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Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 154
Author(s):  
Francisco Javier de La Mata ◽  
Paula Ortega ◽  
Sandra García-Gallego

The COVID-19 pandemic showed more deeply the need of our society to provide new therapeutic strategies to fight infectious diseases, not only against currently known illnesses, where common antibiotics and drugs appear to be not fully effective, but also against new infectious threats that may arise [...]


Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 153
Author(s):  
Arif Khan ◽  
Mohammed A. Alsahli ◽  
Mohammad A. Aljasir ◽  
Hamzah Maswadeh ◽  
Mugahid A. Mobark ◽  
...  

Thymoquinone (TQ), which is one of the main bioactive constituents of Nigella sativa seeds, has demonstrated its potential against various cancer models. The poor solubility of TQ in aqueous solution limits its uses in clinical application. The present study aimed to develop a novel formulation of TQ to increase its bioavailability and therapeutic potential with minimal toxicity. Polyethylene glycol (PEG)-coated DSPC/cholesterol comprising TQ liposomes (PEG-Lip-TQ) were prepared and characterized on various aspects. A computational investigation using molecular docking was used to assess the possible binding interactions of TQ with 12 prospective anticancer drug targets. The in vitro anticancer activity was assessed in A549 and H460 lung cancer cells in a time- and dose-dependent manner, while the oral acute toxicity assay was evaluated in silico as well as in vivo in mice. TQ docked to the Hsp90 target had the lowest binding energy of −6.05 kcal/mol, whereas caspase 3 was recognized as the least likely target for TQ with a binding energy of −1.19 kcal/mol. The results showed 96% EE with 120 nm size, and −10.85 mv, ζ-potential of PEG-Lip-TQ, respectively. The cell cytotoxicity data demonstrated high sensitivity of PEG-Lip-TQ and a several fold decrease in the IC50 while comparing free TQ. The cell cycle analysis showed changes in the distribution of cells with doses. The in vivo data revealed an ~9-fold increase in the LD50 of PEG-Lip-TQ on free TQ as an estimated 775 and 89.5 mg/kg b.w, respectively. This study indicates that the pharmacological and efficacy profile of PEG-lip-TQ is superior to free TQ, which will pave the way for an exploration of the effect of TQ formulation in the treatment of lung cancer in clinical settings.


Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 151
Author(s):  
Aditya R. Darade ◽  
Maria Lapteva ◽  
Thomas Hoffmann ◽  
Markus Mandler ◽  
Achim Schneeberger ◽  
...  

In vitro transcribed messenger ribonucleic acid (mRNA) constitutes an emerging therapeutic class with several clinical applications. This study presents a systematic comparison of different technologies—intradermal injection, microneedle injection, jet injection, and fractional laser ablation—for the topical cutaneous delivery of mRNA. Delivery of Cy5 labeled mRNA and non-labeled enhanced green fluorescent protein (eGFP) expressing mRNA was investigated in a viable ex vivo porcine skin model and monitored for 48 h. Forty 10 µm-thick horizontal sections were prepared from each skin sample and Cy5 labeled mRNA or eGFP expression visualized as a function of depth by confocal laser scanning microscopy and immunohistochemistry. A pixel-based method was used to create a semi-quantitative biodistribution profile. Different spatial distributions of Cy5 labeled mRNA and eGFP expression were observed, depending on the delivery modality; localization of eGFP expression pointed to the cells responsible. Delivery efficiencies and knowledge of delivery sites can facilitate development of efficient, targeted mRNA-based therapeutics.


Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 147
Author(s):  
Adriana Trapani ◽  
Stefania Cometa ◽  
Elvira De Giglio ◽  
Filomena Corbo ◽  
Roberta Cassano ◽  
...  

A widely investigated approach to bypass the blood brain barrier is represented by the intranasal delivery of therapeutic agents exploiting the olfactory or trigeminal connections nose-brain. As for Parkinson’s disease (PD), characterized by dopaminergic midbrain neurons degeneration, currently there is no disease modifying therapy. Although several bio-nanomaterials have been evaluated for encapsulation of neurotransmitter dopamine (DA) or dopaminergic drugs in order to restore the DA content in parkinsonian patients, the premature leakage of the therapeutic agent limits this approach. To tackle this drawback, we undertook a study where the active was linked to the polymeric backbone by a covalent bond. Thus, novel nanoparticles (NPs) based on N,O-Carboxymethylchitosan-DA amide conjugate (N,O-CMCS-DA) were prepared by the nanoprecipitation method and characterized from a technological view point, cytotoxicity and uptake by Olfactory Ensheating Cells (OECs). Thermogravimetric analysis showed high chemical stability of N,O-CMCS-DA NPs and X-ray photoelectron spectroscopy evidenced the presence of amide linkages on the NPs surface. MTT test indicated their cytocompatibility with OECs, while cytofluorimetry and fluorescent microscopy revealed the internalization of labelled N,O-CMCS-DA NPs by OECs, that was increased by the presence of mucin. Altogether, these findings seem promising for further development of N,O-CMCS-DA NPs for nose-to-brain delivery application in PD.


Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 149
Author(s):  
Michael Choi ◽  
Stuart C. Porter ◽  
Axel Meisen

Oral solid dosage forms that contain APIs in the amorphous state have become commonplace because of many drug substances exhibiting poor water solubility, which negatively impacts their absorption in the human GI tract. While micronization, solvent spray-drying, and hot-melt extrusion can address solubility issues, spray coating of the APIs onto beads and tablets offers another option for producing amorphous drug products. High-level comparisons between bead and tablet coating technologies have the potential for simpler equipment and operation that can reduce the cost of development and manufacturing. However, spray coating directly onto tablets is not without challenges, especially with respect to meeting uniformity acceptance value (AV) criteria, comprising accuracy (mean) and precision (variance) objectives. The feasibility of meeting AV criteria is examined, based on mathematical models for accuracy and precision. The results indicate that the main difficulty in manufacturing satisfactory drug-layered tablets by spray coating is caused by the practical limitations of achieving the necessary coating precision. Despite this limitation, it is shown that AV criteria can be consistently met by appropriate materials monitoring and control as well as processing equipment setup, operation, and maintenance.


Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 152
Author(s):  
Daniela Baracaldo-Santamaría ◽  
Daniel Felipe Ariza-Salamanca ◽  
María Gabriela Corrales-Hernández ◽  
Maria José Pachón-Londoño ◽  
Isabella Hernandez-Duarte ◽  
...  

Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality. Consequences vary from mild cognitive impairment to death and, no matter the severity of subsequent sequelae, it represents a high burden for affected patients and for the health care system. Brain trauma can cause neuronal death through mechanical forces that disrupt cell architecture, and other secondary consequences through mechanisms such as inflammation, oxidative stress, programmed cell death, and, most importantly, excitotoxicity. This review aims to provide a comprehensive understanding of the many classical and novel pathways implicated in tissue damage following TBI. We summarize the preclinical evidence of potential therapeutic interventions and describe the available clinical evaluation of novel drug targets such as vitamin B12 and ifenprodil, among others.


Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 150
Author(s):  
Siddesh V. Hartimath ◽  
Boominathan Ramasamy ◽  
Tan Yun Xuan ◽  
Tang Jun Rong ◽  
Shivashankar Khanapur ◽  
...  

Immune checkpoint inhibitors (ICIs) block checkpoint receptors that tumours use for immune evasion, allowing immune cells to target and destroy cancer cells. Despite rapid advancements in immunotherapy, durable response rates to ICIs remains low. To address this, combination clinical trials are underway assessing whether adjuvants can enhance responsiveness by increasing tumour immunogenicity. CpG-oligodeoxynucleotides (CpG-ODN) are synthetic DNA fragments containing an unmethylated cysteine-guanosine motif that stimulate the innate and adaptive immune systems by engaging Toll-like receptor 9 (TLR9) present on the plasmacytoid dendritic cells (pDCs) and B cells. Here, we have assessed the ability of AlF-mNOTA-GZP, a peptide tracer targeting granzyme B, to serve as a PET imaging biomarker in response to CpG-ODN 1585 in situ vaccine therapy delivered intratumourally (IT) or intraperitoneally (IP) either as monotherapy or in combination with αPD1. [18F]AlF-mNOTA-GZP was able to differentiate treatment responders from non-responders based on tumour uptake. Furthermore, [18F]AlF-mNOTA-GZP showed positive associations with changes in tumour-associated lymphocytes expressing GZB, namely GZB+ CD8+ T cells, and decreases in suppressive F4/80+ cells. [18F]AlF-mNOTA-GZP tumour uptake was mediated by GZB expressing CD8+ cells and successfully stratifies therapy responders from non-responders, potentially acting as a non-invasive biomarker for ICIs and combination therapy evaluation in a clinical setting.


Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 148
Author(s):  
Woo Tak Lee ◽  
Johyun Yoon ◽  
Sung Soo Kim ◽  
Hanju Kim ◽  
Nguyen Thi Nguyen ◽  
...  

Combined therapy using photothermal and photodynamic treatments together with chemotherapeutic agents is considered one of the most synergistic treatment protocols to ablate hypoxic tumors. Herein, we sought to fabricate an in situ-injectable PEG hydrogel system having such multifunctional effects. This PEG hydrogel was prepared with (i) nabTM-technique-based paclitaxel (PTX)-bound albumin nanoparticles with chlorin-e6 (Ce6)-conjugated bovine serum albumin (BSA-Ce6) and indocyanine green (ICG), named ICG/PTX/BSA-Ce6-NPs (~175 nm), and (ii) an albumin-stabilized perfluorocarbon (PFC) nano-emulsion (BSA-PFC-NEs; ~320 nm). This multifunctional PEG hydrogel induced moderate and severe hyperthermia (41−42 °C and >48 °C, respectively) at the target site under two different 808 nm laser irradiation protocols, and also induced efficient singlet oxygen (1O2) generation under 660 nm laser irradiation supplemented by oxygen produced by ultrasound-triggered PFC. Due to such multifunctionality, our PEG hydrogel formula displayed significantly enhanced killing of three-dimensional 4T1 cell spheroids and also suppressed the growth of xenografted 4T1 cell tumors in mice (tumor volume: 47.7 ± 11.6 and 63.4 ± 13.0 mm3 for photothermal and photodynamic treatment, respectively, vs. PBS group (805.9 ± 138.5 mm3), presumably based on sufficient generation of moderate heat as well as 1O2/O2 even under hypoxic conditions. Our PEG hydrogel formula also showed excellent hyperthermal efficacy (>50 °C), ablating the 4T1 tumors when the irradiation duration was extended and output intensity was increased. We expect that our multifunctional PEG hydrogel formula will become a prototype for ablation of otherwise poorly responsive hypoxic tumors.


Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 142
Author(s):  
Sherif Ashraf Fahmy ◽  
Noha Khalil Mahdy ◽  
Hadeer Al Mulla ◽  
Aliaa Nabil ElMeshad ◽  
Marwa Y. Issa ◽  
...  

Antimicrobial drugs face numerous challenges, including drug resistance, systemic toxic effects, and poor bioavailability. To date, treatment choices are limited, which warrants the search for novel potent antivirals, including those extracted from natural products. The seeds of Peganum harmala L. (Zygophyllaceae family) have been reported to have antimicrobial, antifungal, and anticancer activities. In the present study, a 2-hydroxy propyl-β-cyclodextrin (HPβCD)/harmala alkaloid-rich fraction (HARF) host–guest complex was prepared using a thin-film hydration method to improve the water solubility and bioavailability of HARF. The designed complex was then co-encapsulated with ascorbic acid into PLGA nanoparticles coated with polyethylene glycol (HARF–HPßCD/[email protected] NPs) using the W/O/W multiple emulsion-solvent evaporation method. The average particle size, PDI, and zeta potential were 207.90 ± 2.60 nm, 0.17 ± 0.01, and 31.6 ± 0.20 mV, respectively. The entrapment efficiency for HARF was 81.60 ± 1.20% and for ascorbic acid was 88 ± 2.20%. HARF–HPßCD/[email protected] NPs had the highest antibacterial activity against Staphylococcus aureus and Escherichia coli (MIC of 0.025 mg/mL). They also exhibited high selective antiviral activity against the H1N1 influenza virus (IC50 2.7 μg/mL) without affecting the host (MDCK cells). In conclusion, the co-encapsulation of HPCD–HARF complex and ascorbic acid into PLGA-PEG nanoparticles significantly increased the selective H1N1 killing activity with minimum host toxic effects.


Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 146
Author(s):  
Yingnan Si ◽  
Kai Chen ◽  
Hanh Giai Ngo ◽  
Jia Shiung Guan ◽  
Angela Totoro ◽  
...  

Triple-negative breast cancers (TNBCs) are heterogeneous and metastatic, and targeted therapy is highly needed for TNBC treatment. Recent studies showed that extracellular vesicles (EV) have great potential to deliver therapies to treat cancers. This study aimed to develop and evaluate a natural compound, verrucarin A (Ver-A), delivered by targeted EV, to treat TNBC. First, the surface expression of epidermal growth factor receptor (EGFR) and CD47 were confirmed with immunohistochemistry (IHC) staining of patient tissue microarray, flow cytometry and Western blotting. EVs were isolated from HEK 293F culture and surface tagged with anti-EGFR/CD47 mAbs to construct mAb-EV. The flow cytometry, confocal imaging and live-animal In Vivo Imaging System (IVIS) demonstrated that mAb-EV could effectively target TNBC and deliver the drug. The drug Ver-A, with dosage-dependent high cytotoxicity to TNBC cells, was packed in mAb-EV. The anti-TNBC efficacy study showed that Ver-A blocked tumor growth in both 4T1 xenografted immunocompetent mouse models and TNBC patient-derived xenograft models with minimal side effects. This study demonstrated that the targeted mAb-EV-Ver-A had great potential to treat TNBCs.


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