SELF-ASSEMBLED NANOPARTICLES BASED ON DENDRIMER-POLYETHYLENE GLYCOL-POLYESTER BUILDING BLOCKS FOR DUAL GENE AND DRUG DELIVERY

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Publications

pH-sensitive Laponite®/doxorubicin/alginate nanohybrids with improved anticancer efficacy

Publication . Gonçalves, Mara; Figueira, Priscilla; Maciel, Dina; Rodrigues, João; Qu, Xue; Liu, Changsheng; Tomás, Helena; Li, Yulin

The efficacy of the anticancer drug doxorubicin (Dox) is limited by an insufficient cellular uptake and drug resistance, which is partially due to ion trapping in acidic environments such as the extracellular environment of solid tumors and the interior of endolysosome vesicles. Herein, we describe the preparation and in vitro evaluation of a new type of nanohybrid for anticancer drug delivery which is capable of carrying a high load of the cationic Dox through the cell membrane. In addition, the nanohybrids use the acidic environment of the endolysosomes to release the drug, simultaneously helping to disrupt the endolysosomes and diminishing endolysosome Dox trapping. Furthermore, as the nanohybrid carriers are capable of sustained drug delivery, those that remain in the cytoplasm and still contain Dox are expected to exert a prolonged anticancer activity. Briefly, Dox is loaded onto biocompatible anionic Laponite(®) (LP) nanodisks with a high aspect ratio (25 nm in diameter and 0.92 nm in thickness) through strong electrostatic interactions to get Dox-loaded LP disks. Alginate (AG), a biocompatible natural polymer, is then coated onto the Dox-loaded LP disks (LP/Dox/AG nanohybrids) to prevent the burst release of the drug. The results demonstrate that the nanohybrids have a high encapsulation efficiency (80.8 ± 10.6%), are sensitive to pH and display a sustained drug release behavior. Cell culture experiments indicate that the LP/Dox/AG nanohybrids can be effectively internalized by CAL-72 cells (an osteosarcoma cell line), and exhibit a remarkable higher cytotoxicity to cancer cells than the free Dox. The merits of Laponite(®)/alginate nanohybrids, such as biocompatibility, high loading capacity and stimulus responsive release of cationic chemotherapeutic drugs, render them as excellent platforms for drug delivery.

2014Journal article

Restricted access

Polyester Dendrimers Based on Bis-MPA for Doxorubicin Delivery

Publication . Gonçalves, Mara; Kairys, Visvaldas; Rodrigues, João; Tomás, Helena

Although doxorubicin (DOX) is one of the most used chemotherapeutic drugs due to its efficacy against a wide group of cancer types, it presents severe side effects. As such, intensive research is being carried out to find new nanoscale systems that can help to overcome this problem. Polyester dendrimers based on the monomer 2,2-bis- (hydroxymethyl)propionic acid (bis-MPA) are very promising systems for biomedical applications due to their biodegradability properties. In this study, bis-MPA-based dendrimers were, for the first time, evaluated as DOX delivery vehicles. Generations 4 and 5 of bis-MPA-based dendrimers with hydroxyl groups at the surface were used (B-G4-OH and B-G5-OH), together with dendrimers partially functionalized with amine groups (B-G4-NH2/OH and B-G5-NH2/OH). Partial functionalization was chosen because the main purpose was to compare the effect of different functional groups on dendrimers’ drug delivery behavior without compromising cell viability, which is often affected by dendrimers’ cationic charge. Results revealed that bis-MPA-based dendrimers were cytocompatible, independently of the chemical groups that were present at their surface. The B-G4-NH2/OH and B-G5-NH2/OH dendrimers were able to retain a higher number of DOX molecules, but the in vitro release of the drug was faster. On the contrary, the hydroxyl-terminated dendrimers exhibited a lower loading capacity but were able to deliver the drug in a more sustained manner. These results were in accordance with the cytotoxicity studies performed in several models of cancer cell lines and human mesenchymal stem cells. Overall, the results confirmed that it is possible to tune the drug delivery properties of bis-MPA-based dendrimers by modifying surface functionalization. Moreover, molecular modeling studies provided insights into the nature of the interactions established between the drug and the bis-MPA based dendrimersDOX molecules attach to their surface rather than being physically encapsulated.

2021Journal article

Open access

Nanotechnology approaches for the delivery of antitumor drugs: the case of doxorubicin

Publication . Gonçalves, Mara Isabel Jesus; Tomás, Helena Maria Pires Gaspar; Rodrigues, João Manuel Cunha; Lin, Yulin

Over the years, nanotechnology had a huge evolution and gathered the attention of many scientists, including those involved in medical sciences. Nanomedicine thus appeared, trying to overcome obstacles that still exist in conventional medicine, by providing innovative approaches for the diagnosis and treatment of diseases. Nowadays, cancer is considered one of the major causes of worldwide death. Doxorubicin (DOX) is a chemotherapeutic drug which is routinely used for cancer treatment. Due to its broad spectrum of activity, DOX is used as a first-line treatment combined with other drugs and procedures. However, this drug has several associated side effects, being the injury of the cardiac muscle tissue and myelosuppression the most reported. Cancer nanomedicine stands up as an alternative to conventional cancer therapy by using nanomaterials as drug carriers which, potentially, make the treatment more efficient and safe. Polymer-based nanomaterials are very promising vehicles for drug delivery, due to the easiness in modelling their properties. Over the years, polymers have proven to be capable of encapsulating and releasing drugs in a sustained manner, improving their biodistribution and accumulation in tumours. The main goal of this thesis was to find new drug delivery systems that could be able to encapsulate DOX and successfully deliver it inside cancer cells. Hopefully, using nanomaterials for DOX delivery, it will be possible to overcome the side effects which are frequently associated to this antitumor drug.

2018-07-05Doctoral thesis

Open access