Combined visible and near-infrared OPA for wavelength scaling experiments in strong-field physics

We report the operation of an optical parametric amplifier (OPA) capable of producing gigawatt peak-power laser pulses with tunable wavelength in either the visible or near-infrared spectrum. The OPA has two distinct operation modes (i) generation of >350 uJ, sub 100 fs pulses, tunable between 1250 - 1550 nm; (ii) generation of >190 uJ, sub 150 fs pulses tunable between 490 - 530 nm. We have recorded high-order harmonic spectra over a wide range of driving wavelengths. This flexible source of femtosecond pulses presents a useful tool for exploring the wavelength-dependence of strong-field phenomena, in both the multi-photon and tunnel ionization regimes.Comment: 14 pages, 9 figures, This paper was published in Proceedings of SPIE 10088, Nonlinear Frequency Generation and Conversion: Materials and Devices XVI, doi 10.1117/12.225077

Designing Highly Stable Poly(sarcosine)-Based Telodendrimer Micelles with High Drug Content Exemplified with Fulvestrant

Polymeric micelles have been extensively used as nanocarriers for the delivery of chemotherapeutic agents, aiming to improve their efficacy in cancer treatment. However, the poor loading capacity, premature drug release, non-uniformity, and reproducibility still remain the major challenges. To create a stable polymeric micelle with high drug loading, a telodendrimer micelle was developed as a nanocarrier for fulvestrant, as an example of a drug that has extremely poor water solubility (sub-nanomolar range). Telodendrimers were prepared by the synthesis of hydrophilic linear poly(sarcosine) and growing a lysine dendron from the chain terminal amine by divergent synthesis. At the periphery of the dendritic block, either 4, 8, or 16 fulvestrant molecules were conjugated to the lysine dendron creating a hydrophobic block. Having drug molecules as a part of the carrier not only reduces the usage of the inert carrier materials but also prevents the drugs from leakage and premature release by diffusion. The self-assembled telodendrimer micelles demonstrated good colloidal stability (cmc < 2 mu M) in buffer and were uniform in size. In addition, these telodendrimer micelles could solubilize additional fulvestrant yielding an excellent overall drug loading capacity of up to 77 wt % total drug load (summation of conjugated and encapsulated). Importantly, the size of the micelles could be tuned between 25 and 150 nm by controlling (i) the ratio between hydrophilic and hydrophobic blocks and (ii) the amount of encapsulated fulvestrant. The versatility of these telodendrimer-based micelle systems to both conjugated and encapsulated drugs with high efficiency and stability, in addition to possessing other tuneable properties, makes it a promising drug delivery system for a range of active pharmaceutical ingredients and therapeutic targets.Peer reviewe

Evaluation of the critical quality attributes of lipid nanoparticles stored under different conditions

Lipid nanoparticles (LNPs) are emerging new modalities for mRNA therapeutics which have been in the spotlight for the past decade. Since these are relatively new drug delivery systems compared to conventional medicines, new analytical techniques for the robust characterization of their critical quality attributes (CQAs) are needed [1]. It has been reported that several stimuli can affect the stability of the LNPs such as leakage of the nucleic acid cargo from the nanoparticle and LNP aggregation, resulting in low translation efficiency. Hence, understanding the duration of stability is key during formulation development. The aim of the present study is to evaluate the stability of PolyA-LNPs: 1) Stored at different temperatures (4oC and 25oC); 2) Dialysed in the absence and presence of cryoprotectant sucrose. We measured the impact of the above storage conditions on LNP physicochemical parameters

Rapid nano-gram scale screening method of micro-arrays to evaluate drug-polymer blends using high-throughput printing technology

A miniaturized, high-throughput assay was optimized to screen polymer-drug solid dispersions using a 2-D Ink-jet printer. By simply printing nanoliter amounts of polymer and drug solutions onto an inert surface, drug:polymer micro-dots of tunable composition were produced in an easily-addressable micro-array format. The amount of material printed for each dried spot ranged from 25 ng to 650 ng. These arrays were used to assess the stability of drug:polymer dispersions with respect to recrystallization, using polarized light microscopy. One array with a panel of 6 drugs formulated at different ratios with Poly (vinylpyrrolidone-vinyl acetate) copolymer (PVPVA) was developed to estimate a possible bulk (gram-scale) approximation threshold from the final printed nano amount of formulation. Another array was printed at a fixed final amount of material to establish a literature comparison of one drug formulated with different commercial polymers for validation. This new approach may offer significant efficiency in pharmaceutical formulation screening, with each experiment in the nano-micro-array format requiring from 3 up to 6 orders of magnitude lower amounts of sample than conventional screening methods

Physicochemical characterisation of poly(A) lipid nanoparticles : effect of cryoprotectant and temperature storage conditions

Lipid nanoparticles (LNPs) are emerging new modalities for mRNA therapeutics which have been in the spotlight for the past decade. Since these are relatively new drug delivery systems compared to conventional medicines, new analytical techniques for the robust characterization of their critical quality attributes (CQAs) are needed [1]. It has been reported that several stimuli can affect the stability of the LNPs such as leakage of the nucleic acid cargo from the nanoparticle and LNP aggregation, resulting in low translation efficiency [2]. Hence, understanding the duration of stability is key during formulation development. The aim of the present study is to evaluate the stability of PolyA-LNPs: 1) Stored at different temperatures (4oC and 25oC); 2) Dialysed in the absence and presence of cryoprotectant sucrose. We measured the impact of the above storage conditions on LNP physicochemical parameters

Real time Raman imaging to understand dissolution performance of amorphous solid dispersions

We have employed for the first time Raman spectroscopic imaging along with multi-variate curve resolution (MCR) analysis to investigate in real time and in-situ the dissolution mechanisms that underpin amorphous solid dispersions, with data being collected directly from the dosage form itself. We have also employed a novel rotating disk dissolution rate (RDDR) methodology to track, through the use of high-performance liquid chromatography (HPLC), the dissolution trends of both drug and polymer simultaneously in multi-component systems. Two formulations of poorly water-soluble felodipine in a polymeric matrix of copovidone VA64 which have different drug loadings of 5% and 50% w/w were used as models with the aim of studying the effects of increasing the amount of active ingredient on the dissolution performance. It was found that felodipine and copovidone in the 5% dispersion dissolve with the same dissolution rate and that no Raman spectral changes accompanied the dissolution, indicating that the two components dissolve as single entity, whose behaviour is dominated by water-soluble copovidone. For the 50% drug-loaded dispersion, partial RDDR values of both felodipine and copovidone were found to be extremely low. MCR Raman maps along with classical Raman/X-ray powder diffraction (XRPD) characterisation revealed that after an initial loss of copovidone from the extrudate the drug re-crystallises, pointing to a release dynamics dependent on the low water solubility and high hydrophobicity of felodipine. Raman imaging revealed different rates of transition from amorphous to crystalline felodipine at different locations within the dosage form

Designing Highly Stable Poly(sarcosine)-based Telodendrimer Micelles with High Drug Content Exemplified with Fulvestrant

Polymeric micelles have been extensively used as nanocarriers for the delivery of chemotherapeutic agents aiming to improve their efficacy in cancer treatment. However, poor loading capacity, premature drug release, non-uniformity and reproducibility still remain the major challenges. To create a stable polymeric micelle with high drug loading, a telodendrimer micelle was developed as a nanocarrier for fulvestrant, as an example of a drug that has extremely poor water solubility (sub nanomolar range). Telodendrimers were prepared by synthesis of a hydrophilic linear poly(sarcosine) and growing a lysine dendron from the chain terminal amine by a divergent synthesis. At the periphery of the dendritic block, 4, 8, and 16 fulvestrant molecules were conjugated to the lysine dendron creating a hydrophobic block. Having drug as part of the carrier not only reduces the usage of the inert carrier materials but also prevent the drugs from leakage and premature release by diffusion. The self-assembled telodendrimer micelles demonstrated good colloidal stability (CMC < 2 µM) in buffer and were uniform in size. In addition, these telodendrimer micelles could solubilize additional fulvestrant yielding an excellent overall drug loading capacity of up to 77 wt.% total drug load (summation of conjugated and encapsulated). Importantly, the size of the micelles could be tuned between 25-150 nm by controlling (i) the ratio between hydrophilic and hydrophobic blocks and (ii) the amount of encapsulated fulvestrant. The versatility of these telodendrimer-based micelle systems to both conjugate and encapsulate drug with high efficiency and stability, in addition to possessing other tuneable properties makes it a promising drug delivery system for a range of active pharmaceutical ingredients and therapeutic targets

<i>In Vitro</i> Release from Polymeric Core/Shell Nanoparticles through the Lens of Multiscale Modeling

The large number of studies involving nanoparticles for cancer therapy is due to their peculiar features: they protect loaded active molecules while extending circulation time and can extravasate from the blood flow to the tumor to deliver drugs directly in the target area. Mathematical modeling can provide a preliminary in silico exploration of design space to optimize an experimental activity that often relies on a trial-and-error approach. However, because of the characteristic size of these vectors (10–1000 nm), numerous phenomena of interest occur at different time and length scales, making a single modeling technique insufficient to fully characterize the system of interest. In this work we employed a multiscale modeling approach, which bridges the phenomena of interest across different scales, to study the in vitro release from polymeric core/shell nanoparticles for cancer therapy loaded with an active compound assembled as a hydrophobic ion pair. The “computational microscope” provided by molecular dynamics simulations was used to track drug molecules through the release process at an atomic scale. The outcomes suggested that the drug is mainly partitioned in the polymer and released as hydrophobic ion pair rather than a free molecule, and that the hydrophobic ion pair is preferentially partitioned in Tween 20 micelles in the release media. A model at macroscale, aimed at describing the release rate and elucidating the release mechanism, was developed according to the results from molecular simulations and validated against experimental data. The outcomes provided insights that are challenging to be obtained experimentally and which supported the development and validation of a release model at macroscale. Overall, the adopted multiscale approach corroborated the experimental findings and provided significant insights into the mechanisms of release