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Nanoparticles (NPs) have gained importance in addressing drug delivery challenges across biological barriers. Here, we reformulated pentamidine, a drug used to treat Human African Trypanosomiasis (HAT) in polymer based nanoparticles and liposomes and compared their capability to enhance pentamidine penetration across blood brain barrier (BBB). Size...
Citations
... The state of aggregation and the chemical form of a given metal are other factors affecting its toxic properties. Numerous animal studies have confirmed that NPs relatively quickly and easily overcome all the protective barriers of the body [8][9][10][11]. Works by Tjälve et al. [12], Oberdörster et al. [13], as well as Engin and Engin [14] have indicated that nanometer size particles reach the brain via the olfactory nerve. Therefore, they may come into contact with olfactory neurons in the olfactory epithelium, and be transported through olfactory cell axons to the olfactory bulb, where they directly affect the central nervous system [13]. ...
There is still little literature data on the toxicity and safety of the commonly used molybdenum (Mo) disulfide which is present in the working as well as living environments. Thus, an experiment was carried out involving rats, with single and repeated intratracheal exposure (in the latter case, 7 administrations at 2-week intervals with the analysis performed after 90 days) to lower (1.5 mg Mo kg−1 b.w.) and higher (5 mg Mo kg−1 b.w.) doses of molybdenum(IV) sulfide nanoparticles (MoS2-NPs) and microparticles (MoS2-MPs). The analysis of Mo concentrations in the tail and heart blood as well as in soft tissues (lung, liver, spleen, brain), after mineralization and bioimaging, was meant to facilitate an assessment of its accumulation and potential effects on the body following short- and long-term exposure. The multi-compartment model with an exponential curve of Mo concentration over time with different half-lives for the distribution and elimination phases of MoS2-MPs and MoS2-NPs was observed. After 24 h of exposure, a slight increase in Mo concentration in blood was observed. Next, Mo concentration indicated a decrease in blood concentration from 24 h to day 14 (the Mo concentration before the second administration), below the pre-exposure concentration. The next phase was linear, less abrupt and practically flat, but with an increasing trend towards the end of the experiment. Significantly higher Mo concentrations in MoS2-NPs and MoS2-MPs was found in the lungs of repeatedly exposed rats compared to those exposed to a single dose. The analysis of Mo content in the liver and the spleen tissue showed a slightly higher concentration for MoS2-NPs compared to MoS2-MPs. The results for the brain were below the calculated detection limit. Results were consistent with results obtained by bioimaging technique.
... Studies have demonstrated that liposomes and SLNs loaded with drugs such as pentamidine can effectively reduce parasitaemia in animal models of African trypanosomiasis with improved drug delivery efficacy. 31 For example, when using liposomes to assess drug delivery across the blood−brain barrier, it was observed that 87% of the encapsulated pentamidine reached its target, surpassing the delivery rate of the free drug. 31 This work illustrates how liposomal drug formulations represent a more efficient approach for delivering hydrophilic drugs, such as pentamidine, across biological membranes. ...
... 31 For example, when using liposomes to assess drug delivery across the blood−brain barrier, it was observed that 87% of the encapsulated pentamidine reached its target, surpassing the delivery rate of the free drug. 31 This work illustrates how liposomal drug formulations represent a more efficient approach for delivering hydrophilic drugs, such as pentamidine, across biological membranes. ...
Parasitic infections are a major global health issue causing significant mortality and morbidity. Despite substantial advances in the diagnostics and treatment of these diseases, the currently available options fall far short of expectations. From diagnosis and treatment to prevention and control, nanotechnology-based techniques show promise as an alternative approach. Nanoparticles can be designed with specific properties to target parasites and deliver antiparasitic medications and vaccines. Nanoparticles such as liposomes, nanosuspensions, polymer-based nanoparticles, and solid lipid nanoparticles have been shown to overcome limitations such as limited bioavailability, poor cellular permeability, nonspecific distribution, and rapid drug elimination from the body. These nanoparticles also serve as nanobiosensors for the early detection and treatment of these diseases. This review aims to summarize the potential applications of nanoparticles in the prevention, diagnosis, and treatment of parasitic diseases such as leishmaniasis, malaria, and trypanosomiasis. It also discusses the advantages and disadvantages of these applications and their market values and highlights the need for further research in this field.
... 51 Another reason for the low CNS availability of pentamidine could be its low membrane permeability. 56 Pentamidine uptake into T. b. cells is mediated by various parasite transporters: the P2 aminopurine transporter, the high-affinity pentamidine transporter (HAPT 1) and the low-affinity pentamidine transporter (LAPT 1). 49 Until now, the only human transporter involved in pentamidine uptake was OCT1 41,57 and, while OCT1 expression could be demonstrated in the immortalized human BBB model cell line hCMEC/D3, 57 OCT1 is a liver-type transporter 58,59 with low expression in BBB endothelial cells. ...
... 64 Pentamidine toxicity was investigated only in few human cell lines. 41,56 Based on our data, OATP1A2-mediated uptake can result in a dramatic increase of pentamidine toxicity. Oral pentamidine absorption is low; hence, it is generally administered intramuscularly or intravenously. ...
Organic anion transporting polypeptides OATP1A2, OATP1B1, OATP1B3 and OATP2B1 are Na⁺‐ and ATP‐independent exchangers of large, organic compounds, encompassing structurally diverse xenobiotics, including various drugs. These OATPs influence intestinal absorption (OATP2B1), hepatic clearance (OATP1B1/3) and blood to brain penetration (OATP1A2, OATP2B1) of their drug substrates. Consequently, OATP‐mediated drug or food interactions may lead to altered pharmacokinetics and toxicity. During drug development, investigation of hepatic OATP1B1 and OATP1B3 is recommended by international regulatory agencies. Most frequently, OATP‐drug interactions are investigated in an indirect assay, i.e., by examining uptake inhibition of a radioactive or fluorescent probe. However, indirect assays do not distinguish between transported substrates and non‐transported OATP inhibitors. To fill this hiatus, a novel assay, termed competitive counterflow (CCF) has been developed and has since been applied for several OATPs to differentiate between substrates and non‐transported inhibitors. However, previous OATP CCF assays, with the exception of that for OATP1B1, used radioactive probes. In the current study, we demonstrate that sulforhodamine 101 or pyranine can be used as fluorescent probes in a CCF assay to identify transported substrates of OATP1A2, or OATPs 1B1, 1B3 and 2B1, respectively. With the help of the newly developed fluorescence‐based CCF method, we identify the FDA‐approved anti‐protozoal drug, pentamidine as a unique substrate of OATP1A2. Furthermore, we confirm the selective, OATP1A2‐mediated uptake of pentamidine in a cytotoxicity assay. Based on our results, OATP1A2 may be an important determinant of pentamidine transport through the blood–brain barrier.
... NLB-SLN brain targeting was confirmed by noninvasive scintigraphy, reaching its maximum permeability eighth h after intranasal administration. Omarch et al. [145] conducted a comparative study; the authors developed polymeric PCL NPs and phosphatidylcholine LP to evaluate pentamidine in vitro transport through the BBB. The pentamidine-loaded PCL NPs had a mean size of 267.58 nm, PDI of 0.25, and zeta potential of -28.1 mV, while pentamidine-loaded LP had a mean size of 119.61 nm, PDI of 0.25, and zeta potential 11.78 mV. ...
Parkinson’s disease (PD) significantly affects patients’ quality of life and represents a high economic burden for health systems. Given the lack of safe and effective treatments for PD, drug repositioning seeks to offer new medication alternatives, reducing research time and costs compared to the traditional drug development strategy. This review aimed to collect evidence of drugs proposed as candidates to be reused in PD and identify those with the potential to be reformulated into nanocarriers to optimize future repositioning trials. We conducted a detailed search in PubMed, Web of Science, and Scopus from January 2015 at the end of 2021, with the descriptors “Parkinson’s disease” and “drug repositioning” or “drug repurposing”. We identified 28 drugs as potential candidates, and six of them were found in repositioning clinical trials for PD. However, a limitation of many of these drugs to achieve therapeutic success is their inability to cross the blood–brain barrier (BBB), as is the case with nilotinib, which has shown promising outcomes in clinical trials. We suggest reformulating these drugs in biodegradable nanoparticles (NPs) based on lipids and polymers to perform future trials. As a complementary strategy, we propose functionalizing the NPs surface by adding materials to the surface layer. Among other advantages, functionalization can promote efficient crossing through the BBB and improve the affinity of NPs towards certain brain regions. The main parameters to consider for the design of NPs targeting the central nervous system are highlighted, such as size, PDI, morphology, drug load, and Z potential. Finally, current advances in the use of NPs for Parkinson's disease are cited.
... Pentamidine-loaded nanoparticles and phosphatidylcholine liposomes were compared by Geofrey [72]. The goal of this study was to see if these two formulations could cross the blood-brain barrier in vitro. ...
... When the PDI of these two formulations was measured, it was discovered that freeze-dried pentamidine loaded liposomes had a PDI greater than 0.6. Non-lyophilized pentamidine loaded PCL NPs, on the other hand, showed particle size uniformity with a low PDI (0.25 ± 0.15) and lower aggregation [72]. ...
For non-small cell lung cancer (NSCLC) treatment, a BCS class II drug, Gefitinib, was widely used. Due to poor bioavailability, uncontrollable drug release, Gefitinib witnessed side effects. To circumvent such associated problems, optimized Gefitinib encapsulated polycaprolactone (PCL) nanoparticles with three different molecular weights of PCL (average Mn∼10,000, Mn∼45,000 & Mn∼80,000) were developed using Box–Behnken design while understanding the influence of critical process parameters of the nanoparticles. For morphological characterizations, SEM, TEM, AFM were used. Hemocompatibility, platelet aggregation, and erythrocyte membrane integrity tests were used to test nanoparticles for biocompatibility; excellent biocompatibility was reported during these tests. The in-vitro drug release studies confirmed that Gefitinib-PCL10,000NPs, Gefitinib-PCL45,000NPs, and Gefitinib-PCL80,000 NPs, show significant initial burst effects, and later nanoparticles possessed zero-order kinetics. The genotoxicity of PCL nanoparticles was assessed by cytokinesis-block micronucleus (CBMN) assay, indicating DNA damage in NCI-H460 cell and micronuclei and nuclear buds’ formation. Further, reactive oxygen species studies, MTT cytotoxicity assays at 24 & 48 h, stability, in-vitro cellular uptake of optimized fluorescent Gefitinib PCL80,000NPs, and apoptosis studies were also carried out. As a result, investigating stable Gefitinib-loaded poly-caprolactone (PCL) nanoparticles could open up new research avenues, potentially lowering side effects and improving Gefitinib's profile in the treatment of NSCLC.
... Their spherical shape decreased from 345 to 270 nm after complexation with PTM, with a negative zeta potential value of around −30 mV and 12% drug release over a period of 24 h. The integrity of the BBB was evaluated in vitro on brain endothelial cells after loaded and unloaded nanoparticles were added; no significant tight junction alterations were observed, while loaded nanoparticles were shown to transport 66% of the PTM across the BBB [116]. ...
Pentamidine (PTM), which is a diamine that is widely known for its antimicrobial activity, is a very interesting drug whose mechanism of action is not fully understood. In recent years, PTM has been proposed as a novel potential drug candidate for the treatment of mental illnesses, myotonic dystrophy, diabetes, and tumors. Nevertheless, the systemic administration of PTM causes severe side effects, especially nephrotoxicity. In order to efficiently deliver PTM and reduce its side effects, several nanosystems that take advantage of the chemical characteristics of PTM, such as the presence of two positively charged amidine groups at physiological pH, have been proposed as useful delivery tools. Polymeric, lipidic, inorganic, and other types of nanocarriers have been reported in the literature for PTM delivery, and they are all in different development phases. The available approaches for the design of PTM nanoparticulate delivery systems are reported in this review, with a particular emphasis on formulation strategies and in vitro/in vivo applications. Furthermore, a critical view of the future developments of nanomedicine for PTM applications, based on recent repurposing studies, is provided.
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... Infusion-related adverse effects and nephrotoxicity are its major limiting parameters [42]. Pentamidine (PTM) therapy is often accompanied by problems such as painful necrotic injection site lesions, nephrotoxicity, and hypoglycemia; the main reasons for its poor adherence and associated lower cure rates [43,44]. The discovery of anti-leishmanial activity of MFS is, merely, a novelty because it is the first oral anti-leishmanial drug for the treatment of Leishmaniasis [45,46]. ...
... Orally administered NPs were found to exhibit a remarkable reduction in organ mass (liver and spleen) and parasitic burden in the murine model induced by L. infantum [44,149]. In addition, multiple studies aiming to fabricate oral NPs have been conducted and some potentially important ones are mentioned in Table 3. ...
As a neglected tropical disease, Leishmaniasis is significantly instigating morbidity and mortality across the globe.
Its clinical spectrum varies from ulcerative cutaneous lesions to systemic immersion causing hyperthermic hepatosplenomegaly.
Curbing leishmanial parasite is toughly attributable to the myriad obstacles in existing chemotherapy
and immunization. Since the 1990s, extensive research has been conducted for ameliorating disease prognosis, by
resolving certain obstacles of conventional therapeutics viz. poor efficacy, systemic toxicity, inadequate drug accumulation
inside the macrophage, scarce antigenic presentation to body’s immune cells, protracted length and cost
of the treatment. Mentioned hurdles can be restricted by designing nano-drug delivery system (nano-DDS) of extant
anti-leishmanials, phyto-nano-DDS, surface modified—mannosylated and thiolated nano-DDS. Likewise, antigen
delivery with co-transportation of suitable adjuvants would be achievable through nano-vaccines. In the past decade,
researchers have engineered nano-DDS to improve the safety profile of existing drugs by restricting their release
parameters. Polymerically-derived nano-DDS were found as a suitable option for oral delivery as well as SLNs due to
pharmacokinetic re-modeling of drugs. Mannosylated nano-DDS have upgraded macrophage internalizing of nanosystem
and the entrapped drug, provided with minimal toxicity. Cutaneous Leishmaniasis (CL) was tackling by the utilization
of nano-DDS designed for topical delivery including niosomes, liposomes, and transfersomes. Transfersomes,
however, appears to be superior for this purpose. The nanotechnology-based solution to prevent parasitic resistance
is the use of Thiolated drug-loaded and multiple drugs loaded nano-DDS. These surfaces amended nano-DDS possess
augmented IC50
values in comparison to conventional drugs and un-modified nano-DDS. Phyto-nano-DDS, another
obscure horizon, have also been evaluated for their anti-leishmanial response, however, more intense assessment is
a prerequisite. Impoverished Cytotoxic T-cells response followed by Leishmanial antigen proteins delivery have also
been vanquished using nano-adjuvants. The eminence of nano-DDS for curtailment of anti-leishmanial chemotherapy
and immunization associated challenges are extensively summed up in this review. This expedited approach is
ameliorating the Leishmaniasis management successfully. Alongside, total to partial eradication of this disease can be
sought along with associated co-morbidities.
... Among them, vector-mediated brain delivery, involving enhanced brain bioavailability through drug-carrier conjugates, seems particularly promising because of its versatility and reduced side effects compared to other delivery options (Li et al., 2017;Gondim et al., 2019). Omarch et al. (2019) investigated the permeability of polycaprolactone nanoparticles and liposomes containing both pentamidine across a monolayer of immortalized mouse brain endothelioma cells. Pentamidine-loaded polycaprolactone nanoparticles showed a mean diameter of 267.6 nm and zeta potential of −28.1 mV, whereas liposomes had a mean diameter of 119.6 nm and zeta potential of 11.78. ...
Trypanosomatid-caused conditions (African trypanosomiasis, Chagas disease, and leishmaniasis) are neglected tropical infectious diseases that mainly affect socioeconomically vulnerable populations. The available therapeutics display substantial limitations, among them limited efficacy, safety issues, drug resistance, and, in some cases, inconvenient routes of administration, which made the scenarios with insufficient health infrastructure settings inconvenient. Pharmaceutical nanocarriers may provide solutions to some of these obstacles, improving the efficacy–safety balance and tolerability to therapeutic interventions. Here, we overview the state of the art of therapeutics for trypanosomatid-caused diseases (including approved drugs and drugs undergoing clinical trials) and the literature on nanolipid pharmaceutical carriers encapsulating approved and non-approved drugs for these diseases. Numerous studies have focused on the obtention and preclinical assessment of lipid nanocarriers, particularly those addressing the two currently most challenging trypanosomatid-caused diseases, Chagas disease, and leishmaniasis. In general, in vitro and in vivo studies suggest that delivering the drugs using such type of nanocarriers could improve the efficacy–safety balance, diminishing cytotoxicity and organ toxicity, especially in leishmaniasis. This constitutes a very relevant outcome, as it opens the possibility to extended treatment regimens and improved compliance. Despite these advances, last-generation nanosystems, such as targeted nanocarriers and hybrid systems, have still not been extensively explored in the field of trypanosomatid-caused conditions and represent promising opportunities for future developments. The potential use of nanotechnology in extended, well-tolerated drug regimens is particularly interesting in the light of recent descriptions of quiescent/dormant stages of Leishmania and Trypanosoma cruzi, which have been linked to therapeutic failure.
... Hence, there is a pressing need for the development of efficient strategies to overcome the challenges in antifungal therapy. To address this need, nanoparticles are emerging as novel potential antifungal agents (Kathiresan et al. 2010;Ogar et al. 2015;Parveen et al. 2018;Pinto et al. 2013;Pulit et al. 2013;Rodrigues et al. 2013;Xu et al. 2013;Yu et al. 2013) as well as novel carriers of antifungal drugs (Khames et al. 2019;Omarch et al. 2019;Pereira et al. 2019;Spadari et al. 2019;Wang et al. 2019). ...
Over the past several years, numerous studies have demonstrated the feasibility of using engineered nanoparticles as antifungals, especially against those fungal pathogens that produce mycotoxins and infect plants, animals, and humans. The high dosage of nanoparticles has been a concern in such antifungal applications due to the potential toxicological and ecotoxicological impacts. To address such concerns, we have recently introduced the idea of inhibiting mycotoxin biosynthesis using low doses of engineered nanoparticles. At such low doses these particles are minimally toxic to humans and the environment. From our studies we realize that for the effective use of nanotechnology to intervene in the biology of fungal pathogens and for an accurate evaluation of the impacts of the increasingly growing nanomaterials in the environment on fungi and their interacting biotic partners, there is a pressing need for a rigorous understanding of nano-fungal interactions, which is currently far from complete. In this minireview, we build on the available evidence from nano-bio interaction research and our recent interaction studies with Aspergillus cells and engineered silver nanoparticles to introduce a potential theoretical model for nano-fungal interactions. The aim of the proposed model is to provide an initial insight on how nanoparticle uptake and their transformation inside fungal cells, possibly influence the production of mycotoxins and other secondary metabolites of filamentous fungi .
... Sortilin mAb, in the case of brain tumors), which act as a great therapeutic agent in highly-selective drug delivery, are also unable to cross BBB. Thus, researchers are focusing on different strategies executable for delivery of small therapeutic medications across BBB and more specifically to the target brain cells [89,90]. In this context, efficient nanoscale drug delivery systems are being developed to overcome the limitations related to the BBB (Fig. 6). ...
Obviously, delivery of the medications to the brain is more difficult than other tissues due to the existence of a strong obstacle, which is called blood-brain barrier (BBB). Because of the lipophilic nature of this barrier, it would be a complex (and in many cases impossible) process to cross the medications with hydrophilic behavior from BBB and deliver them to the brain. Thus, novel intricate drug-carriers in nano scales have been recently developed and suitably applied for this purpose. One of the most important categories of these hydrophilic medications, are reactivators for acetyl cholinesterase (AChE) enzyme that facilitates the breakdown of acetylcholine (as a neurotransmitter). The AChE function is inhibited by organophosphorus (OP) nerve agents that are extremely used in military conflicts. In this review, the abilities of the nanosized drug delivery systems to perform as suitable vehicles for AChE reactivators are comprehensively discussed.
