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Efficient delivery of highly lipophilic drugs or prodrugs to the mesenteric lymph nodes (MLN) can be achieved following oral administration with lipids. However, it remains unclear ...which specific MLN can be targeted and to what extent. Moreover, the efficiency of drug delivery to the retroperitoneal lymph nodes (RPLN) has not been assessed. The aim of this study was to assess the distribution of a highly lipophilic model drug cannabidiol (CBD), known to undergo intestinal lymphatic transport following administration with lipids, into specific MLN and RPLN in rats at various time-points post dosing. In vivo studies showed that at 2 h following administration, significantly higher concentrations of CBD were present in the region second from the apex of the MLN chain. From 3 h following administration, concentrations in all MLN were similar. CBD was also found at substantial levels in RPLN. This study demonstrates that drug concentrations in specific MLN are different, at least at the peak of the absorption process. Moreover, in addition to the MLN, the RPLN may also be targeted by oral route of administration, which may have further implications for treatment of a range of diseases.
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We have employed microfluidics (cross-shaped chip) for the preparation of drug-loaded poly(lactic acid-co-glycolic acid) (PLGA) nanoparticles. The polymer precipitates from an acetone ...solution upon its controlled laminar mixing (flow focusing) with an aqueous solution of a surfactant, allowing for an operator-independent, up-scalable and reproducible preparative process of nanoformulations.
Firstly, using PEGylated surfactants we have compared batch and microfluidic processes, and showed the superior reproducibility of the latter and its strong dependency on the acetone/water ratio (flow rate ratio). We have then focused on the issue of purification from free surfactant, and employed advanced characterization techniques such as flow-through dynamic light scattering as the in-line quality control technique, and field flow fractionation (FFF) with dynamic and static light scattering detection, which allowed the detection of surfactant micelles in mixture with nanoparticles (hardly possible with stand-alone dynamic light scattering). Finally, we have shown that the choice of polymer and surfactant affects the release behaviour of a model drug (paclitaxel), with high molecular weight PLGA (RG756) and low molecular weight surfactant (tocopheryl poly(ethylene glycol) 1000 succinate, TPGS) apparently showing higher burst and accelerated release.
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•Drug-dendrimer conjugates are complex drug delivery systems which fall under the nanomaterials family.•The physicochemical characterization of AZD0466, a drug-dendrimer conjugate in ...clinical trials, by orthogonal techniques is reported.•The results helped to identify the stage and techniques to use to measure Critical Quality Attributes (CQAs) of drug-dendrimer conjugates.
A deep and detailed understanding of drug-dendrimer conjugates key properties is needed to define the critical quality attributes that affect drug product performance. The characterization must be executed both in the formulation media and in biological matrices. This, nevertheless, is challenging on account of a very limited number of suitable, established methods for characterizing the physicochemical properties, stability, and interaction with biological environment of complex drug-dendrimer conjugates. In order to fully characterize AZD0466, a drug-dendrimer conjugate currently under clinical development by AstraZeneca, a collaboration was initiated with the European Nanomedicine Characterisation Laboratory to deploy a state-of-the-art multi-step approach to measure physicochemical properties. An incremental complexity characterization approach was applied to two batches of AZD0466 and the corresponding dendrimer not carrying any drug, SPL-8984. Thus, the aim of this work is to guide in depth characterization efforts in the analysis of drug-dendrimer conjugates. Additionally, it serves to highlight the importance of using the adequate complementary techniques to measure physical and chemical stability in both simple and biological media, to drive a complex drug-dendrimer conjugate product from discovery to clinical development.
Nanoparticle (NP) formulations are inherently polydisperse making their structural characterization and justification of specifications complex. It is essential, however, to gain an understanding of ...the physico-chemical properties that drive performance in vivo. To elucidate these properties, drug-containing poly(lactic acid) (PLA)-poly(ethylene glycol) (PEG) block polymeric NP formulations (or PNPs) were sub-divided into discrete size fractions and analyzed using a combination of advanced techniques, namely cryogenic transmission electron microscopy, small-angle neutron and X-ray scattering, nuclear magnetic resonance, and hard-energy X-ray photoelectron spectroscopy. Together, these techniques revealed a uniquely detailed picture of PNP size, surface structure, internal molecular architecture and the preferred site(s) of incorporation of the hydrophobic drug, AZD5991, properties which cannot be accessed via conventional characterization methodologies. Within the PNP size distribution, it was shown that the smallest PNPs contained significantly less drug than their larger sized counterparts, reducing overall drug loading, while PNP molecular architecture was critical in understanding the nature of in vitro drug release. The effect of PNP size and structure on drug biodistribution was determined by administrating selected PNP size fractions to mice, with the smaller sized NP fractions increasing the total drug-plasma concentration area under the curve and reducing drug concentrations in liver and spleen, due to greater avoidance of the reticuloendothelial system. In contrast, administration of unfractionated PNPs, containing a large population of NPs with extremely low drug load, did not significantly impact the drug's pharmacokinetic behavior - a significant result for nanomedicine development where a uniform formulation is usually an important driver. We also demonstrate how, in this study, it is not practicable to validate the bioanalytical methodology for drug released in vivo due to the NP formulation properties, a process which is applicable for most small molecule-releasing nanomedicines. In conclusion, this work details a strategy for determining the effect of formulation variability on in vivo performance, thereby informing the translation of PNPs, and other NPs, from the laboratory to the clinic.
Hybrids composed of liposomes (L) and metallic nanoparticles (NPs) hold great potential for imaging and drug delivery purposes. However, the efficient incorporation of metallic NPs into liposomes ...using conventional methodologies has so far proved to be challenging. In this study, we report the fabrication of hybrids of liposomes and hydrophobic gold NPs of size 2–4 nm (Au) using a microfluidic-assisted self-assembly process. The incorporation of increasing amounts of AuNPs into liposomes was examined using microfluidics and compared to L–AuNP hybrids prepared by the reverse-phase evaporation method. Our microfluidics strategy produced L–AuNP hybrids with a homogeneous size distribution, a smaller polydispersity index, and a threefold increase in loading efficiency when compared to those hybrids prepared using the reverse-phase method of production. Quantification of the loading efficiency was determined by ultraviolet spectroscopy, inductively coupled plasma mass spectroscopy, and centrifugal field flow fractionation, and qualitative validation was confirmed by transmission electron microscopy. The higher loading of gold NPs into the liposomes achieved using microfluidics produced a slightly thicker and more rigid bilayer as determined with small-angle neutron scattering. These observations were confirmed using fluorescent anisotropy and atomic force microscopy. Structural characterization of the liposomal–NP hybrids with cryo-electron microscopy revealed the coexistence of membrane-embedded and interdigitated NP-rich domains, suggesting AuNP incorporation through hydrophobic interactions. The microfluidic technique that we describe in this study allows for the automated production of monodisperse liposomal–NP hybrids with high loading capacity, highlighting the utility of microfluidics to improve the payload of metallic NPs within liposomes, thereby enhancing their application for imaging and drug delivery.
Abstract
Treatment for glioblastoma multiforme (GBM) consists of surgery, radiotherapy and temozolomide (TMZ) chemotherapy. Nevertheless, patient prognosis remains poor; in England 5-year survival is ...< 10%. Resistance to TMZ is a major obstacle thwarting successful treatment, due to overexpression of the O6-methylguanine DNA-methyltransferase (MGMT) and deficiency in mismatch repair (MMR). To overcome resistance, novel N3-substituted analogues of TMZ have been developed. An N3-propargyl analogue, T3, has promising activity irrespective of MGMT or MMR status. However, poor brain drug bioavailability and systemic toxicity remain to be resolved. We use apoferritin (AFt) as a biocompatible nano-delivery system for encapsulation of therapeutic agents via molecular diffusion, through channels in the AFt cage. Around 520 molecules of TMZ and T3 per AFt cage were encapsulated. AFt`s small size (diameter: 12 nm) and numerous transferrin receptor recognition sites on its surface; alongside enhanced expression of transferrin receptors (TfR1; which sequester AFt) on the membranes of cancer cells, offer a dual targeting approach towards greater cancer-selectivity. The encapsulated agents have demonstrated significantly increased anti-tumour activity in brain cancer GBM cell lines, U373V (vector control) and U373M (MGMT over-expressing), with growth inhibition GI50 values < 1 μM, compared to > 30 μM for naked drugs. Clonogenic and cell cycle analyses further corroborate these findings. Hence, the AFt nano-delivery system offers a promising route for enhanced specificity, selectivity and potency of TMZ analogues.
Despite some notable successes, there are still relatively few agents approved for cancer prevention. Here we review progress thus far in the development of medicines for cancer prevention, and we ...outline some key concepts that could further enable or accelerate drug development for cancer prevention in the future. These are summarized under six key themes: (i) unmet clinical need, (ii) patient identification, (iii) risk stratification, (iv) pharmacological intervention, (v) clinical trials, and (vi) health care policy. These concepts, if successfully realized, may help to increase the number of medicines available for cancer prevention.
The huge potential public health benefits of preventing cancer, combined with recent advances in the availability of novel early detection technologies and new treatment modalities, has caused us to revisit the opportunities and challenges associated with developing medicines to prevent cancer. Here we review progress in the field of developing medicines to prevent cancer to date, and we present a series of ideas that might help in the development of more medicines to prevent cancer in the future.
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Clustering superparamagnetic iron oxide nanoparticles (SPIONs) is one method of providing the biomedical benefits of larger SPIONs e.g. superior T2 weighted magnetic resonance imaging ...(MRI) contrast without increasing particle size. The work presented herein, describes the facile synthesis of clustered SPIONs that are suitable for MRI applications, by using a chitosan based polymer: N-palmitoyl-N-monomethyl-N-N-dimethyl-N-N-N-trimethyl-6-O-glycolchitosan (GCPQ) and aqueous nanoprecipitation followed by probe sonication, in the absence of organic solvents or elevated temperatures. The resulting clustered SPIONs consist of individual 8 nm iron oxide nanoparticles clustered into a 150 nm particle with a positive zeta potential (+23 mV) at neutral pH. X-ray diffraction confirms the presence of crystalline magnetic iron oxide, while magnetometer experiments show the clustered SPIONs are superparamagnetic giving an overall Ms of 63.5 ± 1.3 emu g−1. Relaxometry analyses revealed that the clustered SPIONs (inclusive of coatings) had a high r2 value of 294.8 mM−1 s−1 and an r2/r1 of 21.1 making the clustered SPIONs suitable for T2 weighted (negative) MRI contrast imaging applications. The resulting clustered SPIONs demonstrate that highly sensitive T2 contrast agents may be produced in mild room temperature conditions, without the need for organic solvents or low molecular weight surfactants.
A physiologically based pharmacokinetic model was developed to describe the tissue distribution kinetics of a dendritic nanoparticle and its conjugated active pharmaceutical ingredient (API) in ...plasma, liver, spleen, and tumors. Tumor growth data from MV-4-11 tumor-bearing mice were incorporated to investigate the exposure/efficacy relationship. The nanoparticle demonstrated improved antitumor activity compared to the conventional API formulation, owing to the extended released API concentrations at the site of action. Model simulations further enabled the identification of critical parameters that influence API exposure in tumors and downstream efficacy outcomes upon nanoparticle administration. The model was utilized to explore a range of dosing schedules and their effect on tumor growth kinetics, demonstrating the improved antitumor activity of nanoparticles with less frequent dosing compared to the same dose of naked APIs in conventional formulations.
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