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30 pages, 3915 KiB

Open AccessArticle

Harnessing Folate-Functionalized Nasal Delivery of Dox–Erlo-Loaded Biopolymeric Nanoparticles in Cancer Treatment: Development, Optimization, Characterization, and Biodistribution Analysis

by Ms Farheen, Md Habban Akhter, Havagiray Chitme, Md Sayeed Akhter, Fauzia Tabassum, Mariusz Jaremko and Abdul-Hamid Emwas

Pharmaceuticals 2023, 16(2), 207; https://doi.org/10.3390/ph16020207 - 30 Jan 2023

Cited by 8 | Viewed by 2027

Abstract

The aim of the present study is to develop Doxorubicin–Erlotinib nanoparticles (Dox–Erlo NPs) and folate-armored Dox–Erlo-NP conjugates for targeting glioma cancer. Glioma is one of the most common progressive cancerous growths originating from brain glial cells. However, the blood–brain barrier (BBB) is only [...] Read more.

The aim of the present study is to develop Doxorubicin–Erlotinib nanoparticles (Dox–Erlo NPs) and folate-armored Dox–Erlo-NP conjugates for targeting glioma cancer. Glioma is one of the most common progressive cancerous growths originating from brain glial cells. However, the blood–brain barrier (BBB) is only semi-permeable and is highly selective as to which compounds are let through; designing compounds that overcome this constraint is therefore a major challenge in the development of pharmaceutical agents. We demonstrate that the NP conjugates studied in this paper may ameliorate the BBB penetration and enrich the drug concentration in the target bypassing the BBB. NPs were prepared using a biopolymer with a double-emulsion solvent evaporation technique and functionalized with folic acid for site-specific targeting. Dox–Erlo NPs and Dox–Erlo-NP conjugates were extensively characterized in vitro for various parameters. Dox–Erlo NPs and Dox–Erlo-NP conjugates incurred a z-average of 95.35 ± 10.25 nm and 110.12 ± 9.2 nm, respectively. The zeta potentials of the Dox–Erlo NPs and Dox–Erlo-NP conjugates were observed at −18.1 mV and −25.1 mV, respectively. A TEM image has shown that the NPs were well-dispersed, uniform, de-aggregated, and consistent. A hemolytic assay confirmed hemocompatibility with the developed formulation and that it can be safely administered. Dox–Erlo-NP conjugates significantly reduced the number of viable cells to 24.66 ± 2.08% and 32.33 ± 2.51% in U87 and C6 cells, respectively, and IC50 values of 3.064 µM and 3.350 µM in U87 and C6 cells were reported after 24 h, respectively. A biodistribution study revealed that a significant concentration of Dox and Erlo were estimated in the brain relative to drug suspension. Dox–Erlo-NP conjugates were also stable for three months. The findings suggest that the developed Dox–Erlo-NP conjugates may be a promising agent for administration in glioma therapy. Full article

(This article belongs to the Special Issue Recent Progress of Nanomedicine and Targeted Drug Delivery for Cancer Treatment)

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16 pages, 2589 KiB

Open AccessArticle

Tumor Microenvironment-Responsive Magnetic Nanofluid for Enhanced Tumor MRI and Tumor multi-treatments

by Liangju Sheng, Xuanlei Zhu, Miao Sun, Zhe Lan, Yong Yang, Yuanrong Xin and Yuefeng Li

Pharmaceuticals 2023, 16(2), 166; https://doi.org/10.3390/ph16020166 - 23 Jan 2023

Cited by 1 | Viewed by 1583

Abstract

We prepared a tumor microenvironment-responsive magnetic nanofluid (MNF) for improving tumor targeting, imaging and treatment simultaneously. For this purpose, we synthesized sulfonamide-based amphiphilic copolymers with a suitable pK_a at 7.0; then, we utilized them to prepare the tumor microenvironment-responsive MNF by [...] Read more.

We prepared a tumor microenvironment-responsive magnetic nanofluid (MNF) for improving tumor targeting, imaging and treatment simultaneously. For this purpose, we synthesized sulfonamide-based amphiphilic copolymers with a suitable pK_a at 7.0; then, we utilized them to prepare the tumor microenvironment-responsive MNF by self-assembly of the sulfonamide-based amphiphilic copolymers and hydrophobic monodispersed Fe₃O₄ nanoparticles at approximately 8 nm. After a series of characterizations, the MNF showed excellent application potential due to the fact of its high stability under physiological conditions and its hypersensitivity toward tumor stroma by forming aggregations within neutral or weak acidic environments. Due to the fact of its tumor microenvironment-responsiveness, the MNF showed great potential for accumulation in tumors, which could enhance MNF-mediated magnetic resonance imaging (MRI), magnetic hyperthermia (MH) and Fenton reaction (FR) in tumor. Moreover, in vitro cell experiment did not only show high biocompatibility of tumor microenvironment-responsive MNF in physiological environment, but also exhibit high efficacy on inhibiting cell proliferation by MH-dependent chemodynamic therapy (CDT), because CDT was triggered and promoted efficiently by MH with increasing strength of alternating magnetic field. Although the current research is limited to in vitro study, these positive results still suggest the great potential of the MNF on effective targeting, diagnosis, and therapy of tumor. Full article

(This article belongs to the Special Issue Recent Progress of Nanomedicine and Targeted Drug Delivery for Cancer Treatment)

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22 pages, 4222 KiB

Open AccessArticle

Sesamol Loaded Albumin Nanoparticles: A Boosted Protective Property in Animal Models of Oxidative Stress

by Sara Zaher, Mahmoud E. Soliman, Mahmoud Elsabahy and Rania M. Hathout

Pharmaceuticals 2022, 15(6), 733; https://doi.org/10.3390/ph15060733 - 10 Jun 2022

Cited by 6 | Viewed by 2154

Abstract

The current study evaluated the ability of sesamol-loaded albumin nanoparticles to impart protection against oxidative stress induced by anthracyclines in comparison to the free drug. Albumin nanoparticles were prepared via the desolvation technique and then freeze-dried with the cryoprotectant, trehalose. Albumin concentration, pH, [...] Read more.

The current study evaluated the ability of sesamol-loaded albumin nanoparticles to impart protection against oxidative stress induced by anthracyclines in comparison to the free drug. Albumin nanoparticles were prepared via the desolvation technique and then freeze-dried with the cryoprotectant, trehalose. Albumin concentration, pH, and type of desolvating agent were assessed as determining factors for successful albumin nanoparticle fabrication. The optimal nanoparticles were spherical in shape, and they had an average particle diameter of 127.24 ± 2.12 nm with a sesamol payload of 96.89 ± 2.4 μg/mg. The drug cellular protection was tested on rat hepatocytes pretreated with 1 µM doxorubicin, which showed a 1.2-fold higher protective activity than the free sesamol. In a pharmacokinetic study, the loading of a drug onto nanoparticles resulted in a longer half-life and mean residence time, as compared to the free drug. Furthermore, in vivo efficacy and biochemical assessment of lipid peroxidation, cardiac biomarkers, and liver enzymes were significantly ameliorated after administration of the sesamol-loaded albumin nanoparticles. The biochemical assessments were also corroborated with the histopathological examination data. Sesamol-loaded albumin nanoparticles, prepared under controlled conditions, may provide an enhanced protective effect against off-target doxorubicin toxicity. Full article

(This article belongs to the Special Issue Recent Progress of Nanomedicine and Targeted Drug Delivery for Cancer Treatment)

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26 pages, 10266 KiB

Open AccessArticle

Formulation and Characterization of Metformin-Loaded Ethosomes for Topical Application to Experimentally Induced Skin Cancer in Mice

by Ibrahim A. Mousa, Taha M. Hammady, Shadeed Gad, Sawsan A. Zaitone, Mohamed El-Sherbiny and Ossama M. Sayed

Pharmaceuticals 2022, 15(6), 657; https://doi.org/10.3390/ph15060657 - 25 May 2022

Cited by 17 | Viewed by 3496

Abstract

To achieve the best treatment of skin cancer, drug penetration inside the deepest layers of the skin is an important scientific interest. We designed an ethosome formulation that serves as a carrier for metformin and measured the in vitro skin permeation. We also [...] Read more.

To achieve the best treatment of skin cancer, drug penetration inside the deepest layers of the skin is an important scientific interest. We designed an ethosome formulation that serves as a carrier for metformin and measured the in vitro skin permeation. We also aimed to measure the antitumor activity of the optimal ethosomal preparation when applied topically to chemically induced skin cancer in mice. We utilized a statistical Box–Behnken experimental design and applied three variables at three levels: lecithin concentration, cholesterol concentration and a mixture of ethanol and isopropyl alcohol concentrations. All formulations were prepared to calculate the entrapment efficiency %, zeta potential, size of the vesicles and drug release % after 1, 2, 4, 8 and 24 h. The size of the vesicles for the formulations was between 124 ± 14.2 nm and 560 ± 127 nm, while the entrapment efficiency was between 97.8 ± 0.23% and 99.4 ± 0.24%, and the drug release % after 8 h was between 38 ± 0.82% and 66 ± 0.52%. All formulations were introduced into the Box–Behnken software, which selected three formulations; then, one was assigned as an optimal formula. The in vivo antitumor activity of metformin-loaded ethosomal gel on skin cancer was greater than the antitumor activity of the gel preparation containing free metformin. Lower lecithin, high ethanol and isopropyl alcohol and moderate cholesterol contents improved the permeation rate. Overall, we can conclude that metformin-loaded ethosomes are a promising remedy for treating skin cancers, and more studies are warranted to approve this activity in other animal models of skin cancers. Full article

(This article belongs to the Special Issue Recent Progress of Nanomedicine and Targeted Drug Delivery for Cancer Treatment)

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20 pages, 3916 KiB

Open AccessArticle

Identification of Potential RBPJ-Specific Inhibitors for Blocking Notch Signaling in Breast Cancer Using a Drug Repurposing Strategy

by Mengjie Rui, Min Cai, Yu Zhou, Wen Zhang, Lianglai Gao, Ke Mi, Wei Ji, Dan Wang and Chunlai Feng

Pharmaceuticals 2022, 15(5), 556; https://doi.org/10.3390/ph15050556 - 29 Apr 2022

Cited by 5 | Viewed by 1964

Abstract

Notch signaling is a key parameter in regulating cell fate during tissue homeostasis, and an aberrant Notch pathway can result in mammary gland carcinoma and has been associated with poor breast cancer diagnosis. Although inhibiting Notch signaling would be advantageous in the treatment [...] Read more.

Notch signaling is a key parameter in regulating cell fate during tissue homeostasis, and an aberrant Notch pathway can result in mammary gland carcinoma and has been associated with poor breast cancer diagnosis. Although inhibiting Notch signaling would be advantageous in the treatment of breast cancer, the currently available Notch inhibitors have a variety of side effects and their clinical trials have been discontinued. Thus, in search of a more effective and safer Notch inhibitor, inhibiting recombinant signal binding protein for immunoglobin kappaJ region (RBPJ) specifically makes sense, as RBPJ forms a transcriptional complex that activates Notch signaling. From our established database of more than 10,527 compounds, a drug repurposing strategy-combined docking study and molecular dynamic simulation were used to identify novel RBPJ-specific inhibitors. The compounds with the best performance were examined using an in vitro cellular assay and an in vivo anticancer investigation. Finally, an FDA-approved antibiotic, fidaxomicin, was identified as a potential RBPJ inhibitor, and its ability to block RBPJ-dependent transcription and thereby inhibit breast cancer growth was experimentally verified. Our study demonstrated that fidaxomicin suppressed Notch signaling and may be repurposed for the treatment of breast cancer. Full article

(This article belongs to the Special Issue Recent Progress of Nanomedicine and Targeted Drug Delivery for Cancer Treatment)

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16 pages, 3528 KiB

Open AccessArticle

Adenosine Conjugated Docetaxel Nanoparticles—Proof of Concept Studies for Non-Small Cell Lung Cancer

by Hibah M. Aldawsari, Sima Singh, Nabil A. Alhakamy, Rana B. Bakhaidar, Abdulrahman A. Halwani, Nagaraja Sreeharsha and Shaimaa M. Badr-Eldin

Pharmaceuticals 2022, 15(5), 544; https://doi.org/10.3390/ph15050544 - 28 Apr 2022

Cited by 8 | Viewed by 2029

Abstract

Non-small cell lung cancer, a molecularly diverse disease, is the most prevalent cause of cancer mortality globally. Increasing understanding of the clinicopathology of the disease and mechanisms of tumor progression has facilitated early detection and multimodal care. Despite the advancements, survival rates are [...] Read more.

Non-small cell lung cancer, a molecularly diverse disease, is the most prevalent cause of cancer mortality globally. Increasing understanding of the clinicopathology of the disease and mechanisms of tumor progression has facilitated early detection and multimodal care. Despite the advancements, survival rates are extremely low due to non-targeted therapeutics and correspondingly increased risk of metastasis. At some phases of cancer, patients need to face the ghost of chemotherapy. It is a difficult decision near the end of life. Such treatments have the capability to prolong survival or reduce symptoms, but can cause serious adverse effects, affecting quality of life of the patient. It is evident that many patients do not die from burden of the disease alone, but they die due to the toxic effect of treatment. Thus, increasing the efficacy is one aspect and decreasing the toxicity is another critical aspect of cancer formulation design. Through our current research, we tried to uncover both mentioned potentials of the formulation. Therefore, we designed actively targeted nanoparticles for improved therapeutics considering the overexpression of adenosine (ADN) receptors on non-small cell lung cancer (NSCLC) cells. Docetaxel (DTX), an essential therapeutic as part of combination therapy or as monotherapy for the treatment of NSCLC, was encapsulated in biodegradable poly(lactic-co-glycolic acid) nanoparticles. ADN was conjugated on the surface of nanoparticles using EDC-NHS chemistry. The particles were characterized in vitro for physicochemical properties, cellular uptake, and biocompatibility. The size and zeta potential of DTX nanoparticles (DPLGA) were found to be 138.4 ± 5.45 nm and −16.7 ± 2.3 mV which were found to change after ADN conjugation. The size was increased to 158.2 ± 6.3 nm, whereas zeta potential was decreased to −11.7 ± 1.4 mV for ADN-conjugated DTX nanoparticles (ADN-DPLGA) indicative of surface conjugation. As observed from transmission electron microscopy (TEM), the nanoparticles were spherical and showed no significant change in encapsulation efficiency even after surface conjugation. Careful and systematic optimization leads to ADN-conjugated PLGA nanoparticles having distinctive characteristic features such as particle size, surface potential, encapsulation efficacy, etc., that may play crucial roles in the fate of nanoparticles (NPs). Consequently, higher cellular uptake in the A549 lung cancer cell line was exhibited by ADN-DPLGA compared to DPLGA, illustrating the role of ADN receptors (ARs) in facilitating the uptake of NPs. Further in vivo pharmacokinetics and tissue distribution experiments revealed prolonged circulation in plasma and significantly higher lung tissue distribution than in other organs, dictating the targeting potential of the developed formulation over naïve drug and unconjugated formulations. Further, in vivo acute toxicity was examined using multiple parameters for non-toxic attributes of the developed formulation compared to other non-targeted organs. Further, it also supports the selection of biocompatible polymers in the formulation. The current study presents a proof-of-concept for a multipronged formulation technology strategy that might be used to maximize anticancer therapeutic responses in the lungs in the treatment of NSCLC. An improved therapeutic and safety profile would help achieve maximum efficacy at a reduced dose that would eventually help reduce the toxicity. Full article

(This article belongs to the Special Issue Recent Progress of Nanomedicine and Targeted Drug Delivery for Cancer Treatment)

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18 pages, 4195 KiB

Open AccessArticle

A Theranostic Nanocomplex Combining with Magnetic Hyperthermia for Enhanced Accumulation and Efficacy of pH-Triggering Polymeric Cisplatin(IV) Prodrugs

by Yang Qu, Zhiqi Wang, Miao Sun, Tian Zhao, Xuanlei Zhu, Xiaoli Deng, Man Zhang, Ying Xu and Hongfei Liu

Pharmaceuticals 2022, 15(4), 480; https://doi.org/10.3390/ph15040480 - 14 Apr 2022

Cited by 7 | Viewed by 1800

Abstract

Although polymeric platinum(IV) (Pt(IV)) prodrugs can reduce the side effects of cisplatin, the efficacy of the prodrug is still limited by its non-targeted distribution, poor penetration in deep tumor tissue, and low cytotoxicity in tumor cells. To improve the clinical potential of polymeric [...] Read more.

Although polymeric platinum(IV) (Pt(IV)) prodrugs can reduce the side effects of cisplatin, the efficacy of the prodrug is still limited by its non-targeted distribution, poor penetration in deep tumor tissue, and low cytotoxicity in tumor cells. To improve the clinical potential of polymeric prodrug micelle, we synthesized amphiphilic polymeric Pt(IV) with high Pt content (22.5%), then developed a theranostic nanocomplex by integrating polymeric Pt(IV) with superparamagnetic Mn_0.6Zn_0.4Fe₂O₄ via simple self-assembly. Due to the high content of Mn_0.6Zn_0.4Fe₂O₄ (41.7% w/w), the theranostic nanocomplex showed high saturation magnetization (103.1 emu g⁻¹) and excellent magnetocaloric effect (404 W g⁻¹), both of them indicating its advantages in efficient magnetic targeting (MT), magnetic hyperthermia (MH), and magnetic resonance imaging (MRI). In vitro, in combination with MH, the theranostic nanocomplex showed as high cytotoxicity as cisplatin because of a significant increase in platinum of cellular uptake. In vivo, the accumulation of theranostic nanocomplex in tumors was increased by MT and confirmed by MRI. Furthermore, MH improved penetration of theranostic nanocomplex in tumors as expanding blackened area in tumors was observed by MRI. Based on these properties, the theranostic nanocomplex, under the assistance of MT and MH, showed the highest tumor growth inhibition rate (88.38%) after different treatments, while the body weight of mice increased slightly, indicating low side effects compared to those of cisplatin. The study provided an advanced theranostic nanocomplex with low toxicity and high efficacy, indicating a great clinical potential of polymeric Pt(IV). Full article

(This article belongs to the Special Issue Recent Progress of Nanomedicine and Targeted Drug Delivery for Cancer Treatment)

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15 pages, 3701 KiB

Open AccessArticle

Homotypic Cancer Cell Membranes Camouflaged Nanoparticles for Targeting Drug Delivery and Enhanced Chemo-Photothermal Therapy of Glioma

by Yajing Ren, Chenlin Miao, Liang Tang, Yuxiang Liu, Pinyue Ni, Yan Gong, Hui Li, Fuxue Chen and Shini Feng

Pharmaceuticals 2022, 15(2), 157; https://doi.org/10.3390/ph15020157 - 27 Jan 2022

Cited by 17 | Viewed by 3245

Abstract

Glioma is among the deadliest types of brain cancer, for which there currently is no effective treatment. Chemotherapy is mainstay in the treatment of glioma. However, drug tolerance, non-targeting, and poor blood–brain barrier penetrance severely inhibits the efficacy of chemotherapeutics. An improved treatment [...] Read more.

Glioma is among the deadliest types of brain cancer, for which there currently is no effective treatment. Chemotherapy is mainstay in the treatment of glioma. However, drug tolerance, non-targeting, and poor blood–brain barrier penetrance severely inhibits the efficacy of chemotherapeutics. An improved treatment method is thus urgently needed. Herein, a multifunctional biomimetic nanoplatform was developed by encapsulating graphene quantum dots (GQDs) and doxorubicin (DOX) inside a homotypic cancer cell membrane (CCM) for targeted chemo-photothermal therapy of glioma. The GQDs with stable fluorescence and a superior light-to-heat conversion property were synthesized as photothermal therapeutic agents and co-encapsulated with DOX in CCM. The as-prepared nanoplatform exhibited a high DOX loading efficiency. The cell membrane coating protected drugs from leakage. Upon an external laser stimuli, the membrane could be destroyed, resulting in rapid DOX release. By taking advantage of the homologous targeting of the cancer cell membrane, the GQDs/DOX@CCM were found to actively target tumor cells, resulting in significantly enhanced cellular uptake. Moreover, a superior suppression efficiency of GQDs/DOX@CCM to cancer cells through chemo-photothermal treatment was also observed. The results suggest that this biomimetic nanoplatform holds potential for efficient targeting of drug delivery and synergistic chemo-photothermal therapy of glioma. Full article

(This article belongs to the Special Issue Recent Progress of Nanomedicine and Targeted Drug Delivery for Cancer Treatment)

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Review

Jump to: Research

11 pages, 639 KiB

Open AccessReview

Recent Development of LDL-Based Nanoparticles for Cancer Therapy

by Binghong He and Qiong Yang

Pharmaceuticals 2023, 16(1), 18; https://doi.org/10.3390/ph16010018 - 23 Dec 2022

Cited by 4 | Viewed by 1800

Abstract

Low-density lipoprotein (LDL), a natural lipoprotein transporting cholesterol in the circulatory system, has been a possible drug carrier for targeted delivery. LDL can bind to the LDL receptor (LDLR) with its outside apolipoprotein B-100 and then enter the cell via LDLR-mediated endocytosis. This [...] Read more.

Low-density lipoprotein (LDL), a natural lipoprotein transporting cholesterol in the circulatory system, has been a possible drug carrier for targeted delivery. LDL can bind to the LDL receptor (LDLR) with its outside apolipoprotein B-100 and then enter the cell via LDLR-mediated endocytosis. This targeting function inspires researchers to modify LDL to deliver different therapeutic drugs. Drugs can be loaded in the surficial phospholipids, hydrophobic core, or apolipoprotein for the structure of LDL. In addition, LDL-like synthetic nanoparticles carrying therapeutic drugs are also under investigation for the scarcity of natural LDL. In addition to being a carrier, LDL can also be a targeting molecule, decorated to the surface of synthetic nanoparticles loaded with cytotoxic compounds. This review summarizes the properties of LDL and the different kinds of LDL-based delivery nanoparticles, their loading strategies, and the achievements of the recent anti-tumor advancement. Full article

(This article belongs to the Special Issue Recent Progress of Nanomedicine and Targeted Drug Delivery for Cancer Treatment)

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27 pages, 3393 KiB

Open AccessReview

Tumor-Derived Membrane Vesicles: A Promising Tool for Personalized Immunotherapy

by Jiabin Xu, Wenqiang Cao, Penglai Wang and Hong Liu

Pharmaceuticals 2022, 15(7), 876; https://doi.org/10.3390/ph15070876 - 16 Jul 2022

Cited by 6 | Viewed by 3078

Abstract

Tumor-derived membrane vesicles (TDMVs) are non-invasive, chemotactic, easily obtained characteristics and contain various tumor-borne substances, such as nucleic acid and proteins. The unique properties of tumor cells and membranes make them widely used in drug loading, membrane fusion and vaccines. In particular, personalized [...] Read more.

Tumor-derived membrane vesicles (TDMVs) are non-invasive, chemotactic, easily obtained characteristics and contain various tumor-borne substances, such as nucleic acid and proteins. The unique properties of tumor cells and membranes make them widely used in drug loading, membrane fusion and vaccines. In particular, personalized vectors prepared using the editable properties of cells can help in the design of personalized vaccines. This review focuses on recent research on TDMV technology and its application in personalized immunotherapy. We elucidate the strengths and challenges of TDMVs to promote their application from theory to clinical practice. Full article

(This article belongs to the Special Issue Recent Progress of Nanomedicine and Targeted Drug Delivery for Cancer Treatment)

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