Cancer-targeted Drug Delivery Research Articles

Magnetic nano-particles retrievable biodegradable hydrogel microrobot

Drug therapy using cancer-targeted drug delivery particles is widely adopted as a general anti-cancer therapy. In this approach, anticancer drug particles target mainly cancer cells, thereby reducing the side effects caused by anticancer drug particles against normal cells. However, these cancer-targeted drug delivery particles still have many risks due to uncertainty in their ability to target cancer cells. Microrobots may overcome this problem by delivering therapeutic drugs to a cancer cell target lesion via electromagnetic actuation. Generally, microrobots include an anti-cancer drug and magnetic nanoparticles (MNPs) for their electromagnetic actuation. However, the MNPs may remain and cause toxicity in the body after the drug delivery. To remedy this, we propose a new type of microrobot that can deliver an anti-cancer drug to cancer target lesion and retrieve the problematic MNPs. The proposed microrobot consists of a gelatin/poly vinyl alcohol (PVA) based hydrogel, MNPs and poly lactic-co-glycolic acid particles carrying doxorubicin (PLGA–DOX particles). The targeting and the retrieval of MNPs from the hydrogel microrobot is accomplished by a fabricated customized electromagnetic actuation (EMA) and near-infra red (NIR) integrated system. First, the hydrogel microrobot reaches a pre-determined target lesion by the magnetic field of the EMA system. Next, after NIR irradiation, the gelatin/PVA of the hydrogel microrobot is decomposed and the MNPs and PLGA–DOX drug particles are left in the target area. After the disassembled MNPs are recovered out of the target lesion by the magnetic field of the EMA system, only the PLGA–DOX particles remain in the target area. Finally, the anti-cancer drug can be released from the remaining PLGA–DOX particles and can generate a therapeutic effect in the target lesion. In this study, we fabricated the hydrogel microrobot, analyzed its characteristics (shape, size, magnetization, and drug encapsulation), verified the possibilities of targeting and disassembly of the hydrogel microrobot, and proved the retrieval of MNPs and the drug delivery from the remaining PLGA–DOX particles. Additionally, we executed the drug-releasing experiment using PLGA–DOX particles and confirmed the therapeutic effect of the hydrogel microrobot through an in vitro test using Hep3B cancer cell. We conclude that the proposed hydrogel microrobot is a new type of biocompatible microrobot with the capability of active targeting as well as toxic MNP retrieval.

A Smart Nanovector for Cancer Targeted Drug Delivery Based on Graphene Quantum Dots.

Graphene quantum dots (GQD), the new generation members of graphene-family, have shown promising applications in anticancer therapy. In this study, we report the synthesis of a fluorescent and biocompatible nanovector, based on GQD, for the targeted delivery of an anticancer drug with benzofuran structure (BFG) and bearing the targeting ligand riboflavin (RF, vitamin B2). The highly water-dispersible nanoparticles, synthesized from multi-walled carbon nanotubes (MWCNT) by prolonged acidic treatment, were linked covalently to the drug by means of a cleavable PEG linker while the targeting ligand RF was conjugated to the GQD by π–π interaction using a pyrene linker. The cytotoxic effect of the synthesized drug delivery system (DDS) GQD-PEG-BFG@Pyr-RF was tested on three cancer cell lines and this effect was compared with that exerted by the same nanovector lacking the RF ligand (GQD-PEG-BFG) or the anticancer drug (GQD@Pyr-RF). The results of biological tests underlined the low cytotoxicity of the GQD sample and the cytotoxic activity of the DDS against the investigated cancer cell lines with a higher or similar potency to that exerted by the BFG alone, thus opening new possibilities for the use of this drug or other anticancer agents endowed of cytotoxicity and serious side effects.

Chondroitin sulfate-functionalized polymeric nanoparticles for colon cancer-targeted chemotherapy.

Targeted delivery of chemotherapeutic drugs to tumors is a major challenge in colon cancer chemotherapy. To overcome this bottleneck, we loaded camptothecin (CPT) into polymeric nanoparticles (NPs), and further functionalized their surface with chondroitin sulfate (CS). The resulting CS-CPT-NPs had a desirable hydrodynamic diameter (289 nm), narrow particle size distribution (polydispersity index = 0.192) and neutral surface charge. Furthermore, in vitro experiments revealed that the surface functionalization of CS endowed NPs with the capacity of colon cancer-targeted drug delivery, and significantly improved the anti-colon cancer activities and pro-apoptosis effects against colon cancer cells. Strikingly, treatment of colon tumor-bearing mice with different NPs clearly indicated that CS-CPT-NPs showed much better therapeutic outcomes than non-targeted NPs and no systemic toxicity. Taken together, these results demonstrated the promising potential of CS-CPT-NP as an effective drug delivery system for colon cancer-targeted chemotherapy.

PH Sensitive Peptide Functionalized High Stability Polymeric Nanoparticles for Mitochondria Targeted Cancer Drug Delivery

A major focus of cancer nanomedicine is to achieve a high therapeutic index for cancer therapy. Despite the unprecedented growth in the development of polymeric self-assembled nanosystems, only a few of them end up in clinics (e.g. Doxil) as a result of (i) poor stability, (ii) drug leakage and (iii) dissociation kinetics due to the strong influence of blood components in vivo. The most common method for improving nanocarrier stability is to tune the drug hydrophobicity and polymer matrix miscibility under complex chemical reaction conditions, that leads to poor drug cytotoxicity and attenuation of therapeutic efficacy. To address these challenges, we have designed a simple and robust poly (lactide-co-glycolide) (PLGA) and bovine serum albumin (BSA) hybrid nanoparticles to provide high stability and trigger drug release inside cancer cells. The hybrid nanoparticles were prepared by covalently wrapping BSA over the surface of drug-loaded PLGA nanoparticles using simple carbodiimide-chemistry in mild reaction conditions. To increase the stability, the BSA shells were crosslinked. The BSA shells can be dissociated in the high redox microenvironment of the tumor and within the cancer cells. Subsequently, the drugs loaded into the PLGA core can be released by accelerated degradation (hydrolysis) due to the low pH conditions in the tumor microenvironment and lysosomal compartments. The cancer cell targeting ability of the hybrid NPs was achieved by coupling of the amino groups of the BSA shell with a pH-sensitive peptide (acidity-triggered rational membrane peptide, ATRAM). The insertion of the ATRAM-BSA-PLGA nanoparticles into cancer cell membranes occurs at the peritumoral pH (6.5). In vitro studies showed highly-efficient pH-dependent uptake and remarkable cytotoxicity of doxorubicin triphenylphosphine loaded ATRAM-BSA-PLGA NPs. Our results demonstrate that the novel pH-sensitive peptide-functionalized high stability BSA-PLGA nanoparticles are a highly promising nanoplatforms.

Stem cell membrane vesicle–coated nanoparticles for efficient tumor‐targeted therapy of orthotopic breast cancer

Nanoparticles‐based drug delivery strategies have been widely researched for cancer therapy. However, most of them are expected to accumulate in tumor sites via the enhanced permeability and retention (EPR) effect, which is insufficient to deliver the loaded drug into tumors. Cell membrane–camouflaged nanoparticles have obtained much attention for their excellent stability and long blood circulation and reduced the macrophage cells uptake in drug delivery. Herein, bone marrow–derived mesenchymal stem cell membrane vesicle (SCV)–coated paclitaxel (PTX)–loaded poly (lactide‐co‐glycolide) (PLGA) nanoparticles (SCV/PLGA/PTX) were fabricated as the efficient orthotopic breast cancer–targeted drug delivery system. The SCV/PLGA/PTX showed excellent stability, more controlled PTX release, and more effective antitumor effect in vitro. After administration in vivo, SCV/PLGA/PTX exhibited the long‐term retention and enhanced accumulation at tumor sites due to the immune escape and mesenchymal stem cell–mimicking cancer‐targeting capacity. As expected, the SCV/PLGA/PTX could significantly suppress the primary tumor growth by increased apoptosis and necrosis areas within tumor tissues and attenuated the toxic side effects of PTX in 4T1 orthotopic breast cancer model. The study indicated the mesenchymal stem cell membrane coating strategy was highly efficient for targeted drug delivery, which provided a new insight for precise and effective breast cancer treatment.

Synthesis of Folate-Appended <i>β</i>-Cyclodextrin Using Phenanthroline as Linker for Cancer Targeting Drug Delivery

Here we have synthesized cancer targeting drug delivery system that contains β-cyclodextrin as a drug carrier and folic acid as a targeting ligand. Folic acid was selected as a cancer targeting ligand because folic acid receptors are highly expressed in a variety of tumor types. β-cyclodextrin and folic acid were connected through a linker [1,10-phenanthroline or 5-(hydroxymethyl) furfural]. β-cyclodextrin and folic acid were attached to the linker by formation of Schiffbase and ester, respectively. Our targeted synthetic products were confirmed by NMR, Mass and IR spectroscopy. We anticipate that our synthetic products can confer cancer cell-specific drug delivery as well as desired properties such as nanoparticle formation.

Size-controlled synthesis of polymerized DNA nanoparticles for targeted anticancer drug delivery.

We synthesized size-tunable polymerized DNA nanoparticles (PDNs) for cancer-targeted drug delivery via sequential processes of rolling circle amplification, condensation, and layer-by-layer assembly. The PDNs selectively delivered anti-sense oligonucleotides to target cancer cells and exhibited size-dependent gene regulation efficacy.

Advances in refunctionalization of erythrocyte-based nanomedicine for enhancing cancer-targeted drug delivery.

Cancer remains a daunting and cureless disease, which is responsible for one-sixth of human deaths worldwide. These mortality rates have been expected to rise in the future due to the side effects of conventional treatments (chemotherapy, radiotherapy, and surgery), which can be addressed by applying nanomedicine. In order to escape from biological barriers, such nanomedicine should be mimicked and designed to be stealthy while navigating in the bloodstream. To achieve this, scientists take advantage of erythrocytes (red blood cells; RBCs) as drug carriers and develop RBC membrane (RBCm) coating nanotechnology. Thanks to the significant advances in nanoengineering, various facile surface functionalization methods can be applied to arm RBCm with not only targeting moieties, but also imaging agents, therapeutic agents, and nanoparticles, which are useful for theranostic nanomedicine. This review focuses on refunctionalization of erythrocyte-based nanomedicine for enhancing cancer-targeted drug delivery.

Glucose-installed biodegradable polymeric micelles for cancer-targeted drug delivery system: synthesis, characterization and in vitro evaluation.

Glucose metabolism of cancer can be used as a strategy to target cancer cells which exhibit altered glycolytic rate. The facilitated glucose transporter (Glut) plays an important role in enhancement glycolytic rate resulting in increased glucose uptake into cancer cells. 18FGD-PET image is an example for using Glut as a targeting to diagnose the high glycolytic rate of tumor. Thus, Glut may be adapted to target cancer cells for drug delivery system. Herein, biodegradation polymeric micelles target cancer cells by Glut was fabricated. The amphiphilic block copolymer of poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) was synthesized where terminal group of the PEG chain was installed with glucose molecules. The 1H-NMR confirmed the existence of glucose moiety from two distinct peaks (5.2 and 4.7 ppm) of protons at anomeric carbon of glucose. Glucose-PEG-b-PCL spontaneously forms micelles in an aqueous solution. The size and zeta potential were 22 nm and -7 mv, respectively. Glucose-micelles have high stability, and no evidence of cytotoxicity was found after incubation for 7 days. Doxorubicin, used as a fluorescent probe, was loaded into glucose-micelles. The enhanced amount of doxorubicin as a result of glucose-micelles in PC-3, MCF-7 and HepG2 was evaluated by fluorescence microscopy and flow cytometer. Glucose molecules on the surface of micelles increased internalization and enhanced uptake of micelles via bypassing endocytosis pathway. These results show the use of glucose as a targeting ligand on the micelle surface to target cancer cells via Glut.

Facile Fabrication of Oxidation-Responsive Polymeric Nanoparticles for Effective Anticancer Drug Delivery.

Reactive oxygen species (ROS) are highly overproduced in cancerous tissues, and thus oxidation-responsive nanoparticles (NPs) have emerged as a promising drug carrier for cancer-targeted drug delivery. In this study, we successfully synthesized poly(vanillyl alcohol- co-oxalate) (PVAX) polymer with an excellent ROS-responsive capacity. A well-established emulsion-solvent evaporation method was used to fabricate PVAX-based curcumin (CUR)-loaded NPs (PVAX-NPs) and their counterparts (poly(lactic- co-glycolic acid)-based CUR-loaded NPs, PLGA-NPs). It was found that these NPs had a hydrodynamic particle size of approximately 245 nm, narrow size distribution (polydispersity index less than 0.1), negative zeta potential (around -18 mV), smooth surface appearance, and high drug encapsulation efficiency. Moreover, we found that the CUR release rate of PVAX-NPs was greatly increased in the presence of a hydrogen peroxide-rich environment due to the cleavage of polyoxalate ester bonds in PVAX polymer, resulting in the evenly distribution of CUR within the whole cancer cells. More importantly, PVAX-NPs exhibited much stronger anticancer activities and pro-apoptotic capacities than PLGA-NPs both in vitro and in vivo. These results clearly demonstrate that these ROS-responsive PVAX-NPs can be exploited as a robust anticancer drug delivery platform in chemotherapy.

Functional graphene oxide as cancer-targeted drug delivery system to selectively induce oesophageal cancer cell apoptosis

Graphene oxides (GO) is a promising building material to fabricate desired drug delivery system due to its excellent physicochemical properties. In this study, an innovative nano-drug (Ori@GE11-GO) was constructed based on GE11 peptide functionalized GO for targeted delivery of oridonin to realize the specific recognition of tumour cells and enhance anticancer efficiency. GE11 surface modification onto GO significantly increased the cellular uptake of GO in EGFR overexpressed oesophageal cancer cells (KYSE-30 and EC109 cells) than that of normal cells, indicating the EGFR targeting effects of Ori@GE11-GO. The internalized Ori@GE11-GO could accumulate into lysosomes and significantly inhibit the viability of cancer cells. Moreover, Ori@GE11-GO could effectively induce KYSE-30 and EC109 cells cycle arrest, apoptosis, mitochondrial membrane potential (△Ψm) disruption through the activation of apoptotic signalling pathways and the inhibition of EGFR/Ras/Raf/MEK/ERK signalling pathway, showing potential use of Ori@GE11-GO for cancer treatment. Taken together, this study demonstrates a good strategy for the construction of bio-functionalized GO drug delivery nanosystem to improve the cancer targeting efficiency of anticancer medicines.

Efficient lung cancer-targeted drug delivery via a nanoparticle/MSC system

Low targeting efficiency limits the applications of nanoparticles in cancer therapy. The fact that mesenchymal stem cells (MSC) trapped in the lung after systemic infusion is a disadvantage for cell therapy purposes. Here, we utilized MSC as lung cancer-targeted drug delivery vehicles by loading nanoparticles (NP) with anti-cancer drug. MSC showed a higher drug intake capacity than fibroblasts. In addition, MSC showed predominant lung trapping in both rabbit and monkey. IR-780 dye, a fluorescent probe used to represent docetaxel (DTX) in NP, delivered via MSC accumulated in the lung. Both in vitro MSC/A549 cell experiments and in vivo MSC/lung cancer experiments validated the intercellular transportation of NP between MSC and cancer cells. In vivo assays showed that the MSC/NP/DTX drug delivery system exerted primary tumor inhibition efficiency similar to that of a NP/DTX drug system. Collectively, the MSC/NP drug delivery system is promising for lung-targeted drug delivery for the treatment of lung cancer and other lung-related diseases.

Synthesis of Folic Acid-Modified DOX@ZIF-8 Nanoparticles for Targeted Therapy of Liver Cancer

The effective chemotherapy treatment for liver cancer patients remains an urgent issue due to the difficulty in precisely delivering drugs to the tumor site. The targeted delivery of drugs by nanoparticles is a promising strategy to address this problem. However, the fabrication of drug targeted delivery nanosystem still remains a major challenge. In this study, a novel folic acid-functionalized (doxorubicin, DOX) DOX@ZIF-8 nanoparticles (DOX@ZIF-8-FA) were prepared as a liver cancer-targeted drug delivery system. The delivery nanosystem exhibited a high drug loading capacity (15.7 wt%) and presented excellent drug-sustained release performances and good pH-responsive properties. Compared with free DOX and DOX@ZIF-8 nanoparticles, the DOX@ZIF-8-FA nanoparticles displayed much higher anticancer efficiency in HepG2 cells, suggesting that the folic acid-functionalized DOX@ZIF-8 nanoparticles have promising applications in targeted treatment of cancer cells.

Construction and application of a liver cancer-targeting drug delivery system based on core-shell gold nanocages

Construction and application of a liver cancer-targeting drug delivery system based on core-shell gold nanocages

Construction and application of a liver cancer-targeting drug delivery system based on core-shell gold nanocages.

BackgroundIn order to achieve drug targeting and controlled release, we have successfully developed a novel drug release system DOX/AuNCs-PM-HA with gold nanocages (AuNCs) as photothermal cores, thermally responsive copolymer P(NIPAM-co-Am) (PM) as the near-infrared (NIR) stimuli gatekeeper and hyaluronic acid as a targeting ligand as well as a capping agent.MethodsCell uptake and cell viability were investigated. In vivo photoacoustic tomography imaging in H22 tumor bearing mice was analyzed for the tumor targeting effect of the nanocomplexes. Antitumor efficacy and the tissue distribution in vivo were investigated.ResultsIn vitro results demonstrated that the DOX/AuNCs-PM-HA had significant anticancer activity against SMMC-7721 cells under NIR irradiation. Furthermore, in vivo photoacoustic tomography imaging of the nanocomplexes in H22 tumor bearing mice could indicate effective tumor targeting. Our studies on antitumor efficacy and the tissue distribution in vivo showed that many DOX/AuNCs-PM-HA nanocomplexes could efficiently accumulate at the tumor site so that they could inhibit the tumor growth effectively with limited side effects. The in vitro and in vivo results confirmed that the tumor-targeting and controlled-release drug system DOX/AuNCs-PM-HA with the combination of chemotherapy and photothermal therapy showed strong anti-tumor effect and would have great potential for future cancer therapy.ConclusionThis tumor targeting DOX/AuNCs-PM-HA nanocomplex responded not only to the external stimuli of NIR, but also the internal stimuli of hyaluronidase, providing the potential for pinpointed and multi-stimuli responsive intracellular drug release.

Development of novel biofunctionalized chitosan decorated nanocochleates as a cancer targeted drug delivery platform

A new family of biofunctionalized chitosan decorated nanocochleates-mediated drug delivery system was developed that involves uniquely combining nanocochleates with anticancer drug for controlled drug release, targeted delivery, improved bioavailability with reduced toxicity. This system was developed by loading of doxorubicin (DOX) to nanocochleates (DOX-NC) through conversion of negatively charged dimyristoylphosphatidylcholine (DMPC) phospholipid and cholesterol-bearing vesicles on addition of calcium ions, followed by encapsulation DOX-NC with folic acid conjugated chitosan (FA-CHI-DOX-NC). The release of DOX indicated strong pH dependence and implies hydrogen-bonding interaction between nanocochleates and DOX. Formulated FA-CHI-DOX-NC demonstrated higher in-vitro anticancer activity in folate overexpressed human breast cancer MCF-7 cells. The targeting effect for the FA-CHI-DOX-NC was also demonstrated. The concentration of the drug needed for growth inhibition of 50% of cells in a designed time period (GI50) was 9.1 µg/ml for DOX while it was decreased by 31.68% for the DOX-NC (6.2 µg/ml). Furthermore, the GI50 value of FA-CHI-DOX-NC was 4.4 µg/ml, i.e. a 51.64% decrease was observed as compared to DOX solution. Moreover, bioavailability of DOX from FA-CHI-DOX-NC increased by 4-fold with long circulation time, slower plasma elimination and no sign of tissue toxicity as compared to DOX solution. The proposed strategy is advantageous in terms of targeted drug delivery and has high potential to address the current challenges in drug delivery. Thus, the prepared new carrier offers a novel formulation that combines the unique properties of a biodegradable material, chitosan and nanocochleates for biomedical applications.

Engineered Peptides for Applications in Cancer-Targeted Drug Delivery and Tumor Detection.

Cancer-targeting peptides as ligands for targeted delivery of anticancer drugs or drug carriers have the potential to significantly enhance the selectivity and the therapeutic benefit of current chemotherapeutic agents. Identification of tumor-specific biomarkers like integrins, aminopeptidase N, and epidermal growth factor receptor as well as the popularity of phage display techniques along with synthetic combinatorial methods used for peptide design and structure optimization have fueled the advancement and application of peptide ligands for targeted drug delivery and tumor detection in cancer treatment, detection and guided therapy. Although considerable preclinical data have shown remarkable success in the use of tumor targeting peptides, peptides generally suffer from poor pharmacokinetics, enzymatic instability, and weak receptor affinity, and they need further structural modification before successful translation to clinics is possible. The current review gives an overview of the different engineering strategies that have been developed for peptide structure optimization to confer selectivity and stability. We also provide an update on the methods used for peptide ligand identification, and peptide- receptor interactions. Additionally, some applications for the use of peptides in targeted delivery of chemotherapeutics and diagnostics over the past 5 years are summarized.

Values in Nanomedical Research: A Discussion Based on the NANOCAN Project on Nanoparticles in Cancer Therapy and Diagnosis

The NANOCAN project aims to enhance our understanding of the behavior of nanomaterials in the body, focusing on biodegradable nanoparticles for cancer diagnostics, and targeted cancer drug delivery. There is a range of available and potentially useful nanoparticles and drugs that might be of interest to such a project. In this paper, we make values implied in—and relevant to—choices between these alternatives explicit, thereby offering a case study of how values enter research processes in this area. From a project centered perspective, we observe that values often play their role implicitly, as a result of funding incentives, regulations, and structural and organizational features of the research process. Based on our observations and categorization of relevant values, we turn to a broader discussion of how responsible research and innovation can be facilitated by making value priorities, value conflicts, and biases explicit targets of normative assessment.

Design and development of hyaluronan-functionalized polybenzofulvene nanoparticles as CD44 receptor mediated drug delivery system

A tri-component polymer brush (TCPB), composed of a polybenzofulvene copolymer bearing low molecular weight hyaluronic acid (HA) on the surface of its cylindrical brush-like backbone and oligo-PEG fractions, was employed in the preparation of 350 nm nanostructured drug delivery systems capable of delivering the anticancer drug doxorubicin. The obtained drug delivery systems were characterized on the basis of drug loading and release, dimensions and zeta potential, morphology and in vitro cell activity, and uptake on three different human cell lines, namely the bronchial epithelial 16HBE, the breast adenocarcinoma MCF-7, and the colon cancer HCT116 cells. Finally, the ability of doxorubicin-loaded TCPB nanoparticles (DOXO-TCPB) to be internalized into cancer cells by CD44 receptor mediated uptake was assessed by means of uptake studies in HCT cells. These data were supported by anti-CD44-FITC staining assay. The proposed TCPB nanostructured drug delivery systems have many potential applications in nanomedicine, including cancer targeted drug delivery.

Graphene quantum dots for cancer targeted drug delivery

A biocompatible and cell traceable drug delivery system Graphene Quantum Dots (GQD) based, for the targeted delivery of the DNA intercalating drug doxorubicin (DOX) to cancer cells, is here reported. Highly dispersible and water soluble GQD, synthesized by acidic oxidation and exfoliation of multi-walled carbon nanotubes (MWCNT), were covalently linked to the tumor targeting module biotin (BTN), able to efficiently recognize biotin receptors over-expressed on cancer cells and loaded with DOX. Biological test performed on A549 cells reported a very low toxicity of the synthesized carrier (GQD and GQD-BTN). In GQD-BTN-DOX treated cancer cells, the cytotoxicity was strongly dependent from cell uptake which was greater and delayed after treatment with GQD-BTN-DOX system with respect to what observed for cells treated with the same system lacking of the targeting module BTN (GQD-DOX) or with the free drug alone. A delayed nuclear internalization of the drug is reported, due to the drug detachment from the nanosystem, triggered by the acidic environment of cancer cells.