for cancer theragnostics. Therefore, this review fulfills this gap in the literature by providing a critical analysis of the data available on the use of GNP nanohybrids for cancer treatment with a specific focus on synergistic approaches (i.e., triggered drug release, photothermal therapy, and radiotherapy). It also highlights some of the challenges that hinder the clinical translation of GNP hybrid nanostructures from bench to bedside. Future studies that could expedite the clinical progress of GNPs, as well as the future possibility of improving GNP nanohybrids for cancer theragnostics, are also summarized.

Multifunctional stimuli-responsive hybrid nanogels for cancer therapy: Current status and challenges.

With cancer research shifting focus to achieving multifunctionality in cancer treatment strategies, hybrid nanogels are making a rapid rise to the spotlight as novel, multifunctional, stimuli-responsive, and biocompatible cancer therapeutic strategies. They can possess cancer cell-specific cytotoxic effects themselves, carry drugs or enzymes that can produce cytotoxic effects, improve imaging modalities, and target tumor cells over normal cells. Hybrid nanogels bring together a wide range of desirable properties for cancer treatment such as stimuli-responsiveness, efficient loading and protection of molecules such as drugs or enzymes, and effective crossing of cellular barriers among other properties. Despite their promising abilities, hybrid nanogels are still far from being used in the clinic, and their available data remains relatively limited. However, many studies can be done to facilitate this clinical transition. This review is critically summarizing and analyzing the recent information and progress on the use of hybrid nanogels particularly inorganic nanoparticle-based and organic nanoparticle-based hybrid nanogels in the field of oncology and future directions to aid in transferring those results to the clinic. This work concludes that the future of hybrid nanogels is greatly impacted by therapeutic and non-therapeutic factors. Therapeutic factors include the lack of hemocompatibility studies, acute and chronic toxicological studies, and information on agglomeration capability and extent, tumor heterogeneity, interaction with proteins in physiological fluids, endocytosis-exocytosis, and toxicity of the nanogels' breakdown products. Non-therapeutic factors include the lack of clear regulatory guidelines and standardized assays, limitations of animal models, and difficulties associated with good manufacture practices (GMP).

Triazine-based porous organic polymers for reversible capture of iodine and utilization in antibacterial application.

The capture and safe storage of radioactive iodine (129I or 131I) are of a compelling significance in the generation of nuclear energy and waste storage. Because of their physiochemical properties, Porous Organic Polymers (POPs) are considered to be one of the most sought classes of materials for iodine capture and storage. Herein, we report on the preparation and characterization of two triazine-based, nitrogen-rich, porous organic polymers, NRPOP-1 (SABET = 519 m2 g-1) and NRPOP-2 (SABET = 456 m2 g-1), by reacting 1,3,5-triazine-2,4,6-triamine or 1,4-bis-(2,4-diamino-1,3,5-triazine)-benzene with thieno[2,3-b]thiophene-2,5-dicarboxaldehyde, respectively, and their use in the capture of volatile iodine. NRPOP-1 and NRPOP-2 showed a high adsorption capacity of iodine vapor with an uptake of up to 317 wt % at 80 °C and 1 bar and adequate recyclability. The NRPOPs were also capable of removing up to 87% of iodine from 300 mg L-1 iodine-cyclohexane solution. Furthermore, the iodine-loaded polymers, I2@NRPOP-1 and I2@NRPOP-2, displayed good antibacterial activity against Micrococcus luteus (ML), Escherichia coli (EC), and Pseudomonas aeruginosa (PSA). The synergic functionality of these novel polymers makes them promising materials to the environment and public health.

Transferrin-modified liposomes triggered with ultrasound to treat HeLa cells.

Targeted liposomes are designed to target specific receptors overexpressed on the surfaces of cancer cells. This technique ensures site-specific drug delivery to reduce undesirable side effects while enhancing the efficiency of the encapsulated therapeutics. Upon reaching the tumor site, these liposomes can be triggered to release their content in a controlled manner using ultrasound (US). In this study, drug release from pegylated calcein-loaded liposomes modified with transferrin (Tf) and triggered with US was evaluated. Low-frequency ultrasound at 20-kHz using three different power densities (6.2 mW/cm2, 9 mW/cm2 and 10 mW/cm2) was found to increase calcein release. In addition, transferrin-conjugated pegylated liposomes (Tf-PEG liposomes) were found to be more sonosensitive compared to the non-targeted (control) liposomes. Calcein uptake by HeLa cells was found to be significantly higher with the Tf-PEG liposomes compared to the non-targeted control liposomes. This uptake was further enhanced following the exposure to low-frequency ultrasound (at 35 kHz). These findings show that targeted liposomes triggered with US have promising potential as a safe and effective drug delivery platform.

Ultrasound-triggered herceptin liposomes for breast cancer therapy.

The functionalization of liposomes with monoclonal antibodies is a potential strategy to increase the specificity of liposomes and reduce the side-effects associated with chemotherapeutic agents. The active targeting of the Human Epidermal growth factor Receptor 2 (HER2), which is overexpressed in HER2 positive breast cancer cells, can be achieved by coating liposomes with an anti-HER2 monoclonal antibody. In this study, we synthesized calcein and Doxorubicin-loaded immunoliposomes functionalized with the monoclonal antibody Trastuzumab (TRA). Both liposomes were characterized for their size, phospholipid content and antibody conjugation. Exposing the liposomes to low-frequency ultrasound (LFUS) triggered drug release which increased with the increase in power density. Trastuzumab conjugation resulted in enhancing the sensitivity of the liposomes to LFUS. Compared to the control liposomes, TRA-liposomes showed higher cellular toxicity and higher drug uptake by the HER2 + cell line (SKBR3) which was further improved following sonication with LFUS. Combining immunoliposomes with LFUS is a promising technique in the field of targeted drug delivery that can enhance efficiency and reduce the cytotoxicity of antineoplastic drugs.

Targeting Breast Cancer Using Hyaluronic Acid-Conjugated Liposomes Triggered with Ultrasound.

The successful targeting of tumors can be achieved by conjugating targeting moieties to nanoparticles. These modifications allow nannocarriers to achieve greater targeting specificity through binding to specific receptors overexpressed on the surface of the tumor cells. In this study, pegylated liposomes encapsulating the model drug/dye calcein and conjugated to hyaluronic acid (HA) molecules were successfully synthesized, and their ability to target HA receptors overexpressed on a breast cancer cell line was investigated in vitro. Low-frequency ultrasound (LFUS), applied at three different power densities (6.2, 9, and 10 mW/cm²) were used to trigger the release of the entrapped calcein. Both the control and HAconjugated liposomes showed similar release profiles. HA conjugation to the liposomes resulted in a significant increase in calcein uptake by the breast cancer cell line MDA-MB-231 known for its CD44 (HA receptor) overexpression, while such an effect was not recorded with NIH-3T3, an embryonic mouse fibroblast, with low levels of CD44 expression. The application of low LFUS showed a significant enhancement of calcein uptake by MDA-MB-231 cells from our liposome compared to calcein uptake without cell exposure to ultrasound. These findings suggest that combining HA-conjugated liposomes with ultrasound is a promising drug delivery platform in breast cancer treatment.

Effect of Pegylation and Targeting Moieties on the Ultrasound-Mediated Drug Release from Liposomes.

The use of targeted liposomes encapsulating chemotherapy drugs enhances the specific targeting of cancer cells, thus reducing the side effects of these drugs and providing patient-friendly chemotherapy treatment. Targeted pegylated (stealth) liposomes have the ability to safely deliver their loaded drugs to the cancer cells by targeting specific receptors overly expressed on the surface of these cells. Applying ultrasound as an external stimulus will safely trigger drug release from these liposomes in a controlled manner. In this study, we investigated the release kinetics of the model drug "calcein" from targeted liposomes sonicated with low-frequency ultrasound (20 kHz). Our results showed that pegylated liposomes were more sonosensitive compared to nonpegylated liposomes. A comparison of the effect of three targeting moieties conjugated to the surface of pegylated liposomes, namely human serum albumin (HSA), transferrin (Tf) and arginylglycylaspartic acid (RGD), on calcein release kinetics was conducted. The fluorescent results showed that HSA-PEG and Tf-PEG liposomes were more sonosensitive (showing higher calcein release following the exposure to pulsed LFUS) compared to the control pegylated liposomes, thus adding more acoustic benefits to their targeting efficacy.

Factors Affecting the Acoustic In Vitro Release of Calcein from PEGylated Liposomes.

Typical methods used in cancer treatment, including chemotherapy, are debilitating because of the various adverse side effects experienced by cancer patients. The free drug injected into the patient at given doses affects both healthy and cancerous cells. Therefore, novel methods are being researched to ensure the selectivity of the treatment. The purpose of this study is to test the release of a model fluorescent drug, calcein, from echogenic stealth liposomes, triggered by lowfrequency pulsed ultrasound. Several experimental parameters related to the ultrasound (US) and the investigated liposomes were varied in order to examine their effect on the acoustic release. Upon analysis of experimental results, the study concluded that release can be maximized by optimizing the sonication frequency, power density, and US pulse duration. When a non-isothermal chamber is used to conduct the experiments, it is important to have longer 'Off' than 'On' US periods in order to avoid overheating the liposomes. Applying such pulsation pattern can also be utilized to achieve slower release rates, which safely meet the desired drug levels at the end of the session. Our study also concluded that optimizing the liposome concentration is vital to delivering desired drug doses. Additionally, the type of lipids used in the synthesis should be carefully selected to produce stable yet acoustically sensitive liposomes capable of releasing at desired rates.

Ultrasonically controlled albumin-conjugated liposomes for breast cancer therapy.

Targeted liposomes have high potentials in the specific and effective delivery of their loaded therapeutic agents to the tumour site. Once at the tumour site, it is important that these liposomes are triggered to release their load in a controlled and effective manner. In this study, pegylated (stealth) liposomes conjugated to human serum albumin (HSA) were investigated for the delivery of a model drug (calcein) to breast cancer cells. The fluorescent results showed that calcein uptake by the two breast cancer cell lines (MDA-MB-231 and MCF-7) was significantly higher with the HSA-PEG liposomes compared to the non-targeted control liposomes. Furthermore, the exposure to low-frequency ultrasound (LFUS) resulted in a statistically significant uptake of calcein compared to the uptake without ultrasound. The described drug delivery (DD) system, which involves combining the targeted liposomal formulation with ultrasonic triggering techniques, promises a safe, effective and site-specific breast cancer therapy.

Charge Tunneling along Short Oligoglycine Chains.

This work examines charge transport (CT) through self-assembled monolayers (SAMs) of oligoglycines having an N-terminal cysteine group that anchors the molecule to a gold substrate, and demonstrate that CT is rapid (relative to SAMs of n-alkanethiolates). Comparisons of rates of charge transport-using junctions with the structure Au(TS)/SAM//Ga2O3/EGaIn (across these SAMs of oligoglycines, and across SAMs of a number of structurally and electronically related molecules) established that rates of charge tunneling along SAMs of oligoglycines are comparable to that along SAMs of oligophenyl groups (of comparable length). The mechanism of tunneling in oligoglycines is compatible with superexchange, and involves interactions among high-energy occupied orbitals in multiple, consecutive amide bonds, which may by separated by one to three methylene groups. This mechanistic conclusion is supported by density functional theory (DFT).