Next Generation Multiresponsive Nanocarriers for Targeted Drug Delivery to Cancer Cells

C?H bond activation of 2‐methoxyethylamino‐bis(phenolate)‐yttrium catalysts allowed the synthesis of BAB block copolymers comprised of 2‐vinylpyridine (2VP; monomer A) and diethylvinylphosphonate (DEVP; monomer B) as the A and B blocks, respectively, by rare‐earth‐metal‐mediated group‐transfer polymerization (REM‐GTP). The inherent multi‐stimuli‐responsive character and drug‐loading and ‐release capabilities were observed to be dependent on the chain length and monomer ratios. Cytotoxicity assays revealed the biocompatibility and nontoxic nature of the obtained micelles toward ovarian cancer (HeLa) cells. The BAB block copolymers effectively encapsulated, transported, and released doxorubicin (DOX) within HeLa cells. REM‐GTP enables access to previously unattainable vinylphosphonate copolymer structures, and thereby unlocks their full potential as nanocarriers for stimuli‐responsive drug delivery in HeLa cells. The self‐evident consequence is the application of these new micelles as potent drug‐delivery vehicles with reduced side effects in future cancer therapies.     

Controlled Multi‐functionalization Facilitates Targeted Delivery of Nanoparticles to Cancer Cells

A major objective of nanomedicine is to combine in a controlled manner multiple functional entities into a single nanoscale device to target particles with great spatial precision, thereby increasing the selectivity and potency of therapeutic drugs. A multifunctional nanoparticle is described for controlled conjugation of a cytotoxic drug, a cancer cell targeting ligand, and an imaging moiety. The approach is based on the chemical synthesis of polyethylene glycol that at one end is modified by a thioctic acid for controlled attachment to a gold core. The other end of the PEG polymers is modified by a hydrazine, amine, or dibenzocyclooctynol moiety for conjugation with functional entities having a ketone, activated ester, or azide moiety, respectively. The conjugation approach allowed the controlled attachment of doxorubicin through an acid‐labile hydrazone linkage, an Alexa Fluor dye through an amide bond, and a glycan‐based ligand for the cell surface receptor CD22 of B‐cells using strain promoted azide‐alkyne cycloaddition. The incorporation of the ligand for CD22 led to rapid entry of the nanoparticle by receptor‐mediated endocytosis. Covalent attachment of doxorubicin via hydrazone linkage caused pH‐responsive intracellular release of doxorubicin and significantly enhanced the cytotoxicity of nanoparticles. A remarkable 60‐fold enhancement in cytotoxicity of CD22 (+) lymphoma cells was observed compared to non‐ targeted nanoparticles.     

Biodegradable Micelles Capable of Mannose‐Mediated Targeted Drug Delivery to Cancer Cells

A targeted micellar drug delivery system is developed from a biocompatible and biodegradable amphiphilic polyester, poly(Lac‐OCA)‐b‐(poly(Tyr(alkynyl)‐OCA)‐g‐mannose) (PLA‐b‐(PTA‐g‐mannose), that is synthesized via controlled ring‐opening polymerization of O‐carboxyanhydride (OCA) and highly efficient “Click” chemistry. Doxorubicin (DOX), a model lipophilic anticancer drug, can be effectively encapsulated into the micelles, and the mannose moiety allows active targeting of the micelles to cancer cells that specifically express mannose receptors, which thereafter enhances the anticancer efficiency of the drug. Comprised entirely of biodegradable and biocompatible polyesters, this micellar system demonstrates promising potentials for targeted drug delivery and cancer therapy.

     

Halloysite Clay Nanotubes for Resveratrol Delivery to Cancer Cells

Halloysite is natural aluminosilicate clay with hollow tubular structure which allows loading with low soluble drugs using their saturated solutions in organic solvents. Resveratrol, a polyphenol known for having antioxidant and antineoplastic properties, is loaded inside these clay nanotubes lumens. Release time of 48 h is demonstrated. Spectroscopic and ζ‐potential measurements are used to study the drug loading/release and for monitoring the nanotube layer‐by‐layer (LbL) coating with polyelectrolytes for further release control. Resveratrol‐loaded clay nanotubes are added to breast cell cultures for toxicity tests. Halloysite functionalization with LbL polyelectrolyte multilayers remarkably decrease nanotube self‐toxicity. MTT measurements performed with a neoplastic cell lines model system (MCF‐7) as function of the resveratrol‐loaded nanotubes concentration and incubation time indicate that drug‐loaded halloysite strongly increase of cytotoxicity leading to cell apoptosis.

     

Lysinated Multiwalled Carbon Nanotubes with Carbohydrate Ligands as an Effective Nanocarrier for Targeted Doxorubicin Delivery to Breast Cancer Cells

Multiwalled carbon nanotubes (MWCNTs) are elongated, hollow cylindrical nanotubes made of sp2 carbon. MWCNTs have attracted significant attention in the area of drug delivery due to their high drug-loading capacity and large surface area. Furthermore, they can be linked to bioactive ligands molecules via covalent and noncovalent bonds that allow for the targeted delivery of anticancer drugs such as doxorubicin. The majority of methodologies reported for the functionalization of MWCNTs for drug delivery are quite complex and use expensive linkers and ligands. In the present study, we report a simple, cost-effective approach for functionalizing MWCNTs with the carbohydrate ligands, galactose (GA), mannose (MA) and lactose (LA), using lysine as a linker. The doxorubicin (Dox)-loaded functionalized MWCNTs were characterized using FT-IR, NMR, Raman, XRD and FE-SEM. The drug–loaded MWCNTs were evaluated for drug loading, drug release and cell toxicity in vitro, in breast cancer cells. The results indicated that the carbohydrate-modified lysinated MWCNTs had greater Dox loading capacity, compared to carboxylated MWCNTs (COOHMWCNTs) and lysinated MWCNTs (LyMWCNTs). In vitro drug release experiments indicated that the carbohydrate functionalized LyMWCNTs had higher Dox release at pH 5.0, compared to the physiological pH of 7.4, over 120 h, indicating that they are suitable candidates for targeting the tumor microenvironment as a result of their sustained release profile of Dox. Doxorubicin-loaded galactosylated MWCNTs (Dox-GAMWCNTs) and doxorubicin loaded mannosylated MWCNTs (Dox-MAMWCNTs) had greater anticancer efficacy and cellular uptake, compared to doxorubicin–loaded lactosylated MWCNTs (Dox-LAMWCNTs) and pure Dox, in MDA-MB231 and MCF7 breast cancer cells. However, neither the ligand conjugated multiwall blank carbon nanotubes (GAMWCNTs, MAMWCNTs and LAMWCNTs) nor the lysinated multiwalled blank carbon nanotubes produced significant toxicity in the normal cells. Our results suggest that sugar-tethered multiwalled carbon nanotubes, especially the galactosylated (Dox-GAMWCNTs) and mannosylated (Dox-MAMWCNTs) formulations, may be used to improve the targeted delivery of anticancer drugs to breast cancer cells.     

Multivalent Aptamer-modified DNA Origami as Drug Delivery System for Targeted Cancer Therapy

In spite of great development in nanoparticle-based drug delivery systems(DDSs)for improved therapeutic efficacy,it remains challenging for effective delivery of chemotherapeutic drugs to targeted tumor cells.In this work,we report a triangle DNA origami as targeted DDS for cancer therapy.DNA origami shows excellent biocompatibility and stability in cell culture medium for 24 h.In addition,the DNA origami structures conjugated with multivalent aptamers enable for efficient delivery of anticancer drug doxorubicin(Dox)into targeted cancer cell due to their targeting function,reducing side effects associated with nonspecific distribution.Moreover,we also demonstrated that the multivalent aptamer-modified DNA origami loading Dox exhibits prominent therapeutic efficacy in vitro.Accordingly,this work provides a good paradigm for the development of DNA origami nanostructure-based targeted DDS for cancer therapy.     

Ribbon of DNA Lattice on Gold Nanoparticles for Selective Drug Delivery to Cancer Cells

Herein, we report on the design of a programmable DNA ribbon using long‐chain DNA molecules with a user‐defined repetitive padlock sequence. The DNA ribbon can be further combined with gold nanoparticles (AuNPs) to create a composite nanomaterial that contains an AuNP core and a high‐density DNA crown carrying a cancer‐cell‐targeting DNA aptamer, a fluorescent tag for location tracking, and a cell‐killing drug. This composite material can be efficiently internalized by cancer cells and its cellular location can be tracked by fluorescence imaging. The system offers several attractive characteristics, including simple design, tunable DNA crown, high drug‐loading capacity, selective cell targeting, and pH‐sensitive drug release. These features make such a material a promising therapeutic agent.     

Targeted Drug Delivery for the Treatment of Blood Cancers

Blood cancers are a type of liquid tumor which means cancer is present in the body fluid. Multiple myeloma, leukemia, and lymphoma are the three common types of blood cancers. Chemotherapy is the major therapy of blood cancers by systemic administration of anticancer agents into the blood. However, a high incidence of relapse often happens, due to the low efficiency of the anticancer agents that accumulate in the tumor site, and therefore lead to a low survival rate of patients. This indicates an urgent need for a targeted drug delivery system to improve the safety and efficacy of therapeutics for blood cancers. In this review, we describe the current targeting strategies for blood cancers and recently investigated and approved drug delivery system formulations for blood cancers. In addition, we also discuss current challenges in the application of drug delivery systems for treating blood cancers.     

Nano-Drug Delivery Systems Based on Different Targeting Mechanisms in the Targeted Therapy of Colorectal Cancer

Colorectal cancer (CRC) is a usual digestive tract malignancy and the third main cause of cancer death around the world, with a high occurrence rate and mortality rate. Conventional therapies for CRC have certain side effects and restrictions. However, the exciting thing is that with the rapid development of nanotechnology, nanoparticles have gradually become more valuable drug delivery systems than traditional therapies because of their capacity to control drug release and target CRC. This also promotes the application of nano-drug targeted delivery systems in the therapy of CRC. Moreover, to make nanoparticles have a better colon targeting effect, many approaches have been used, including nanoparticles targeting CRC and in response to environmental signals. In this review, we focus on various targeting mechanisms of CRC-targeted nanoparticles and their latest research progress in the last three years, hoping to give researchers some inspiration on the design of CRC-targeted nanoparticles.     

Intracellular Delivery of Glucose Oxidase for Enhanced Cytotoxicity toward PSMA‐Expressing Prostate Cancer Cells

Reactive oxygen species (ROS) forming enzymes are of significant interest as anticancer agents due to their potent cytotoxicity. A key challenge in their clinical translation is attaining site‐specific delivery and minimizing biodistribution to healthy tissues. Here, complexes composed of the ROS enzyme glucose oxidase (GOX), poly‐l ‐lysine‐grafted‐polyethylene glycol (PLL‐g‐PEG), and anti‐prostate specific membrane antigen (anti‐PSMA) monoclonal antibody are synthesized for localized delivery and uptake in prostate cancer cells. Formation of anti‐PSMA‐PLL‐g‐PEG/GOX results in nanoscale complexes ≈30 nm in diameter with a ζ‐potential of 6 mV. The anti‐PSMA‐PLL‐g‐PEG/GOX complexes show significant cytotoxicity (≈60% reduction in cell viability) against PSMA‐expressing LNCaP cells compared to unmodified GOX. Importantly, cytotoxicity in LNCaP cells occurrs concurrently with anti‐PSMA‐PLL‐g‐PEG/GOX uptake and increases in intracellular generation of ROS. These results demonstrate that cytotoxicity of ROS inducing enzymes can be enhanced by intracellular delivery compared to equivalent concentrations of free enzyme, providing a novel means for cancer therapy.     

Towards Targeted Drug Delivery by Covalent Ligand-Modified Polymeric Nanocontainers

Here we present a novel strategy for specific cellular targeting of polymeric nanocontainers by using self-assembly of block copolymers consisting of either Polydimethoxysiloxane-b-Polymethyloxazoline-b-Polydimethoxysiloxane (PDMS-b-PMOXA-b-PDMS) or functionalized PDMS-b-PMOXA-b-PDMS. Covalent functionalization of the above copolymer was accomplished using either the fluorescent dye sulforhodamine B or a poly-guanosin ligand, the latter by using the Huisgen 1,3-dipolar cycloaddition. The success of the covalent modification of the block copolymer has been determined by studying functionalized sulforhodamine B by NMR and fluorescence correlation spectroscopy. The covalent click chemistry approach leads to efficiently functionalized polymeric nanocontainers which enables specific uptake by activated macrophages overexpressing the scavenger receptor A1.     

Delivery of myo-Inositol Hexakisphosphate to the Cell Nucleus with a Proline-Based Cell-Penetrating Peptide

Inositol hexakisphosphate (InsP₆) is a central member of the inositol phosphate messengers in eukaryotic cells. Tools to manipulate the level of InsP₆, particularly with compartment selectivity, are needed to enable functional cellular studies. We present cationic octa-(4S)guanidiniumproline ( Z8 ) for the delivery of InsP₆ into the cell nucleus. CD spectroscopy, binding affinity, dynamic light scattering, and computational studies revealed that Z8 binds tightly to InsP₆ and upon binding undergoes a conformational change from a PPII-helical structure to a structure that forms aggregates. The unique conformational features of the cationic oligoproline enable complex formation and cellular delivery of InsP₆ with considerably greater efficacy than the flexible counterpart octaarginine.     

The Methylene Alkoxy Carbamate Self‐Immolative Unit: Utilization for the Targeted Delivery of Alcohol‐Containing Payloads with Antibody–Drug Conjugates

A strategy for the conjugation of alcohol‐containing payloads to antibodies has been developed and involves the methylene alkoxy carbamate (MAC) self‐immolative unit. A series of MAC β‐glucuronide model constructs were prepared to evaluate stability and enzymatic release, and the results demonstrated high stability at physiological pH in a substitution‐dependent manner. All the MAC model compounds efficiently released alcohol drug surrogates under the action of β‐glucuronidase. To assess the MAC technology for ADCs, the potent microtubule‐disrupting agent auristatin E (AE) was incorporated through the norephedrine alcohol. Conjugation of the MAC β‐glucuronide AE drug linker to the anti‐CD30 antibody cAC10, and an IgG control antibody, gave potent and immunologically specific activities in vitro and in vivo. These studies validate the MAC self‐immolative unit for alcohol‐containing payloads within ADCs, a class that has not been widely exploited.     

Near‐IR Light‐Mediated Cleavage of Antibody–Drug Conjugates Using Cyanine Photocages

Despite significant progress in the clinical application of antibody drug conjugates (ADCs), novel cleavage strategies that provide improved selectivity are still needed. Herein is reported the first approach that uses near‐IR light to cleave a small molecule from a biomacromolecule, and its application to the problem of ADC linkage. The preparation of cyanine antibody conjugates, drug cleavage mediated by 690 nm light, and initial in vitro and in vivo evaluation is described. These studies provide the critical chemical underpinning from which to develop this near‐IR light cleavable linker strategy.     

Targeted delivery of proteins by nanosized carriers

Proteic drug administration poses some additional issues as compared with conventional drugs because of protein high molecular weight and short half‐life in plasma. It is well known that protein delivery canbe significantly improved by using targeted nanocarriers. Among the diverse investigated systems, this overview focuses onliposomes and nanoparticles. Indeed, because of their subcellular size, nanocarriers can cross the fenestration of the vascular epithelium and penetrate tissues. Moreover, nanosystems can be confined at the location of choice by conjugation to molecules that strongly bind the target cells. In spite of the significant progress made in the design and engineering of liposomes and nanoparticles tailored to the targeted delivery of proteins, these nanocarriers seldom succeed in delivering proteins directly inside the cell cytosol. Accordingly, some attention is also paid to virosomes and fusion proteins. These systems have a few advantages over conventional nanocarriers, particularly the ability to cross the cell membrane. They also share the main drawback of being highly immunogenic. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 1–11, 2008