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- Amphiphilic polymer-mediated formation of laponite-based nanohybrids with robust stability and pH sensitivity for anticancer drug deliveryPublication . Wang, Guoying; Maciel, Dina; Wu, Yilun; Rodrigues, João; Shi, Xiangyang; Yuan, Yuan; Liu, Changsheng; Tomás, Helena; Li, YulinThe development of pH-sensitive drug delivery nanosystems that present a low drug release at the physiological pH and are able to increase the extent of the release at a lower pH value (like those existent in the interstitial space of solid tumors (pH 6.5) and in the intracellular endolysosomal compartments (pH 5.0)) is very important for an efficient and safe cancer therapy. Laponite (LP) is a synthetic silicate nanoparticle with a nanodisk structure (25 nm in diameter and 0.92 nm in thickness) and negative-charged surface, which can be used for the encapsulation of doxorubicin (DOX, a cationic drug) through electrostatic interactions and exhibit good pH sensitivity in drug delivery. However, the colloidal instability of LP still limits its potential clinical applications. In this study, we demonstrate an elegant strategy to develop stable Laponite-based nanohybrids through the functionalization of its surface with an amphiphile PEG-PLA copolymer by a self-assembly process. The hydrophobic block of PEG-PLA acts as an anchor that binds to the surface of drug-loaded LP nanodisks, maintaining the core structure, whereas the hydrophilic PEG part serves as a protective stealth shell that improves the whole stability of the nanohybrids under physiological conditions. The resulting nanocarriers can effectively load the DOX drug (the encapsulation efficiency is 85%), and display a pH-enhanced drug release behavior in a sustained way. In vitro biological evaluation indicated that the DOX-loaded nanocarriers can be effectively internalized by CAL-72 cells (an osteosarcoma cell line), and exhibit a remarkable higher anticancer cytotoxicity than free DOX. The merits of Laponite/PEG-PLA nanohybrids, such as good cytocompatibility, excellent physiological stability, sustained pH-responsive release properties, and improved anticancer activity, make them a promising platform for the delivery of other therapeutic agents beyond DOX.
- Antitumor efficacy of doxorubicin-loaded laponite/alginate hybrid hydrogelsPublication . Gonçalves, Mara; Figueira, Priscilla; Maciel, Dina; Rodrigues, João; Shi, Xiangyang; Tomás, Helena; Li, YulinDegradable hybrid hydrogels with improved stability are prepared by incorporating nanodisks of biocompatible laponite (LP) in alginate (AG) hydrogels using Ca2+ as a crosslinker. The Dox‐loaded hybrid hydrogels give a controlled Dox release at physiological environment in a sustained manner. Under conditions that mimic the tumor environment, both the sustainability in the Dox release (up to 17 d) and the release efficiency from LP/AG‐Dox hydrogels are improved. The in situ degradation of these hybrid hydrogels gives rise to nanohybrids that might serve as vehicles for carrying Dox through the cell membrane and diminish the effect of Dox ion‐trapping in the acidic extracellular environment of the tumor and/or in the endo‐lysosomal cell compartments.
- pH sensitive Laponite/alginate hybrid hydrogels: swelling behaviour and release mechanismPublication . Li, Yulin; Maciel, Dina; Tomás, Helena; Rodrigues, João; Ma, Hui; Shi, Xiangyang
- Thermo/redox/pH-triple sensitive poly(N-isopropylacrylamide-co-acrylic acid) nanogels for anticancer drug deliveryPublication . Zhan, Yuan; Gonçalves, Mara; Yi, Panpan; Capelo, Débora; Zhang, Yuhong; Rodrigues, João; Liu, Changsheng; Tomás, Helena; Li, Yulin; He, PeixinThe clinical application of doxorubicin (DOX), like other anticancer drugs, is limited by insufficient cellular uptake and the numerous drug resistance mechanisms existing in cells. The development of smart nanomaterials capable of carrying the drugs into the cells and of releasing them under the control of the microenvironment is an interesting approach that may increase the success of the anticancer drugs currently in use. Herein, we report an easy process to prepare biocompatible nanogels (NGs) with thermo/ redox/pH-triple sensitivity, which are highly effective in the intracellular delivery of DOX. Redox-sensitive/ degradable NGs (PNA-BAC) and nondegradable NGs (PNA-MBA) were prepared through in situ polymerization of N-isopropylacrylamide (NIPAM) and acrylic acid (AA) in the presence of sodium dodecyl sulfate (SDS) as a surfactant, using N,N0-bis(acryloyl)cystamine (BAC) as a biodegradable crosslinker or N,N0-methylene bisacrylamide (MBA) as a nondegradable crosslinker, respectively. After that, the cationic DOX drug was loaded into the NGs through electrostatic interactions, by simply mixing them in aqueous solution. Compared to nondegradable PNA-MBA NGs, PNA-BAC NGs not only presented a higher DOX drug loading capacity, but also allowed a more sustainable drug release behavior under physiological conditions. More importantly, PNA-BAC NGs displayed thermo-induced drug release properties and an in vitro accelerated release of DOX under conditions that mimic intracellular reductive conditions and acidic tumor microenvironments. The thermo/redox/pH multi-sensitive NGs can quickly be taken up by CAL-72 cells (an osteosarcoma cell line), resulting in a high DOX intracellular accumulation and an improved cytotoxicity when compared with free DOX and DOX-loaded nondegradable PNA-MBA NGs. The developed NGs can be possibly used as an effective platform for the delivery of cationic therapeutic agents for biomedical applications.
- Insight into the role of N,N-dimethylaminoethyl methacrylate (DMAEMA) conjugation onto poly(ethylenimine): cell viability and gene transfection studiesPublication . Nouri, Alireza; Castro, Rita; Kairys, Visvaldas; Santos, José L.; Rodrigues, João; Li, Yulin; Tomás, HelenaIn the present study, the effect of N,N-dimethylaminoethyl methacrylate (DMAEMA) conjugation onto branched poly(ethylenimine) (PEI) with different grafting degree was examined for gene delivery applications. The DMAEMA-grafted-PEI conjugates were characterized and complexed with plasmid DNA (pDNA) at various concentrations, and the physicochemical properties, cell viability, and in vitro transfection efficiency of the complexes were evaluated in HEK 293T cells. Computational techniques were used to analyze the interaction energies and possible binding modes between DNA and conjugates at different grafting degrees. The cytotoxicity analysis and in vitro transfection efficiency of the conjugate/pDNA complexes exhibited a beneficial effect of DMAEMA conjugation when compared to PEI alone. The computational results revealed that the DNA/vector interaction energy decreases with increasing grafting degree, which can be associated to an enhanced release of the pDNA from the carrier once inside cells. The results indicate the significance of DMAEMA conjugation onto PEI as a promising approach for gene delivery applications.
- pH-sensitive Laponite®/doxorubicin/alginate nanohybrids with improved anticancer efficacyPublication . Gonçalves, Mara; Figueira, Priscilla; Maciel, Dina; Rodrigues, João; Qu, Xue; Liu, Changsheng; Tomás, Helena; Li, YulinThe 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.
- Injectable and biodegradable hydrogels: gelation, biodegradation and biomedical applicationsPublication . Li, Yulin; Rodrigues, João; Tomás, HelenaInjectable hydrogels with biodegradability have in situ formability which in vitro/in vivo allows an effective and homogeneous encapsulation of drugs/cells, and convenient in vivo surgical operation in a minimally invasive way, causing smaller scar size and less pain for patients. Therefore, they have found a variety of biomedical applications, such as drug delivery, cell encapsulation, and tissue engineering. This critical review systematically summarizes the recent progresses on biodegradable and injectable hydrogels fabricated from natural polymers (chitosan, hyaluronic acid, alginates, gelatin, heparin, chondroitin sulfate, etc.) and biodegradable synthetic polymers (polypeptides, polyesters, polyphosphazenes, etc.). The review includes the novel naturally based hydrogels with high potential for biomedical applications developed in the past five years which integrate the excellent biocompatibility of natural polymers/synthetic polypeptides with structural controllability via chemical modification. The gelation and biodegradation which are two key factors to affect the cell fate or drug delivery are highlighted. A brief outlook on the future of injectable and biodegradable hydrogels is also presented (326 references).
- Redox-responsive alginate nanogels with enhanced anticancer cytotoxicityPublication . Maciel, Dina; Figueira, Priscilla; Xiao, Shili; Hu, Dengmai; Shi, Xiangyang; Rodrigues, João; Tomás, Helena; Li, YulinAlthough doxorubicin (Dox) has been widely used in the treatment of different types of cancer, its insufficient cellular uptake and intracellular release is still a limitation. Herein, we report an easy process for the preparation of redox-sensitive nanogels that were shown to be highly efficient in the intracellular delivery of Dox. The nanogels (AG/Cys) were obtained through in situ cross-linking of alginate (AG) using cystamine (Cys) as a cross-linker via a miniemulsion method. Dox was loaded into the AG/Cys nanogels by simply mixing it in aqueous solution with the nanogels, that is, by the establishment of electrostatic interactions between the anionic AG and the cationic Dox. The results demonstrated that the AG/Cys nanogels are cytocompatible, have a high drug encapsulation efficiency (95.2 ± 4.7%), show an in vitro accelerated release of Dox in conditions that mimic the intracellular reductive conditions, and can quickly be taken up by CAL-72 cells (an osteosarcoma cell line), resulting in higher Dox intracellular accumulation and a remarkable cell death extension when compared with free Dox. The developed nanogels can be used as a tool to overcome the problem of Dox resistance in anticancer treatments and possibly be used for the delivery of other cationic drugs in applications beyond cancer.
- Antitumor efficacy of doxorubicin encapsulated within PEGylated poly(amidoamine) dendrimersPublication . Liao, Huihui; Liu, Hui; Li, Yulin; Zhang, Mengen; Tomás, Helena; Shen, Mingwu; Shi, XiangyangWe report here a general approach to using poly(amidoamine) (PAMAM) dendrimers modified with polyethylene glycol (PEG) as a platform to encapsulate an anticancer drug doxorubicin (DOX) for in vitro cancer therapy applications. In this approach, PEGylated PAMAM dendrimers were synthesized by conjugating monomethoxypolyethylene glycol with carboxylic acid end group (mPEG-COOH) onto the surface of generation 5 amine-terminated PAMAM dendrimer (G5.NH2), followed by acetylation of the remaining dendrimer terminal amines. By varying the molar ratios of mPEG-COOH/G5.NH2, G5.NHAc-mPEGn (n55, 10, 20, and 40, respectively) with different PEGylation degrees were obtained. We show that the PEGylated dendrimers are able to encapsulate DOX with approximately similar loading capacity regardless of the PEGylation degree. The formed dendrimer/DOX complexes are water soluble and stable. In vitro release studies show that DOX complexed with the PEGylated dendrimers can be released in a sustained manner. Further cell viability assay in conjunction with cell morphology observation demonstrates that the G5.NHAc-mPEGn/DOX complexes display effective antitumor activity, and the DOX molecules encapsulated within complexes can be internalized into the cell nucleus, similar to the free DOX drug. Findings from this study suggest that PEGylated dendrimers may be used as a general drug carrier to encapsulate various hydrophobic drugs for different therapeutic applications.
- Dendrimer-assisted formation of fluorescent nanogels for drug delivery and intracellular imagingPublication . Gonçalves, Mara; Maciel, Dina; Capelo, Débora; Xiao, Shili; Sun, Wenjie; Shi, Xiangyang; Rodrigues, João; Tomás, Helena; Li, YulinAlthough, in general, nanogels present a good biocompatibility and are able to mimic biological tissues, their unstability and uncontrollable release properties still limit their biomedical applications. In this study, a simple approach was used to develop dual-cross-linked dendrimer/alginate nanogels (AG/G5), using CaCl2 as cross-linker and amine-terminated generation 5 dendrimer (G5) as a cocrosslinker, through an emulsion method. Via their strong electrostatic interactions with anionic AG, together with cross-linker Ca(2+), G5 dendrimers can be used to mediate the formation of more compact structural nanogels with smaller size (433 ± 17 nm) than that (873 ± 116 nm) of the Ca(2+)-cross-linked AG nanogels in the absence of G5. Under physiological (pH 7.4) and acidic (pH 5.5) conditions, the sizes of Ca(2+)-cross-linked AG nanogels gradually decrease probably because of their degradation, while dual-cross-linked AG/G5 nanogels maintain a relatively more stable structure. Furthermore, the AG/G5 nanogels effectively encapsulate the anticancer drug doxorubicin (Dox) with a loading capacity 3 times higher than that of AG nanogels. The AG/G5 nanogels were able to release Dox in a sustained way, avoiding the burst release observed for AG nanogels. In vitro studies show that the AG/G5-Dox NGs were effectively taken up by CAL-72 cells (a human osteosarcoma cell line) and maintain the anticancer cytotoxicity levels of free Dox. Interestingly, G5 labeled with a fluorescent marker can be integrated into the nanogels and be used to track the nanogels inside cells by fluorescence microscopy. These findings demonstrate that AG/G5 nanogels may serve as a general platform for therapeutic delivery and/or cell imaging.