Combination Chemotherapy with Cisplatin and Chloroquine: Effect of Encapsulation in Micelles Formed by Self-Assembling Hybrid Dendritic-Linear-Dendritic Block Copolymers.

Clinical outcomes of conventional drug combinations are not ideal due to high toxicity to healthy tissues. Cisplatin (CDDP) is the standard component for many cancer treatments, yet its principal dose-limiting side effect is nephrotoxicity. Thus, CDDP is commonly used in combination with other drugs, such as the autophagy inhibitor chloroquine (CQ), to enhance tumor cell killing efficacy and prevent the development of chemoresistance. In addition, nanocarrier-based drug delivery systems can overcome chemotherapy limitations, decreasing side effects and increasing tumor accumulation. The aim of this study was to evaluate the toxicity of CQ and CDDP against tumor and non-tumor cells when used in a combined treatment. For this purpose, two types of micelles based on Pluronic® F127 hybrid dendritic-linear-dendritic block copolymers (HDLDBCs) modified with polyester or poly(esteramide) dendrons derived from 2,2'-bis(hydroxymethyl)propionic acid (HDLDBC-bMPA) or 2,2'-bis(glycyloxymethyl)propionic acid (HDLDBC-bGMPA) were explored as delivery nanocarriers. Our results indicated that the combined treatment with HDLDBC-bMPA(CQ) or HDLDBC-bGMPA(CQ) and CDDP increased cytotoxicity in tumor cells compared to the single treatment with CDDP. Encapsulations demonstrated less short-term cytotoxicity individually or when used in combination compared to the free drugs. However, and more importantly, a low degree of cytotoxicity against non-tumor cells was maintained, even when drugs were given simultaneously.

Heparin-Coated Dendronized Hyperbranched Polymers for Antimalarial Targeted Delivery.

The rampant evolution of resistance in Plasmodium to all existing antimalarial drugs calls for the development of improved therapeutic compounds and of adequate targeted delivery strategies for them. Loading antimalarials in nanocarriers specifically targeted to the parasite will contribute to the administration of lower overall doses, with reduced side effects for the patient, and of higher local amounts to parasitized cells for an increased lethality toward the pathogen. Here, we report the development of dendronized hyperbranched polymers (DHPs), with capacity for antimalarial loading, that are coated with heparin for their specific targeting to red blood cells parasitized by Plasmodium falciparum. The resulting DHP-heparin complexes exhibit the intrinsic antimalarial activity of heparin, with an IC50 of ca. 400 nM, added to its specific targeting to P. falciparum-infected (vs noninfected) erythrocytes. DHP-heparin nanocarriers represent a potentially interesting contribution to the limited family of structures described so far for the loading and targeted delivery of current and future antimalarial compounds.

Dendron-functionalised hyperbranched bis-MPA polyesters as efficient non-viral vectors for gene therapy in different cell lines.

Gene therapy has become a relevant tool in the biomedical field to treat or even prevent some diseases. The effective delivery of genetic material into the cell remains a crucial step to succeed in this purpose. In the search for efficient non-viral vectors, a series of amino-terminated dendronized hyperbranched polymers (DHPs) of different generations based either on bis-MPA or bis-GMPA have been designed. All of them have demonstrated an accurate ability to complex two types of genetic materials, a plasmid DNA and a siGFP, yielding dendriplexes. Moreover, some of them have proved to be able to deliver the genetic material inside the cells, resulting in the effective accomplishment of the desired genetic modification and improving the activity of some commercial transfection reagents. Different cell lines, including cancer and mesenchymal stem cells, have been studied here to evaluate the ability of DHPs as vectors for transfection. Treatments based on mesenchymal stem cells are gaining importance due to their pluripotency. Thus, it is of special relevance to introduce a genetic modification into a mesenchymal cell line as it allows it to act over a wide spectrum of tissues after inducing cellular differentiation.

Micellar Nanocarriers from Dendritic Macromolecules Containing Fluorescent Coumarin Moieties.

The design of efficient drug-delivery vehicles remains a big challenge in materials science. Herein, we describe a novel class of amphiphilic hybrid dendrimers that consist of a poly(amidoamine) (PAMAM) dendritic core functionalized with bisMPA dendrons bearing cholesterol and coumarin moieties. Their self-assembly behavior both in bulk and in water was investigated. All dendrimers exhibited smectic A or hexagonal columnar liquid crystal organizations, depending on the generation of the dendrimer. In water, these dendrimers self-assembled to form stable spherical micelles that could encapsulate Nile Red, a hydrophobic model compound. The cell viability in vitro of the micelles was studied in HeLa cell line, and proved to be non-toxic up to 72 h of incubation. Therefore, these spherical micelles allow the encapsulation of hydrophobic molecules, and at the same time provided fluorescent traceability due to the presence of coumarin units in their chemical structure, demonstrating the potential of these dendrimers as nanocarriers for drug-delivery applications.

Janus Dendrimers to Assess the Anti-HCV Activity of Molecules in Cell-Assays.

The use of nanocarriers has been revealed as a valid strategy to facilitate drug bioavailability, and this allows for expanding the drug libraries for the treatment of certain diseases such as viral diseases. In the case of Hepatitis C, the compounds iopanoic acid and 3,3',5-triiodothyroacetic acid (or tiratricol) were identified in a primary screening as bioactive allosteric inhibitors of viral NS3 protease, but they did not exhibit accurate activity inhibiting viral replication in cell-based assays. In this work, dendritic nanocarriers are proposed due to their unique properties as drug delivery systems to rescue the bioactivity of these two drugs. Specifically, four different amphiphilic Janus dendrimers synthesized by combining 2,2'-bis(hydroxymethyl)propionic acid (bis-MPA) and 2,2'-bis(glyciloxy)propionic acid (bis-GMPA) functionalized with either hydrophilic or lipophilic moieties at their periphery were used to entrap iopanoic acid and tiratricol. Interestingly, differences were found in the loading efficiencies depending on the dendrimer design, which also led to morphological changes of the resulting dendrimer aggregates. The most remarkable results consist of the increased water solubility of the bioactive compounds within the dendrimers and the improved antiviral activity of some of the dendrimer/drug aggregates, considerably improving antiviral activity in comparison to the free drugs. Moreover, imaging studies have been developed in order to elucidate the mechanism of cellular internalization.

Promising nanomaterials in the fight against malaria.

For more than one hundred years, several treatments against malaria have been proposed but they have systematically failed, mainly due to the occurrence of drug resistance in part resulting from the exposure of the parasite to low drug doses. Several factors are behind this problem, including (i) the formidable barrier imposed by the Plasmodium life cycle with intracellular localization of parasites in hepatocytes and red blood cells, (ii) the adverse fluidic conditions encountered in the blood circulation that affect the interaction of molecular components with target cells, and (iii) the unfavorable physicochemical characteristics of most antimalarial drugs, which have an amphiphilic character and can be widely distributed into body tissues after administration and rapidly metabolized in the liver. To surpass these drawbacks, rather than focusing all efforts on discovering new drugs whose efficacy is quickly decreased by the parasite's evolution of resistance, the development of effective drug delivery carriers is a promising strategy. Nanomaterials have been investigated for their capacity to effectively deliver antimalarial drugs at local doses sufficiently high to kill the parasites and avoid drug resistance evolution, while maintaining a low overall dose to prevent undesirable toxic side effects. In recent years, several nanostructured systems such as liposomes, polymeric nanoparticles or dendrimers have been shown to be capable of improving the efficacy of antimalarial therapies. In this respect, nanomaterials are a promising drug delivery vehicle and can be used in therapeutic strategies designed to fight the parasite both in humans and in the mosquito vector of the disease. The chemical analyses of these nanomaterials are essential for the proposal and development of effective anti-malaria therapies. This review is intended to analyze the application of nanomaterials to improve the drug efficacy on different stages of the malaria parasites in both the human and mosquito hosts.

Micelle carriers based on dendritic macromolecules containing bis-MPA and glycine for antimalarial drug delivery.

Biomaterials for antimalarial drug transport still need to be investigated in order to attain nanocarriers that can tackle essential issues related to malaria treatment, e.g. complying with size requirements and targeting specificity for their entry into Plasmodium-infected red blood cells (pRBCs), and limiting premature drug elimination or drug resistance evolution. Two types of dendritic macromolecule that can form vehicles suitable for antimalarial drug transport are herein explored. A new hybrid dendritic-linear-dendritic block copolymer based on Pluronic® F127 and amino terminated 2,2'-bis(glycyloxymethyl)propionic acid dendrons with a poly(ester amide) skeleton (HDLDBC-bGMPA) and an amino terminated dendronized hyperbranched polymer with a polyester skeleton derived from 2,2'-bis(hydroxymethyl)propionic acid (DHP-bMPA) have provided self-assembled and unimolecular micelles. Both types of micelle carrier are biocompatible and exhibit appropriate sizes to enter into pRBCs. Targeting studies have revealed different behaviors for each nanocarrier that may open new perspectives for antimalarial therapeutic approaches. Whereas DHP-bMPA exhibits a clear targeting specificity for pRBCs, HDLDBC-bGMPA is incorporated by all erythrocytes. It has also been observed that DHP-bMPA and HDLDBC-bGMPA incorporate into human umbilical vein endothelial cells with different subcellular localization, i.e. cytosolic and nuclear, respectively. Drug loading capacity and encapsulation efficiencies for the antimalarial compounds chloroquine, primaquine and quinacrine ranging from 30% to 60% have been determined for both carriers. The resulting drug-loaded nanocarriers have been tested for their capacity to inhibit Plasmodium growth in in vitro and in vivo assays.