Editorial

4 pages, 166 KiB

Open AccessEditorial

Novel Approaches for Overcoming Biological Barriers

by Vibhuti Agrahari and Prashant Kumar

Pharmaceutics 2022, 14(9), 1851; https://doi.org/10.3390/pharmaceutics14091851 - 02 Sep 2022

Cited by 1 | Viewed by 1101

The human body poses a spectrum of biological mechanisms operating at different levels that are important for its normal functioning and development [...] Full article

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

Research

Jump to: Editorial, Review

11 pages, 2602 KiB

Open AccessArticle

Opening the Blood Brain Barrier with an Electropermanent Magnet System

by Sahar Jafari, Ittai S. Baum, Oleg G. Udalov, Yichien Lee, Olga Rodriguez, Stanley T. Fricke, Maryam Jafari, Mostafa Amini, Roland Probst, Xinyao Tang, Cheng Chen, David J. Ariando, Anjana Hevaganinge, Lamar O. Mair, Christopher Albanese and Irving N. Weinberg

Pharmaceutics 2022, 14(7), 1503; https://doi.org/10.3390/pharmaceutics14071503 - 20 Jul 2022

Cited by 2 | Viewed by 2491

Abstract

Opening the blood brain barrier (BBB) under imaging guidance may be useful for the treatment of many brain disorders. Rapidly applied magnetic fields have the potential to generate electric fields in brain tissue that, if properly timed, may enable safe and effective BBB [...] Read more.

Opening the blood brain barrier (BBB) under imaging guidance may be useful for the treatment of many brain disorders. Rapidly applied magnetic fields have the potential to generate electric fields in brain tissue that, if properly timed, may enable safe and effective BBB opening. By tuning magnetic pulses generated by a novel electropermanent magnet (EPM) array, we demonstrate the opening of tight junctions in a BBB model culture in vitro, and show that induced monophasic electrical pulses are more effective than biphasic ones. We confirmed, with in vivo contrast-enhanced MRI, that the BBB can be opened with monophasic pulses. As electropermanent magnets have demonstrated efficacy at tuning B0 fields for magnetic resonance imaging studies, our results suggest the possibility of implementing an EPM-based hybrid theragnostic device that could both image the brain and enhance drug transport across the BBB in a single sitting. Full article

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

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21 pages, 3575 KiB

Open AccessArticle

Retinal Delivery of the Protein Kinase C-β Inhibitor Ruboxistaurin Using Non-Invasive Nanoparticles of Polyamidoamine Dendrimers

by Rehab A. Alshammari, Fadilah S. Aleanizy, Amal Aldarwesh, Fulwah Y. Alqahtani, Wael A. Mahdi, Bushra Alquadeib, Qamraa H. Alqahtani, Nazrul Haq, Faiyaz Shakeel, Hosam G. Abdelhady and Ibrahim A. Alsarra

Pharmaceutics 2022, 14(7), 1444; https://doi.org/10.3390/pharmaceutics14071444 - 11 Jul 2022

Cited by 11 | Viewed by 1569

Abstract

Ruboxistaurin (RBX) is an anti-vascular endothelial growth factor (anti-VEGF) agent that is used in the treatment of diabetic retinopathy and is mainly given intravitreally. To provide a safe and effective method for RBX administration, this study was designed to develop RBX nanoparticles using [...] Read more.

Ruboxistaurin (RBX) is an anti-vascular endothelial growth factor (anti-VEGF) agent that is used in the treatment of diabetic retinopathy and is mainly given intravitreally. To provide a safe and effective method for RBX administration, this study was designed to develop RBX nanoparticles using polyamidoamine (PAMAM) dendrimer generation 5 for the treatment of diabetic retinopathy. Drug loading efficiency, and in vitro release of proposed complexes of RBX: PAMAM dendrimers were determined and the complexation ratio that showed the highest possible loading efficiency was selected. The drug loading efficiency (%) of 1:1, 2.5:1, and 5:1 complexes was 89.2%, 96.4%, and 97.6%, respectively. Loading capacities of 1:1, 2.5:1, and 5:1 complexes were 1.6%, 4.0%, and 7.2% respectively. In comparison, the 5:1 complex showed the best results in the aforementioned measurements. The in vitro release studies showed that in 8 h, the RBX release from 1:1, 2.5:1, and 5:1 complexes was 37.5%, 35.9%, and 77.0%, respectively. In particular, 5:1 complex showed the highest drug release. In addition, particle size measurements showed that the diameter of empty PAMAM dendrimers was 214.9 ± 8.5 nm, whereas the diameters of loaded PAMAM dendrimers in 1:1, 2.5:1, 5:1 complexes were found to be 461.0 ± 6.4, 482.4 ± 12.5, and 420.0 ± 7.1 nm, respectively. Polydispersity index (PDI) showed that there were no significant changes in the PDI between the free and loaded PAMAM dendrimers. The zeta potential measurements showed that the free and loaded nanoparticles possessed neutral charges due to the presence of anionic and cationic terminal structures. Furthermore, the safety of this formulation was apparent on the viability of the MIO-M1 cell lines. This nanoformulation will improve the therapeutic outcomes of anti-VEGF therapy and the bioavailability of RBX to prevent vision loss in patients with diabetic retinopathy. Full article

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

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20 pages, 3807 KiB

Open AccessArticle

Combined Transcriptomic and Proteomic Profiling to Unravel Osimertinib, CARP-1 Functional Mimetic (CFM 4.17) Formulation and Telmisartan Combo Treatment in NSCLC Tumor Xenografts

by Ramesh Nimma, Anil Kumar Kalvala, Nilkumar Patel, Sunil Kumar Surapaneni, Li Sun, Rakesh Singh, Ebony Nottingham, Arvind Bagde, Nagavendra Kommineni, Peggy Arthur, Aakash Nathani, David G. Meckes, Jr. and Mandip Singh

Pharmaceutics 2022, 14(6), 1156; https://doi.org/10.3390/pharmaceutics14061156 - 28 May 2022

Cited by 3 | Viewed by 2807

Abstract

The epidermal growth factor receptor (EGFR) is highly expressed in many non-small cell lung cancers (NSCLC), necessitating the use of EGFR-tyrosine kinase inhibitors (TKIs) as first-line treatments. Osimertinib (OSM), a third-generation TKI, is routinely used in clinics, but T790M mutations in exon 20 [...] Read more.

The epidermal growth factor receptor (EGFR) is highly expressed in many non-small cell lung cancers (NSCLC), necessitating the use of EGFR-tyrosine kinase inhibitors (TKIs) as first-line treatments. Osimertinib (OSM), a third-generation TKI, is routinely used in clinics, but T790M mutations in exon 20 of the EGFR receptor lead to resistance against OSM, necessitating the development of more effective therapeutics. Telmisartan (TLM), OSM, and cell cycle and apoptosis regulatory protein 1 (CARP-1) functional mimetic treatments (CFM4.17) were evaluated in this study against experimental H1975 tumor xenografts to ascertain their anti-cancer effects. Briefly, tumor growth was studied in H1975 xenografts in athymic nude mice, gene and protein expressions were analyzed using next-generation RNA sequencing, proteomics, RT-PCR, and Western blotting. TLM pre-treatment significantly reduced the tumor burden when combined with CFM-4.17 nanoformulation and OSM combination (TLM_CFM-F_OSM) than their respective single treatments or combination of OSM and TLM with CFM 4.17. Data from RNA sequencing and proteomics revealed that TLM_CFM-F_OSM decreased the expression of Lamin B2, STAT3, SOD, NFKB, MMP-1, TGF beta, Sox-2, and PD-L1 proteins while increasing the expression of AMPK proteins, which was also confirmed by RT-PCR, proteomics, and Western blotting. According to our findings, the TLM_CFM-F_OSM combination has a superior anti-cancer effect in the treatment of NSCLC by affecting multiple resistant markers that regulate mitochondrial homeostasis, inflammation, oxidative stress, and apoptosis. Full article

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

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13 pages, 4631 KiB

Open AccessArticle

Targeting Zika Virus with New Brain- and Placenta-Crossing Peptide–Porphyrin Conjugates

by Toni Todorovski, Diogo A. Mendonça, Lorena O. Fernandes-Siqueira, Christine Cruz-Oliveira, Giuseppina Guida, Javier Valle, Marco Cavaco, Fernanda I. V. Limas, Vera Neves, Íris Cadima-Couto, Sira Defaus, Ana Salomé Veiga, Andrea T. Da Poian, Miguel A. R. B. Castanho and David Andreu

Pharmaceutics 2022, 14(4), 738; https://doi.org/10.3390/pharmaceutics14040738 - 29 Mar 2022

Cited by 5 | Viewed by 2700

Abstract

Viral disease outbreaks affect hundreds of millions of people worldwide and remain a serious threat to global health. The current SARS-CoV-2 pandemic and other recent geographically- confined viral outbreaks (severe acute respiratory syndrome (SARS), Ebola, dengue, zika and ever-recurring seasonal influenza), also with [...] Read more.

Viral disease outbreaks affect hundreds of millions of people worldwide and remain a serious threat to global health. The current SARS-CoV-2 pandemic and other recent geographically- confined viral outbreaks (severe acute respiratory syndrome (SARS), Ebola, dengue, zika and ever-recurring seasonal influenza), also with devastating tolls at sanitary and socio-economic levels, are sobering reminders in this respect. Among the respective pathogenic agents, Zika virus (ZIKV), transmitted by Aedes mosquito vectors and causing the eponymous fever, is particularly insidious in that infection during pregnancy results in complications such as foetal loss, preterm birth or irreversible brain abnormalities, including microcephaly. So far, there is no effective remedy for ZIKV infection, mainly due to the limited ability of antiviral drugs to cross blood–placental and/or blood–brain barriers (BPB and BBB, respectively). Despite its restricted permeability, the BBB is penetrable by a variety of molecules, mainly peptide-based, and named BBB peptide shuttles (BBBpS), able to ferry various payloads (e.g., drugs, antibodies, etc.) into the brain. Recently, we have described peptide–porphyrin conjugates (PPCs) as successful BBBpS-associated drug leads for HIV, an enveloped virus in which group ZIKV also belongs. Herein, we report on several brain-directed, low-toxicity PPCs capable of targeting ZIKV. One of the conjugates, PP-P1, crossing both BPB and BBB, has shown to be effective against ZIKV (IC₅₀ 1.08 µM) and has high serum stability (t_1/2 ca. 22 h) without altering cell viability at all tested concentrations. Peptide–porphyrin conjugation stands out as a promising strategy to fill the ZIKV treatment gap. Full article

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

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11 pages, 2643 KiB

Open AccessArticle

Injectable Biodegradable Silica Depot: Two Months of Sustained Release of the Blood Glucose Lowering Peptide, Pramlintide

by Puneet Tyagi, Mika Koskinen, Jari Mikkola, Sanjay Sarkhel, Lasse Leino, Asha Seth, Shimona Madalli, Sarah Will, Victor G. Howard, Helen Brant and Dominic Corkill

Pharmaceutics 2022, 14(3), 553; https://doi.org/10.3390/pharmaceutics14030553 - 02 Mar 2022

Cited by 3 | Viewed by 2446

Abstract

Diabetes mellitus is a major healthcare challenge. Pramlintide, a peptide analogue of the hormone amylin, is currently used as an adjunct with insulin for patients who fail to achieve glycemic control with only insulin therapy. However, hypoglycemia is the dominant risk factor associated [...] Read more.

Diabetes mellitus is a major healthcare challenge. Pramlintide, a peptide analogue of the hormone amylin, is currently used as an adjunct with insulin for patients who fail to achieve glycemic control with only insulin therapy. However, hypoglycemia is the dominant risk factor associated with such approaches and careful dosing of both drugs is needed. To mitigate this risk factor and compliance issues related to multiple dosing of different drugs, sustained delivery of Pramlintide from silica depot administered subcutaneously (SC) was investigated in a rat model. The pramlintide-silica microparticle hydrogel depot was formulated by spray drying of silica sol-gels. In vitro dissolution tests revealed an initial burst of pramlintide followed by controlled release due to the dissolution of the silica matrix. At higher dosing, pramlintide released from subcutaneously administered silica depot in rats showed a steady concentration of 500 pM in serum for 60 days. Released pramlintide retained its pharmacological activity in vivo, as evidenced by loss of weight. The biodegradable silica matrix offers a sustained release of pramlintide for at least two months in the rat model and shows potential for clinical applications. Full article

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

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16 pages, 4658 KiB

Open AccessArticle

Development and Optimization of Nanolipid-Based Formulation of Diclofenac Sodium: In Vitro Characterization and Preclinical Evaluation

by Ameeduzzafar Zafar, Nabil K Alruwaili, Syed Sarim Imam, Mohd Yasir, Omar Awad Alsaidan, Ali Alquraini, Alenazy Rawaf, Bader Alsuwayt, Md. Khalid Anwer, Sultan Alshehri and Mohammed M. Ghoneim

Pharmaceutics 2022, 14(3), 507; https://doi.org/10.3390/pharmaceutics14030507 - 25 Feb 2022

Cited by 10 | Viewed by 1793

Abstract

In the present research study, we formulate bilosomes (BMs) of diclofenac (DC) for oral delivery for enhancement of therapeutic efficacy (anti-inflammatory disease). The BMS were prepared by thin film hydration method and optimized by Box–Behnken design (BBD) using cholesterol (A), lipid (B), surfactant [...] Read more.

In the present research study, we formulate bilosomes (BMs) of diclofenac (DC) for oral delivery for enhancement of therapeutic efficacy (anti-inflammatory disease). The BMS were prepared by thin film hydration method and optimized by Box–Behnken design (BBD) using cholesterol (A), lipid (B), surfactant (C), and bile salt (D) as formulation factors. Their effects were evaluated on vesicle size (Y₁) and entrapment efficacy (Y₂). The optimized DC-BMs-opt showed a vesicle size of 270.21 ± 3.76 nm, PDI of 0.265 ± 0.03, and entrapment efficiency of 79.01 ± 2.54%. DSC study result revealed that DC-BMs-opt exhibited complete entrapment of DC in BM matrix. It also depicted significant enhancement (p < 0.05) in release (91.82 ± 4.65%) as compared to pure DC (36.32 ± 4.23%) and DC-liposomes (74.54 ± 4.76%). A higher apparent permeability coefficient (2.08 × 10⁻³ cm/s) was also achieved compared to pure DC (6.6 × 10⁻⁴ cm/s) and DC-liposomes (1.33 × 10⁻³ cm/s). A 5.21-fold and 1.43-fold enhancement in relative bioavailability was found relative to pure DC and DC liposomes (DC-LP). The anti-inflammatory activity result showed a significant (p < 0.05) reduction of paw edema swelling compared to pure DC and DC-LP. Our findings revealed that encapsulation of DC in BMs matrix is a good alternative for improvement of therapeutic efficacy. Full article

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

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13 pages, 3828 KiB

Open AccessArticle

Physicochemical Characterization and Pharmacological Evaluation of Novel Propofol Micelles with Low-Lipid and Low-Free Propofol

by Yongchao Chu, Tao Sun, Zichen Xie, Keyu Sun and Chen Jiang

Pharmaceutics 2022, 14(2), 414; https://doi.org/10.3390/pharmaceutics14020414 - 14 Feb 2022

Cited by 6 | Viewed by 3372

Abstract

We developed safe and stable mixed polymeric micelles with low lipids and free propofol for intravenous administration, to overcome the biological barrier of the reticuloendothelial system (RES), reduce pain upon injection, and complications of marketed propofol formulation. The propofol-mixed micelles were composed of [...] Read more.

We developed safe and stable mixed polymeric micelles with low lipids and free propofol for intravenous administration, to overcome the biological barrier of the reticuloendothelial system (RES), reduce pain upon injection, and complications of marketed propofol formulation. The propofol-mixed micelles were composed of distearoyl-phosphatidylethanolamine-methoxy-poly (ethylene glycol 2000) (DSPE mPEG2k) and Solutol HS 15 and were optimized using Box Behnken design (BBD). The optimized formulation was evaluated for globule size, zeta potential, loading content, encapsulation efficiency, pain on injection, histological evaluation, hemolysis test, in vivo anesthetic action, and pharmacokinetics, in comparison to the commercialized emulsion Diprivan. The optimized micelle formulation displayed homogenous particle sizes, and the free drug concentration in the micelles was 60.9% lower than that of Diprivan. The paw-lick study demonstrated that propofol-mixed micelles significantly reduced pain symptoms. The anesthetic action of the mixed micelles were similar with the Diprivan. Therefore, we conclude that the novel propofol-mixed micelle reduces injection-site pain and the risk of hyperlipidemia due to the low content of free propofol and low-lipid constituent. It may be a more promising clinical alternative for anesthetic. Full article

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

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22 pages, 4735 KiB

Open AccessArticle

Quantitative Structure-Activity Relationship of Enhancers of Licochalcone A and Glabridin Release and Permeation Enhancement from Carbomer Hydrogel

by Zhuxian Wang, Yaqi Xue, Zhaoming Zhu, Yi Hu, Quanfu Zeng, Yufan Wu, Yuan Wang, Chunyan Shen, Cuiping Jiang, Li Liu, Hongxia Zhu and Qiang Liu

Pharmaceutics 2022, 14(2), 262; https://doi.org/10.3390/pharmaceutics14020262 - 22 Jan 2022

Cited by 16 | Viewed by 2514

Abstract

This study aimed to systematically compare licochalcone A (LicA) and glabridin (Gla) (whitening agents) release and permeation from Carbomer 940 (CP) hydrogels with different enhancers, and evaluate the relationship between the quantitative enhancement efficacy and structures of the enhancers. An in vitro release [...] Read more.

This study aimed to systematically compare licochalcone A (LicA) and glabridin (Gla) (whitening agents) release and permeation from Carbomer 940 (CP) hydrogels with different enhancers, and evaluate the relationship between the quantitative enhancement efficacy and structures of the enhancers. An in vitro release study and an in vitro permeation experiment in solution and hydrogels using porcine skin were performed. We found that the Gla–CP hydrogel showed a higher drug release and skin retention amount than LicA–CP due to the higher solubility in medium and better miscibility with the skin of Gla than that of LicA. Enhancers with a higher molecular weight (MW) and lower polarizability showed a higher release enhancement effect (ER_release) for both LicA and Gla. The Van der Waals forces in the drug–enhancers–CP system were negatively correlated with the drug release percent. Moreover, enhancers with a higher log P and polarizability displayed a higher retention enhancement effect in solution (ER_{solution retention}) for LicA and Gla. Enhancers decreased the whole intermolecular forces indrug–enhancers-skin system, which had a linear inhibitory effect on the drug retention. Moreover, C=O of ceramide acted asthe enhancement site for drug permeation. Consequently, Transcutol^® P (TP) and propylene glycol (PG), seven enhancers showed a higher retention enhancement effect in hydrogel (ER_{hydrogel retention}) for LicA and Gla. Taken together, the conclusions provide a strategy for reasonable utilization of enhancers and formulation optimization in topical hydrogel whitening. Full article

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

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28 pages, 12678 KiB

Open AccessArticle

Intranasal Zolmitriptan-Loaded Bilosomes with Extended Nasal Mucociliary Transit Time for Direct Nose to Brain Delivery

by Mai M. El Taweel, Mona H. Aboul-Einien, Mohammed A. Kassem and Nermeen A. Elkasabgy

Pharmaceutics 2021, 13(11), 1828; https://doi.org/10.3390/pharmaceutics13111828 - 01 Nov 2021

Cited by 30 | Viewed by 3156

Abstract

This study aimed at delivering intranasal zolmitriptan directly to the brain through preparation of bilosomes incorporated into a mucoadhesive in situ gel with extended nasal mucociliary transit time. Zolmitriptan-loaded bilosomes were constructed through a thin film hydration method applying Box–Behnken design. The independent [...] Read more.

This study aimed at delivering intranasal zolmitriptan directly to the brain through preparation of bilosomes incorporated into a mucoadhesive in situ gel with extended nasal mucociliary transit time. Zolmitriptan-loaded bilosomes were constructed through a thin film hydration method applying Box–Behnken design. The independent variables were amount of sodium deoxycholate and the amount and molar ratio of cholesterol/Span^® 40 mixture. Bilosomes were assessed for their entrapment efficiency, particle size and in vitro release. The optimal bilosomes were loaded into mucoadhesive in situ gel consisting of poloxamer 407 and hydroxypropyl methylcellulose. The systemic and brain kinetics of Zolmitriptan were evaluated in rats by comparing intranasal administration of prepared gel to an IV solution. Statistical analysis suggested an optimized bilosomal formulation composition of sodium deoxycholate (5 mg) with an amount and molar ratio of cholesterol/Span^® 40 mixture of 255 mg and 1:7.7, respectively. The mucoadhesive in situ gel containing bilosomal formulation had a sol-gel temperature of 34.03 °C and an extended mucociliary transit time of 22.36 min. The gelling system possessed enhanced brain bioavailability compared to bilosomal dispersion (1176.98 vs. 835.77%, respectively) following intranasal administration. The gel revealed successful brain targeting with improved drug targeting efficiency and direct transport percentage indices. The intranasal delivery of mucoadhesive in situ gel containing zolmitriptan-loaded bilosomes offered direct nose-to-brain drug targeting with enhanced brain bioavailability. Full article

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

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15 pages, 1623 KiB

Open AccessArticle

[¹⁸F]2-Fluoro-2-deoxy-sorbitol PET Imaging for Quantitative Monitoring of Enhanced Blood-Brain Barrier Permeability Induced by Focused Ultrasound

by Gaëlle Hugon, Sébastien Goutal, Ambre Dauba, Louise Breuil, Benoit Larrat, Alexandra Winkeler, Anthony Novell and Nicolas Tournier

Pharmaceutics 2021, 13(11), 1752; https://doi.org/10.3390/pharmaceutics13111752 - 20 Oct 2021

Cited by 18 | Viewed by 2766

Abstract

Focused ultrasound in combination with microbubbles (FUS) provides an effective means to locally enhance the delivery of therapeutics to the brain. Translational and quantitative imaging techniques are needed to noninvasively monitor and optimize the impact of FUS on blood-brain barrier (BBB) permeability in [...] Read more.

Focused ultrasound in combination with microbubbles (FUS) provides an effective means to locally enhance the delivery of therapeutics to the brain. Translational and quantitative imaging techniques are needed to noninvasively monitor and optimize the impact of FUS on blood-brain barrier (BBB) permeability in vivo. Positron-emission tomography (PET) imaging using [¹⁸F]2-fluoro-2-deoxy-sorbitol ([¹⁸F]FDS) was evaluated as a small-molecule (paracellular) marker of blood-brain barrier (BBB) integrity. [¹⁸F]FDS was straightforwardly produced from chemical reduction of commercial [¹⁸F]2-deoxy-2-fluoro-D-glucose. [¹⁸F]FDS and the invasive BBB integrity marker Evan’s blue (EB) were i.v. injected in mice after an optimized FUS protocol designed to generate controlled hemispheric BBB disruption. Quantitative determination of the impact of FUS on the BBB permeability was determined using kinetic modeling. A 2.2 ± 0.5-fold higher PET signal (n = 5; p < 0.01) was obtained in the sonicated hemisphere and colocalized with EB staining observed post mortem. FUS significantly increased the blood-to-brain distribution of [¹⁸F]FDS by 2.4 ± 0.8-fold (V_T; p < 0.01). Low variability (=10.1%) of V_T values in the sonicated hemisphere suggests reproducibility of the estimation of BBB permeability and FUS method. [¹⁸F]FDS PET provides a readily available, sensitive and reproducible marker of BBB permeability to noninvasively monitor the extent of BBB disruption induced by FUS in vivo. Full article

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

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Review

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16 pages, 1085 KiB

Open AccessReview

Targeting the Blood–Brain Tumor Barrier with Tumor Necrosis Factor-α

by Angelo Corti, Teresa Calimeri, Flavio Curnis and Andres J. M. Ferreri

Pharmaceutics 2022, 14(7), 1414; https://doi.org/10.3390/pharmaceutics14071414 - 06 Jul 2022

Cited by 4 | Viewed by 4296

Abstract

The blood–brain tumor barrier represents a major obstacle for anticancer drug delivery to brain tumors. Thus, novel strategies aimed at targeting and breaching this structure are of great experimental and clinical interest. This review is primarily focused on the development and use of [...] Read more.

The blood–brain tumor barrier represents a major obstacle for anticancer drug delivery to brain tumors. Thus, novel strategies aimed at targeting and breaching this structure are of great experimental and clinical interest. This review is primarily focused on the development and use of a derivative of tumor necrosis factor-α (TNF) that can target and alter the blood–brain-tumor-barrier. This drug, called NGR-TNF, consists of a TNF molecule fused to the Cys-Asn-Gly-Arg-Cys-Gly (CNGRCG) peptide (called NGR), a ligand of aminopeptidase N (CD13)-positive tumor blood vessels. Results of preclinical studies suggest that this peptide-cytokine fusion product represents a valuable strategy for delivering TNF to tumor vessels in an amount sufficient to break the biological barriers that restrict drug penetration in cancer lesions. Moreover, clinical studies performed in patients with primary central nervous system lymphoma, have shown that an extremely low dose of NGR-TNF (0.8 µg/m²) is sufficient to promote selective blood–brain-tumor-barrier alteration, increase the efficacy of R-CHOP (a chemo-immunotherapy regimen) and improve patient survival. Besides reviewing these findings, we discuss the potential problems related to the instability and molecular heterogeneity of NGR-TNF and review the various approaches so far developed to obtain more robust and homogeneous TNF derivatives, as well as the pharmacological properties of other peptide/antibody-TNF fusion products, muteins and nanoparticles that are potentially useful for targeting the blood–brain tumor barrier. Compared to other TNF-related drugs, the administration of extremely low-doses of NGR-TNF or its derivatives appear as promising non-immunogenic approaches to overcome TNF counter-regulatory mechanism and systemic toxicity, thereby enabling safe breaking of the BBTB. Full article

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

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14 pages, 1876 KiB

Open AccessReview

Strategies for Targeted Delivery of Exosomes to the Brain: Advantages and Challenges

by Hojun Choi, Kyungsun Choi, Dae-Hwan Kim, Byung-Koo Oh, Hwayoung Yim, Soojin Jo and Chulhee Choi

Pharmaceutics 2022, 14(3), 672; https://doi.org/10.3390/pharmaceutics14030672 - 18 Mar 2022

Cited by 34 | Viewed by 7116

Abstract

Delivering therapeutics to the central nervous system (CNS) is difficult because of the blood–brain barrier (BBB). Therapeutic delivery across the tight junctions of the BBB can be achieved through various endogenous transportation mechanisms. Receptor-mediated transcytosis (RMT) is one of the most widely investigated [...] Read more.

Delivering therapeutics to the central nervous system (CNS) is difficult because of the blood–brain barrier (BBB). Therapeutic delivery across the tight junctions of the BBB can be achieved through various endogenous transportation mechanisms. Receptor-mediated transcytosis (RMT) is one of the most widely investigated and used methods. Drugs can hijack RMT by expressing specific ligands that bind to receptors mediating transcytosis, such as the transferrin receptor (TfR), low-density lipoprotein receptor (LDLR), and insulin receptor (INSR). Cell-penetrating peptides and viral components originating from neurotropic viruses can also be utilized for the efficient BBB crossing of therapeutics. Exosomes, or small extracellular vesicles, have gained attention as natural nanoparticles for treating CNS diseases, owing to their potential for natural BBB crossing and broad surface engineering capability. RMT-mediated transport of exosomes expressing ligands such as LDLR-targeting apolipoprotein B has shown promising results. Although surface-modified exosomes possessing brain targetability have shown enhanced CNS delivery in preclinical studies, the successful development of clinically approved exosome therapeutics for CNS diseases requires the establishment of quantitative and qualitative methods for monitoring exosomal delivery to the brain parenchyma in vivo as well as elucidation of the mechanisms underlying the BBB crossing of surface-modified exosomes. Full article

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

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22 pages, 1983 KiB

Open AccessReview

Strategies to Overcome Biological Barriers Associated with Pulmonary Drug Delivery

by Adam J. Plaunt, Tam L. Nguyen, Michel R. Corboz, Vladimir S. Malinin and David C. Cipolla

Pharmaceutics 2022, 14(2), 302; https://doi.org/10.3390/pharmaceutics14020302 - 27 Jan 2022

Cited by 12 | Viewed by 5782

Abstract

While the inhalation route has been used for millennia for pharmacologic effect, the biological barriers to treating lung disease created real challenges for the pharmaceutical industry until sophisticated device and formulation technologies emerged over the past fifty years. There are now several inhaled [...] Read more.

While the inhalation route has been used for millennia for pharmacologic effect, the biological barriers to treating lung disease created real challenges for the pharmaceutical industry until sophisticated device and formulation technologies emerged over the past fifty years. There are now several inhaled device technologies that enable delivery of therapeutics at high efficiency to the lung and avoid excessive deposition in the oropharyngeal region. Chemistry and formulation technologies have also emerged to prolong retention of drug at the active site by overcoming degradation and clearance mechanisms, or by reducing the rate of systemic absorption. These technologies have also been utilized to improve tolerability or to facilitate uptake within cells when there are intracellular targets. This paper describes the biological barriers and provides recent examples utilizing formulation technologies or drug chemistry modifications to overcome those barriers. Full article

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

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28 pages, 2102 KiB

Open AccessReview

The Monoterpenoid Perillyl Alcohol: Anticancer Agent and Medium to Overcome Biological Barriers

by Thomas C. Chen, Clovis O. da Fonseca, Daniel Levin and Axel H. Schönthal

Pharmaceutics 2021, 13(12), 2167; https://doi.org/10.3390/pharmaceutics13122167 - 16 Dec 2021

Cited by 14 | Viewed by 3537

Abstract

Perillyl alcohol (POH) is a naturally occurring monoterpenoid related to limonene that is present in the essential oils of various plants. It has diverse applications and can be found in household items, including foods, cosmetics, and cleaning supplies. Over the past three decades, [...] Read more.

Perillyl alcohol (POH) is a naturally occurring monoterpenoid related to limonene that is present in the essential oils of various plants. It has diverse applications and can be found in household items, including foods, cosmetics, and cleaning supplies. Over the past three decades, it has also been investigated for its potential anticancer activity. Clinical trials with an oral POH formulation administered to cancer patients failed to realize therapeutic expectations, although an intra-nasal POH formulation yielded encouraging results in malignant glioma patients. Based on its amphipathic nature, POH revealed the ability to overcome biological barriers, primarily the blood–brain barrier (BBB), but also the cytoplasmic membrane and the skin, which appear to be characteristics that critically contribute to POH’s value for drug development and delivery. In this review, we present the physicochemical properties of POH that underlie its ability to overcome the obstacles placed by different types of biological barriers and consequently shape its multifaceted promise for cancer therapy and applications in drug development. We summarized and appraised the great variety of preclinical and clinical studies that investigated the use of POH for intranasal delivery and nose-to-brain drug transport, its intra-arterial delivery for BBB opening, and its permeation-enhancing function in hybrid molecules, where POH is combined with or conjugated to other therapeutic pharmacologic agents, yielding new chemical entities with novel mechanisms of action and applications. Full article

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

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Novel Approaches for Overcoming Biological Barriers

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