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21 pages, 5072 KiB

Open AccessArticle

Folic Acid-Decorated β-Cyclodextrin-Based Poly(ε-caprolactone)-dextran Star Polymer with Disulfide Bond-Linker as Theranostic Nanoparticle for Tumor-Targeted MRI and Chemotherapy

by Huikang Yang, Nianhua Wang, Ruimeng Yang, Liming Zhang and Xinqing Jiang

Pharmaceutics 2022, 14(1), 52; https://doi.org/10.3390/pharmaceutics14010052 - 27 Dec 2021

Cited by 16 | Viewed by 3104

Abstract

β-cyclodextrin(βCD)-based star polymers have attracted much interest because of their unique structures and potential biomedical and biological applications. Herein, a well-defined folic acid (FA)-conjugated and disulfide bond-linked star polymer ((FA-Dex-SS)-βCD-(PCL)₁₄) was synthesized via a couple reaction [...] Read more.

β-cyclodextrin(βCD)-based star polymers have attracted much interest because of their unique structures and potential biomedical and biological applications. Herein, a well-defined folic acid (FA)-conjugated and disulfide bond-linked star polymer ((FA-Dex-SS)-βCD-(PCL)₁₄) was synthesized via a couple reaction between βCD-based 14 arms poly(ε-caprolactone) (βCD-(PCL)₁₄) and disulfide-containing α-alkyne dextran (alkyne-SS-Dex), and acted as theranostic nanoparticles for tumor-targeted MRI and chemotherapy. Theranostic nanoparticles were obtained by loading doxorubicin (DOX), and superparamagnetic iron oxide (SPIO) particles were loaded into the star polymer nanoparticles to obtain ((FA-Dex-SS)-βCD-(PCL)₁₄@DOX-SPIO) theranostic nanoparticles. In vitro drug release studies showed that approximately 100% of the DOX was released from disulfide bond-linked theranostic nanoparticles within 24 h under a reducing environment in the presence of 10.0 mM GSH. DOX and SPIO could be delivered into HepG2 cells efficiently, owing to the folate receptor-mediated endocytosis process of the nanoparticles and glutathione (GSH), which triggered disulfide-bonds cleaving. Moreover, (FA-Dex-SS)-βCD-(PCL)₁₄@DOX-SPIO showed strong MRI contrast enhancement properties. In conclusion, folic acid-decorated reduction-sensitive star polymeric nanoparticles are a potential theranostic nanoparticle candidate for tumor-targeted MRI and chemotherapy. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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17 pages, 5427 KiB

Open AccessArticle

A Melanin-like Nanoenzyme for Acute Lung Injury Therapy via Suppressing Oxidative and Endoplasmic Reticulum Stress Response

by Xue-Fang Lou, Chen Wang, Ju-Cong Zhang, Yong-Zhong Du and Xiao-Ling Xu

Pharmaceutics 2021, 13(11), 1850; https://doi.org/10.3390/pharmaceutics13111850 - 03 Nov 2021

Cited by 6 | Viewed by 2125

Abstract

Nanoenzyme-mediated catalytic activity is emerging as a novel strategy for reactive oxygen species (ROS) scavenging in acute lung injury (ALI) treatment. However, one of the main hurdles for these metal-containing nanoenzymes is their potential toxicity and single therapeutic mechanism. Herein, we uncovered a [...] Read more.

Nanoenzyme-mediated catalytic activity is emerging as a novel strategy for reactive oxygen species (ROS) scavenging in acute lung injury (ALI) treatment. However, one of the main hurdles for these metal-containing nanoenzymes is their potential toxicity and single therapeutic mechanism. Herein, we uncovered a melanin-like nanoparticles derived from the self-polymerization of 1,8-dihydroxynaphthalene (PDH nanoparticles), showing a significant anti-inflammation therapeutic effect on ALI mice. The prepared PDH nanoparticles rich in phenol groups could not only act as radical scavengers to alleviate oxidative stress but could also chelate calcium overload to suppress the endoplasmic reticulum stress response. As revealed by the therapeutic effect in vivo, PDH nanoparticles significantly prohibited neutrophil infiltration and the secretion of proinflammatory cytokines (TNF-α and IL-6), thus improving the inflammatory cascade in the ALI model. Above all, our work provides an effective anti-inflammatory nanoplatform by using the inherent capability of melanin-like nanoenzymes, proposing the potential application prospects of these melanin-like nanoparticles for acute inflammation-induced injury treatment. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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21 pages, 37112 KiB

Open AccessArticle

Enhancement of Skin Delivery of Drugs Using Proposome Depends on Drug Lipophilicity

by Himanshu Kathuria, Harish K. Handral, Saera Cha, Diep T. P. Nguyen, Junyu Cai, Tong Cao, Chunyong Wu and Lifeng Kang

Pharmaceutics 2021, 13(9), 1457; https://doi.org/10.3390/pharmaceutics13091457 - 13 Sep 2021

Cited by 12 | Viewed by 3671

Abstract

The study aims to investigate the propylene glycol-based liposomes named ‘proposomes’ in enhancing skin permeation of drugs with different physicochemical properties. Ibuprofen, tofacitinib citrate, rhodamine B, and lidocaine were loaded into proposomes. These drug formulations were analyzed for particle size, zeta potential, polydispersity [...] Read more.

The study aims to investigate the propylene glycol-based liposomes named ‘proposomes’ in enhancing skin permeation of drugs with different physicochemical properties. Ibuprofen, tofacitinib citrate, rhodamine B, and lidocaine were loaded into proposomes. These drug formulations were analyzed for particle size, zeta potential, polydispersity index, entrapment efficiency, and in vitro skin permeation. The confocal laser scanning microscopy was performed on skin treated with calcein and rhodamine B laden proposomes. The transdermal delivery relative to physicochemical properties of drugs such as logP, melting point, molecular weight, solubility, etc., were analyzed. We tested the safety of the proposomes using reconstructed human skin tissue equivalents, which were fabricated in-house. We also used human cadaver skin samples as a control. The proposomes had an average diameter of 128 to 148 nm. The drug’s entrapment efficiencies were in the range of 42.9–52.7%, translating into the significant enhancement of drug permeation through the skin. The enhancement ratio was 1.4 to 4.0, and linearly correlated to logP, molecular weight, and melting point. Confocal imaging also showed higher skin permeation of calcein and rhodamine B in proposome than in solution. The proposome was found safe for skin application. The enhancement of skin delivery of drugs through proposomes was dependent on the lipophilicity of the drug. The entrapment efficiency was positively correlated with logP of the drug, which led to high drug absorption. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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23 pages, 6552 KiB

Open AccessArticle

Co-Delivery of Curcumin and Bioperine via PLGA Nanoparticles to Prevent Atherosclerotic Foam Cell Formation

by Sindhu C. Pillai, Ankita Borah, Minh Nguyen Tuyet Le, Hiroaki Kawano, Kouichi Hasegawa and D. Sakthi Kumar

Pharmaceutics 2021, 13(9), 1420; https://doi.org/10.3390/pharmaceutics13091420 - 08 Sep 2021

Cited by 18 | Viewed by 2961

Abstract

Cholesterol-rich arterial plaques characterize atherosclerosis, a significant cause of heart disease. Nutraceuticals have received attention over the years, demonstrating potential benefits towards treating and preventing cardiovascular diseases (CVD), including atherosclerosis. Curcumin, a potent polyphenol present in Curcuma longa, has shown remarkable anti-atherosclerotic [...] Read more.

Cholesterol-rich arterial plaques characterize atherosclerosis, a significant cause of heart disease. Nutraceuticals have received attention over the years, demonstrating potential benefits towards treating and preventing cardiovascular diseases (CVD), including atherosclerosis. Curcumin, a potent polyphenol present in Curcuma longa, has shown remarkable anti-atherosclerotic activity via anti-inflammatory and anti-oxidative properties. The bioavailability and low water solubility of curcumin limit its clinical translational purposes. These issues can be circumvented effectively by nano-drug delivery systems that can target atherosclerotic plaque sites. In this work, we chose to use curcumin and a natural bioenhancer called Bioperine (derived from Piper nigrum) inside a polymeric nano-drug delivery system for targeting atherosclerotic plaque sites. We selected two different ratios of curcumin:Bioperine to study its comparative effect on the inhibition of oxidized low-density lipoprotein (Ox-LDL)-induced foam cell formation. Our studies demonstrated that Cur-Bio PLGA NPs (both ratios) maintained the cell viability in THP-1 monocyte-derived macrophages above 80% at all periods. The 1:0.2:10 ratio of Cur-Bio PLGA NPs at a concentration of 250 μg/mL illustrated an enhanced reduction in the relative cholesterol content in the THP-1-derived foam cells compared to the 1:1:10 ratio. Confocal microscopy analysis also revealed a reduction in macrophage-mediated foam cell formation when administered with both the ratios of Cur-Bio PLGA NPs. Relative fold change in the mRNA expression of the genes involved in the inflammatory pathways in the atherosclerotic process downregulated NF-κB, CCL2/MCP-1, CD-36, and STAT-3 activity while upregulating the SCAR-B1 expression when treated with the Cur-Bio PLGA NPs. This study thus highlights the importance of natural-based compounds towards the therapeutic intervention against atherosclerotic activity when administered as preventive medicine. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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17 pages, 4957 KiB

Open AccessArticle

Targeted Photodynamic Therapy Using Alloyed Nanoparticle-Conjugated 5-Aminolevulinic Acid for Breast Cancer

by Hanieh Montaseri, Cherie Ann Kruger and Heidi Abrahamse

Pharmaceutics 2021, 13(9), 1375; https://doi.org/10.3390/pharmaceutics13091375 - 31 Aug 2021

Cited by 15 | Viewed by 2868

Abstract

Photodynamic therapy (PDT) has been investigated as an effective, non-invasive, and alternative tumor-ablative therapy that uses photosensitizers (PSs) and safe irradiation light in the presence of oxygen to generate reactive oxygen species (ROS) to kill malignant cancer cells. However, the off-target activation of [...] Read more.

Photodynamic therapy (PDT) has been investigated as an effective, non-invasive, and alternative tumor-ablative therapy that uses photosensitizers (PSs) and safe irradiation light in the presence of oxygen to generate reactive oxygen species (ROS) to kill malignant cancer cells. However, the off-target activation of the PSs can hinder effective PDT. Therefore, an advanced drug delivery system is required to selectively deliver the PS to the therapeutic region only and reduce off-target side effects in cancer treatment. The integration of laser-initiated PDT with nanotechnology has provided new opportunities in cancer therapy. In this study, plasmonic bimetallic nanoparticles (NPs) were prepared for the targeted PDT (TPDT) of in vitro cultured MCF-7 breast cancer cells. The NPs were functionalized with PEG through Au–thiol linkage to enhance their biocompatibility and subsequently attached to the PS precursor 5-aminolevulinic acid via electrostatic interactions. In order to enhance specific targeting, anti-HER-2 antibodies (Ab) were decorated onto the surface of the nanoconjugate (NC) to fabricate a 5-ALA/Au–Ag-PEG-Ab NC. In vitro studies showed that the synthesized NC can enter MCF-7 cells and localize in the cytoplasm to metabolize 5-ALA to protoporphyrin IX (PpIX). Upon light irradiation, PpIX can efficiently produce ROS for the PDT treatment of MCF-7. Cellular viability studies showed a decrease from 49.8% ± 5.6 ** to 13.8% ± 2.0 *** for free 5-ALA versus the NC, respectively, under equivalent concentrations of the PS (0.5 mM, IC50). These results suggest that the active targeted NC platform has an improved PDT effect on MCF-7 breast cancer cells. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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20 pages, 3238 KiB

Open AccessArticle

An Iron Shield to Protect Epigallocatehin-3-Gallate from Degradation: Multifunctional Self-Assembled Iron Oxide Nanocarrier Enhances Protein Kinase CK2 Intracellular Targeting and Inhibition

by Luca Fasolato, Massimiliano Magro, Giorgio Cozza, Ferruccio Sbarra, Simone Molinari, Enrico Novelli, Fabio Vianello and Andrea Venerando

Pharmaceutics 2021, 13(8), 1266; https://doi.org/10.3390/pharmaceutics13081266 - 16 Aug 2021

Cited by 4 | Viewed by 2652

Abstract

Protein kinase CK2 is largely involved in cell proliferation and apoptosis and is generally recognized as an Achilles’ heel of cancer, being overexpressed in several malignancies. The beneficial effects of (−)-epigallocatechin-3-gallate (EGCG) in the prevention and treatment of several diseases, including cancer, have [...] Read more.

Protein kinase CK2 is largely involved in cell proliferation and apoptosis and is generally recognized as an Achilles’ heel of cancer, being overexpressed in several malignancies. The beneficial effects of (−)-epigallocatechin-3-gallate (EGCG) in the prevention and treatment of several diseases, including cancer, have been widely reported. However, poor stability and limited bioavailability hinder the development of EGCG as an effective therapeutic agent. The combination of innovative nanomaterials and bioactive compounds into nanoparticle-based systems demonstrates the synergistic advantages of nanocomplexes as compared to the individual components. In the present study, we developed a self-assembled core-shell nanohybrid (SAMN@EGCG) combining EGCG and intrinsic dual-signal iron oxide nanoparticles (Surface Active Maghemite Nanoparticles). Interestingly, nano-immobilization on SAMNs protects EGCG from degradation, preventing its auto-oxidation. Most importantly, the nanohybrid was able to successfully deliver EGCG into cancer cells, displaying impressive protein kinase CK2 inhibition comparable to that obtained with the most specific CK2 inhibitor, CX-4945 (5.5 vs. 3 µM), thus promoting the phytochemical exploitation as a valuable alternative for cancer therapy. Finally, to assess the advantages offered by nano-immobilization, we tested SAMN@EGCG against Pseudomonas aeruginosa, a Gram-negative bacterium involved in severe lung infections. An improved antimicrobial effect with a drastic drop of MIC from 500 to 32.7 μM was shown. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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19 pages, 3030 KiB

Open AccessArticle

Development of Tailor-Made Dendrimer Ternary Complexes for Drug/Gene Co-Delivery in Cancer

by Ana Raquel Neves, Tânia Albuquerque, Rúben Faria, Milan Paul, Swati Biswas, Ângela Sousa and Diana Costa

Pharmaceutics 2021, 13(8), 1256; https://doi.org/10.3390/pharmaceutics13081256 - 13 Aug 2021

Cited by 5 | Viewed by 2166

Abstract

Cancer gene therapy, mediated by non-viral systems, remains a major research focus. To contribute to this field, in this work we reported on the development of dendrimer drug/gene ternary complexes. This innovative approach explored the great capacity of both polyamidoamine (PAMAM)-paclitaxel (PTX) conjugate [...] Read more.

Cancer gene therapy, mediated by non-viral systems, remains a major research focus. To contribute to this field, in this work we reported on the development of dendrimer drug/gene ternary complexes. This innovative approach explored the great capacity of both polyamidoamine (PAMAM)-paclitaxel (PTX) conjugate and polyethylenimine (PEI) polymers to complex a p53-encoding plasmid DNA (pDNA), highlighting the utility of considering two compacting agents. The pDNA complexation capacity has been investigated as function of the nitrogen to phosphate groups ratio (N/P), which revealed to be a tailoring parameter. The physicochemical properties of the conceived ternary complexes were revealed and were found to be promising for cellular transfection. Furthermore, the formulated co-delivery systems demonstrated to be biocompatible. The ternary systems were able of cellular internalization and payload intracellular release. Confocal microscopy studies showed the co-localization of stained pDNA with the nucleus of cancer cells, after transfection mediated by these carriers. From this achievement, p53 gene expression occurred with the production of protein. Moreover, the activation of caspase-3 indicated apoptosis of cancer cells. This work represents a great progress on the design of dendrimer drug/gene co-delivery systems towards a more efficient cancer therapy. In this way, it instigates further in vitro studies concerning the evaluation of their therapeutic potential, expectedly supported by the synergistic effect, in tumoral cells. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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27 pages, 5688 KiB

Open AccessArticle

Magnetoliposomes Based on Shape Anisotropic Calcium/Magnesium Ferrite Nanoparticles as Nanocarriers for Doxorubicin

by Beatriz D. Cardoso, Ana Rita O. Rodrigues, Manuel Bañobre-López, Bernardo G. Almeida, Carlos O. Amorim, Vítor S. Amaral, Paulo J. G. Coutinho and Elisabete M. S. Castanheira

Pharmaceutics 2021, 13(8), 1248; https://doi.org/10.3390/pharmaceutics13081248 - 12 Aug 2021

Cited by 15 | Viewed by 3187

Abstract

Multifunctional lipid nanocarriers are a promising therapeutic approach for controlled drug release in cancer therapy. Combining the widely used liposome structure with magnetic nanoparticles in magnetoliposomes allies, the advantages of using liposomes include the possibility to magnetically guide, selectively accumulate, and magnetically control [...] Read more.

Multifunctional lipid nanocarriers are a promising therapeutic approach for controlled drug release in cancer therapy. Combining the widely used liposome structure with magnetic nanoparticles in magnetoliposomes allies, the advantages of using liposomes include the possibility to magnetically guide, selectively accumulate, and magnetically control the release of drugs on target. The effectiveness of these nanosystems is intrinsically related to the individual characteristics of the two main components—lipid formulation and magnetic nanoparticles—and their physicochemical combination. Herein, shape-anisotropic calcium-substituted magnesium ferrite nanoparticles (Ca_0.25Mg_0.75Fe₂O₄) were prepared for the first time, improving the magnetic properties of spherical counterparts. The nanoparticles revealed a superparamagnetic behavior, high saturation magnetization (50.07 emu/g at 300 K), and a large heating capacity. Furthermore, a new method for the synthesis of solid magnetoliposomes (SMLs) was developed to enhance their magnetic response. The manufacturing technicalities were optimized with different lipid compositions (DPPC, DPPC/Ch, and DPPC/DSPE-PEG) originating nanosystems with optimal sizes for biomedical applications (around or below 150 nm) and low polydispersity index. The high encapsulation efficiency of doxorubicin in these magnetoliposomes was proven, as well as the ability of the drug-loaded nanosystems to interact with cell membrane models and release DOX by fusion. SMLs revealed to reduce doxorubicin interaction with human serum albumin, contributing to a prolonged bioavailability of the drug upon systemic administration. Finally, the drug release kinetic assays revealed a preferable DOX release at hyperthermia temperatures (42 °C) and acidic conditions (pH = 5.5), indicating them as promising controlled release nanocarriers by either internal (pH) and external (alternate magnetic field) stimuli in cancer therapy. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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22 pages, 3660 KiB

Open AccessArticle

A Tri-Stimuli Responsive (Maghemite/PLGA)/Chitosan Nanostructure with Promising Applications in Lung Cancer

by Fátima Fernández-Álvarez, Gracia García-García and José L. Arias

Pharmaceutics 2021, 13(8), 1232; https://doi.org/10.3390/pharmaceutics13081232 - 10 Aug 2021

Cited by 10 | Viewed by 2909

Abstract

A (core/shell)/shell nanostructure (production performance ≈ 50%, mean diameter ≈ 330 nm) was built using maghemite, PLGA, and chitosan. An extensive characterization proved the complete inclusion of the maghemite nuclei into the PLGA matrix (by nanoprecipitation solvent evaporation) and the disposition of the [...] Read more.

A (core/shell)/shell nanostructure (production performance ≈ 50%, mean diameter ≈ 330 nm) was built using maghemite, PLGA, and chitosan. An extensive characterization proved the complete inclusion of the maghemite nuclei into the PLGA matrix (by nanoprecipitation solvent evaporation) and the disposition of the chitosan shell onto the nanocomposite (by coacervation). Short-term stability and the adequate magnetism of the nanocomposites were demonstrated by size and electrokinetic determinations, and by defining the first magnetization curve and the responsiveness of the colloid to a permanent magnet, respectively. Safety of the nanoparticles was postulated when considering the results from blood compatibility studies, and toxicity assays against human colonic CCD-18 fibroblasts and colon carcinoma T-84 cells. Cisplatin incorporation to the PLGA matrix generated appropriate loading values (≈15%), and a dual pH- and heat (hyperthermia)-responsive drug release behaviour (≈4.7-fold faster release at pH 5.0 and 45 °C compared to pH 7.4 and 37 °C). The half maximal inhibitory concentration of the cisplatin-loaded nanoparticles against human lung adenocarcinoma A-549 cells was ≈1.6-fold less than that of the free chemotherapeutic. Such a biocompatible and tri-stimuli responsive (maghemite/PLGA)/chitosan nanostructure may found a promising use for the effective treatment of lung cancer. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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11 pages, 3057 KiB

Open AccessArticle

Aptamers with Self-Loading Drug Payload and pH-Controlled Drug Release for Targeted Chemotherapy

by Zihua Zeng, Jianjun Qi, Quanyuan Wan and Youli Zu

Pharmaceutics 2021, 13(8), 1221; https://doi.org/10.3390/pharmaceutics13081221 - 07 Aug 2021

Cited by 10 | Viewed by 2426

Abstract

Doxorubicin (DOX) is a common anti-tumor drug that binds to DNA or RNA via non-covalent intercalation between G-C sequences. As a therapeutic agent, DOX has been used to form aptamer–drug conjugates for targeted cancer therapy in vitro and in vivo. To improve the [...] Read more.

Doxorubicin (DOX) is a common anti-tumor drug that binds to DNA or RNA via non-covalent intercalation between G-C sequences. As a therapeutic agent, DOX has been used to form aptamer–drug conjugates for targeted cancer therapy in vitro and in vivo. To improve the therapeutic potential of aptamer–DOX conjugates, we synthesized trifurcated Newkome-type monomer (TNM) structures with three DOX molecules bound through pH-sensitive hydrazone bonds to formulate TNM-DOX. The aptamer–TNM–DOX conjugate (Apt–TNM-DOX) was produced through a simple self-loading process. Chemical validation revealed that Apt–TNM-DOX stably carried high drug payloads of 15 DOX molecules per aptamer sequence. Functional characterization showed that DOX payload release from Apt–TNM-DOX was pH-dependent and occurred at pH 5.0, which reflects the microenvironment of tumor cell lysosomes. Further, Apt–TNM-DOX specifically targeted lymphoma cells without affecting off-target control cells. Aptamer-mediated cell binding resulted in the uptake of Apt–TNM-DOX into targeted cells and the release of DOX payload within cell lysosomes to inhibit growth of targeted lymphoma cells. The Apt–TNM-DOX provides a simple, non-toxic approach to develop aptamer-based targeted therapeutics and may reduce the non-specific side effects associated with traditional chemotherapy. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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21 pages, 4959 KiB

Open AccessArticle

Multifunctional Lipid-Based Nanoparticles for Codelivery of Anticancer Drugs and siRNA for Treatment of Non-Small Cell Lung Cancer with Different Level of Resistance and EGFR Mutations

by Joydeb Majumder and Tamara Minko

Pharmaceutics 2021, 13(7), 1063; https://doi.org/10.3390/pharmaceutics13071063 - 11 Jul 2021

Cited by 27 | Viewed by 3757

Abstract

Resistance to chemotherapy, enhanced proliferation, invasion, angiogenesis, and metastasis (RPIAM) represent major obstacles that limit the efficacy of cancer treatment especially in advanced stages of cancer. Overcoming or suppressing RPIAM can dramatically improve the treatment outcome. Non-small cell lung cancer (NSCLC) is frequently [...] Read more.

Resistance to chemotherapy, enhanced proliferation, invasion, angiogenesis, and metastasis (RPIAM) represent major obstacles that limit the efficacy of cancer treatment especially in advanced stages of cancer. Overcoming or suppressing RPIAM can dramatically improve the treatment outcome. Non-small cell lung cancer (NSCLC) is frequently diagnosed in an advanced stage and often possesses intrinsic resistance to chemotherapy accompanied by the fast development of acquired resistance during the treatment. Oncogenic receptor tyrosine kinases (TKs), specifically epidermal growth factor (EGF) TKs, play an important role in the activation of MAPK/PI3K/Akt/STAT pathways, finally leading to the development of RPIAM. However, the suppression of EGF-TK by different drugs is limited by various defensive mechanisms and mutations. In order to effectively prevent the development of RPIAM in NSCLC, we formulated and tested a multicomponent and multifunctional cancer targeted delivery system containing Nanostructured Lipid Carriers (NLCs) as vehicles, luteinizing hormone release hormone (LHRH) as a cancer targeting moiety, EFG-TK inhibitor gefitinib and/or paclitaxel as anticancer drug(s), siRNA targeted to EGF receptor (EGFR) mRNA as a suppressor of EGF receptors, and an imaging agent (rhodamine) for the visualization of cancer cells. Experimental data obtained show that this complex delivery system possesses significantly enhanced anticancer activity that cannot be achieved by individual components applied separately. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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14 pages, 2715 KiB

Open AccessArticle

Fabrication of Capsaicin Loaded Nanocrystals: Physical Characterizations and In Vivo Evaluation

by Barkat Ali Khan, Furqan Rashid, Muhammad Khalid Khan, Saad Saeed Alqahtani, Muhammad Hadi Sultan and Yosif Almoshari

Pharmaceutics 2021, 13(6), 841; https://doi.org/10.3390/pharmaceutics13060841 - 07 Jun 2021

Cited by 16 | Viewed by 3100

Abstract

Nano-crystallization is a new emerging strategy to promote the saturation solubility, dissolution rate and subsequent bioavailability of Biopharmaceutical Class II drugs. Capsaicin belongs to BCS class-II drugs having low water solubility and dissolution rate. Nano-crystals (NC) of pure Capsaicin was developed and optimized [...] Read more.

Nano-crystallization is a new emerging strategy to promote the saturation solubility, dissolution rate and subsequent bioavailability of Biopharmaceutical Class II drugs. Capsaicin belongs to BCS class-II drugs having low water solubility and dissolution rate. Nano-crystals (NC) of pure Capsaicin was developed and optimized in order to increase its water solubility, dissolution and further to promote its adhesiveness to skin epidermis layer. NC formulations were subjected to stability studies, droplet size, surface charge, poly-dispensability index, drug content, entrapment efficiency, thermal analysis, surface morphology, crystalline studies, solubility profile, in vitro release and ex vivo permeation studies. In vivo anti-inflammatory assay (Carrageenan-induced paw edema) was performed in Sprague Dawley rats. Nanocrystals loaded with capsaicin showed particle size 120 ± 3.0 nm with surface charge of −20.7 ± 3.5 and PDI was 0.48 ± 1.5. Drug content and entrapment efficiency of T3 was 85% and 90 ± 1.9% respectively. Thermal studies predicted that melting peak of capsaicin was present in the formulation suggested that there was no interaction between active moieties and excipients in NC formulation. Surface morphology confirmed the presence of Nano-size crystals having rough crystalline surface. XRD proved that the capsaicin NC are successfully developed by using high speed homogenization. The solubility of capsaicin was found to be 12.0 ± 0.013 μg/mL in water. In vitro study revealed that 89.94 ± 1.9% of drug was released within 24 h. Similarly, drug permeation was 68.32 ± 1.83%, drug retained in skin was 16.13 ± 1.11% while drug retained on skin was 9.12 ± 0.14% after 12 h. The nanocrystals showed higher anti-inflammatory activity as compared to marketed product (Dicloran^®). The study concluded that improvement in dissolution rate of capsaicin may potentially provide the opportunities in the development of a much cost-effective dosage forms that will produce improved pharmacological effects, but at low dose as compared to the already available products. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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21 pages, 7220 KiB

Open AccessArticle

Safety and Therapeutic Efficacy of Thymoquinone-Loaded Liposomes against Drug-Sensitive and Drug-Resistant Acinetobacter baumannii

by Khaled S. Allemailem, Abdullah M. Alnuqaydan, Ahmad Almatroudi, Faris Alrumaihi, Aseel Aljaghwani, Habibullah Khalilullah, Hina Younus, Arif Khan and Masood A. Khan

Pharmaceutics 2021, 13(5), 677; https://doi.org/10.3390/pharmaceutics13050677 - 08 May 2021

Cited by 17 | Viewed by 2401

Abstract

In the present study, we investigated the activity of free thymoquinone (TQ) or liposomal thymoquinone (Lip-TQ) in comparison to standard antibiotic amoxicillin (AMX) against the drug-sensitive and drug-resistant Acinetobacter baumannii. A liposomal formulation of TQ was prepared and characterized and its toxicity [...] Read more.

In the present study, we investigated the activity of free thymoquinone (TQ) or liposomal thymoquinone (Lip-TQ) in comparison to standard antibiotic amoxicillin (AMX) against the drug-sensitive and drug-resistant Acinetobacter baumannii. A liposomal formulation of TQ was prepared and characterized and its toxicity was evaluated by analyzing the hematological, liver and kidney function parameters. TQ was effective against both drug-sensitive and drug-resistant A. baumannii as shown by the findings of drug susceptibility testing and time kill kinetics. Moreover, the therapeutic efficacy of TQ or Lip-TQ against A. baumannii was assessed by the survival rate and the bacterial load in the lung tissues of treated mice. The mice infected with drug-sensitive A. baumannii exhibited a 90% survival rate on day 30 post treatment with Lip-TQ at a dose of 10 mg/kg, whereas the mice treated with AMX (10 mg/kg) had a 100% survival rate. On the other hand, the mice infected with drug-resistant A. baumannii had a 70% survival rate in the group treated with Lip-TQ, whereas AMX was ineffective against drug-resistant A. baumannii and all the mice died within day 30 after the treatment. Moreover, Lip-TQ treatment effectively reduced the bacterial load in the lung tissues of the mice infected with the drug-sensitive and drug-resistant A. baumannii. Moreover, the blood of the mice treated with Lip-TQ had reduced levels of inflammation markers, leukocytes and neutrophils. The results of the present study suggest that Lip-TQ may prove to be an effective therapeutic formulation in the treatment of the drug-sensitive or drug-resistant A. baumannii infection as well. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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16 pages, 18734 KiB

Open AccessArticle

Asparaginase-Phage P22 Nanoreactors: Toward a Biobetter Development for Acute Lymphoblastic Leukemia Treatment

by Cristina Díaz-Barriga, Francisca Villanueva-Flores, Katrin Quester, Andrés Zárate-Romero, Ruben Dario Cadena-Nava and Alejandro Huerta-Saquero

Pharmaceutics 2021, 13(5), 604; https://doi.org/10.3390/pharmaceutics13050604 - 22 Apr 2021

Cited by 13 | Viewed by 2971

Abstract

Asparaginase (ASNase) is a biopharmaceutical for Acute Lymphoblastic Leukemia (ALL) treatment. However, it shows undesirable side effects such as short lifetimes, susceptibility to proteases, and immunogenicity. Here, ASNase encapsidation was genetically directed in bacteriophage P22-based virus-like particles (VLPs) (ASNase-P22 nanoreactors) as a strategy [...] Read more.

Asparaginase (ASNase) is a biopharmaceutical for Acute Lymphoblastic Leukemia (ALL) treatment. However, it shows undesirable side effects such as short lifetimes, susceptibility to proteases, and immunogenicity. Here, ASNase encapsidation was genetically directed in bacteriophage P22-based virus-like particles (VLPs) (ASNase-P22 nanoreactors) as a strategy to overcome these challenges. ASNase-P22 was composed of 58.4 ± 7.9% of coat protein and 41.6 ± 8.1% of tetrameric ASNase. Km and Kcat values of ASNase-P22 were 15- and 2-fold higher than those obtained for the free enzyme, respectively. Resulting Kcat/Km value was 2.19 × 10⁵ M⁻¹ s⁻¹. ASNase-P22 showed an aggregation of 60% of the volume sample when incubated at 37 °C for 12 days. In comparison, commercial asparaginase was completely aggregated under the same conditions. ASNase-P22 was stable for up to 24 h at 37 °C, independent of the presence of human blood serum (HBS) or whether ASNase-P22 nanoreactors were uncoated or PEGylated. Finally, we found that ASNase-P22 caused cytotoxicity in the leukemic cell line MOLT-4 in a concentration dependent manner. To our knowledge, this is the first work where ASNase is encapsulated inside of VLPs, as a promising alternative to fight ALL. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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Review

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30 pages, 5672 KiB

Open AccessReview

Smart Nanotherapeutics and Lung Cancer

by Mohammad Doroudian, Mohammad H. Azhdari, Nima Goodarzi, David O’Sullivan and Seamas C. Donnelly

Pharmaceutics 2021, 13(11), 1972; https://doi.org/10.3390/pharmaceutics13111972 - 20 Nov 2021

Cited by 30 | Viewed by 4188

Abstract

Lung cancer is a significant health problem worldwide. Unfortunately, current therapeutic strategies lack a sufficient level of specificity and can harm adjacent healthy cells. Consequently, to address the clinical need, novel approaches to improve treatment efficiency with minimal side effects are required. Nanotechnology [...] Read more.

Lung cancer is a significant health problem worldwide. Unfortunately, current therapeutic strategies lack a sufficient level of specificity and can harm adjacent healthy cells. Consequently, to address the clinical need, novel approaches to improve treatment efficiency with minimal side effects are required. Nanotechnology can substantially contribute to the generation of differentiated products and improve patient outcomes. Evidence from previous research suggests that nanotechnology-based drug delivery systems could provide a promising platform for the targeted delivery of traditional chemotherapeutic drugs and novel small molecule therapeutic agents to treat lung cancer cells more effectively. This has also been found to improve the therapeutic index and reduce the required drug dose. Nanodrug delivery systems also provide precise control over drug release, resulting in reduced toxic side effects, controlled biodistribution, and accelerated effects or responses. This review highlights the most advanced and novel nanotechnology-based strategies, including targeted nanodrug delivery systems, stimuli-responsive nanoparticles, and bio-nanocarriers, which have recently been employed in preclinical and clinical investigations to overcome the current challenges in lung cancer treatments. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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19 pages, 38485 KiB

Open AccessReview

Encapsulation of Asparaginase as a Promising Strategy to Improve In Vivo Drug Performance

by Francisca Villanueva-Flores, Andrés Zárate-Romero, Alfredo G. Torres and Alejandro Huerta-Saquero

Pharmaceutics 2021, 13(11), 1965; https://doi.org/10.3390/pharmaceutics13111965 - 19 Nov 2021

Cited by 6 | Viewed by 2863

Abstract

Asparaginase (ASNase) is a widely applied chemotherapeutic drug that is used to treat Acute Lymphoblastic Leukemia (ALL); however, immune responses and silent inactivation of the drug often limit its bioavailability. Many strategies have been proposed to overcome these drawbacks, including the development of [...] Read more.

Asparaginase (ASNase) is a widely applied chemotherapeutic drug that is used to treat Acute Lymphoblastic Leukemia (ALL); however, immune responses and silent inactivation of the drug often limit its bioavailability. Many strategies have been proposed to overcome these drawbacks, including the development of improved formulations (biobetters), but only two of them are currently on the market. Nano- and micro-encapsulation are some of the most promising and novel approaches to enhance in vivo performance of ASNase, preventing the direct contact of the enzyme with the environment, protecting it from protease degradation, increasing the enzymes catalytic half-life, and in some cases, reducing immunogenicity. This review summarizes the strategies, particularly for ASNase nano- and micro-encapsulation, and their main findings, constraints, and current gaps in the state-of-the-art knowledge. The pros and cons of the use of different nanocarriers are discussed with the idea to ultimately provide safer and more effective treatments for patients with ALL. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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20 pages, 1979 KiB

Open AccessReview

Pharmaceutical Aspects of Nanocarriers for Smart Anticancer Therapy

by Seung Rim Hwang, Kushal Chakraborty, Jeong Man An, Jagannath Mondal, Hong Yeol Yoon and Yong-kyu Lee

Pharmaceutics 2021, 13(11), 1875; https://doi.org/10.3390/pharmaceutics13111875 - 05 Nov 2021

Cited by 7 | Viewed by 2324

Abstract

Drug delivery to tumor sites using nanotechnology has been demonstrated to overcome the drawbacks of conventional anticancer drugs. Altering the surface shape and geometry of nanocomposites alters their chemical properties, which can confer multiple attributes to nanocarriers for the treatment of cancer and [...] Read more.

Drug delivery to tumor sites using nanotechnology has been demonstrated to overcome the drawbacks of conventional anticancer drugs. Altering the surface shape and geometry of nanocomposites alters their chemical properties, which can confer multiple attributes to nanocarriers for the treatment of cancer and their use as imaging agents for cancer diagnosis. However, heterogeneity and blood flow in human cancer limit the distribution of nanoparticles at the site of tumor tisues. For targeted delivery and controlled release of drug molecules in harsh tumor microenvironments, smart nanocarriers combined with various stimuli-responsive materials have been developed. In this review, we describe nanomaterials for smart anticancer therapy as well as their pharmaceutical aspects including pharmaceutical process, formulation, controlled drug release, drug targetability, and pharmacokinetic or pharmacodynamic profiles of smart nanocarriers. Inorganic or organic-inorganic hybrid nanoplatforms and the electrospinning process have also been briefly described here. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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52 pages, 4403 KiB

Open AccessReview

Green Metallic Nanoparticles for Cancer Therapy: Evaluation Models and Cancer Applications

by Ernesto Tinajero-Díaz, Daniela Salado-Leza, Carmen Gonzalez, Moisés Martínez Velázquez, Zaira López, Jorge Bravo-Madrigal, Peter Knauth, Flor Y. Flores-Hernández, Sara Elisa Herrera-Rodríguez, Rosa E. Navarro, Alejandro Cabrera-Wrooman, Edgar Krötzsch, Zaira Y. García Carvajal and Rodolfo Hernández-Gutiérrez

Pharmaceutics 2021, 13(10), 1719; https://doi.org/10.3390/pharmaceutics13101719 - 18 Oct 2021

Cited by 30 | Viewed by 5170

Abstract

Metal-based nanoparticles are widely used to deliver bioactive molecules and drugs to improve cancer therapy. Several research works have highlighted the synthesis of gold and silver nanoparticles by green chemistry, using biological entities to minimize the use of solvents and control their physicochemical [...] Read more.

Metal-based nanoparticles are widely used to deliver bioactive molecules and drugs to improve cancer therapy. Several research works have highlighted the synthesis of gold and silver nanoparticles by green chemistry, using biological entities to minimize the use of solvents and control their physicochemical and biological properties. Recent advances in evaluating the anticancer effect of green biogenic Au and Ag nanoparticles are mainly focused on the use of conventional 2D cell culture and in vivo murine models that allow determination of the half-maximal inhibitory concentration, a critical parameter to move forward clinical trials. However, the interaction between nanoparticles and the tumor microenvironment is not yet fully understood. Therefore, it is necessary to develop more human-like evaluation models or to improve the existing ones for a better understanding of the molecular bases of cancer. This review provides recent advances in biosynthesized Au and Ag nanoparticles for seven of the most common and relevant cancers and their biological assessment. In addition, it provides a general idea of the in silico, in vitro, ex vivo, and in vivo models used for the anticancer evaluation of green biogenic metal-based nanoparticles. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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