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Drug Delivery and Translational Research is a journal published by CRS, providing a unique forum for scientific publication of high-quality research that is exclusively focused on translational aspects of drug delivery. The journal is published 6 times a year and will be available online to CRS members as part of their annual dues.
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We welcome research focused on the following areas of translational drug delivery research:
- Designing and developing novel drug delivery systems, with a focus on their application to disease conditions
- Preclinical and clinical data related to drug delivery systems
- Drug distribution, pharmacokinetics, clearance, with drug delivery systems as compared to traditional dosing to demonstrate beneficial outcomes
- Short-term and long-term biocompatibility of drug delivery systems, host response
- Biomaterials with growth factors for stem-cell differentiation in regenerative medicine and tissue engineering
- Image-guided drug therapy
- Nanomedicine
- Devices for drug delivery and drug/device combination products
In addition to original full-length papers, communications, and reviews, the journal will also include editorials, reports of future meetings, research highlights, and announcements pertaining to the activities of CRS.
DDTR Research Editors DDTR Editorial Board
What's New?
Check out the November 2024 Best Paper in Drug Delivery and Translational Research
Irinotecan is one of only two regulatory approved drugs to be administered directly into the resection cavity of glioblastoma patients during resection surgery. A Phase I safety study demonstrated that the intraparenchymal administration or irinotecan was safe. In this study, we formulated irinotecan into PLGA implants for sustained local delivery directly to the tumour margin, gamma sterilised them and demonstrated using a clinically relevant, highly aggressive and invasive patient derived xenograft mouse resection model of glioblastoma their ability to stop tumor recurrence, resulting in long-term survival with no significant toxicity. The poor prognosis of glioblastoma, necessitates the development of highly effective treatments that are safe and well tolerated by patients. For this reason, these irinotecan/PLGA implants have the potential to be transformative for glioblastoma patients. Furthermore, the ability to GMP manufacture the implants and gamma sterilize them means that they could be quickly translated into the clinic.
Unlocking the Potential of Nanomedicine: Advances in Precision Targeting Strategies
RGD-coated polymeric microbubbles promote ultrasound-mediated drug delivery in an
inflamed endothelium-pericyte co-culture model of the blood-brain barrier
https://link.springer.com/article/10.1007/s13346-024-01561-6
Drug delivery to the brain is limited by the blood-brain barrier (BBB). Sonopermeation, which
combines ultrasound (US) and microbubbles (MBs), is a promising strategy to temporarily
open the BBB and enhance drug delivery. We developed an advanced in vitro BBB model
using human cerebral endothelial cells and pericytes to study the effects of sonopermeation
on the delivery of a large polymeric drug carrier (pHPMA) and a small molecule drug
(ribavirin) under normal and inflamed conditions. By measuring trans-endothelial electrical
resistance (TEER), we found that sonopermeation significantly reduced the TEER values
and increased the translocation of pHPMA. Inflammation was induced with tumor necrosis
factor, mimicking the conditions in tumors and CNS infections. RGD-coated MBs specifically
targeted inflamed endothelium, enhancing the delivery of both pHPMA and ribavirin across
the BBB. Our study demonstrates how combining in vitro BBB models with targeted
sonopermeation can optimize drug delivery to the (inflamed) brain, laying the foundation for
future research.
September 2024
Nose to brain delivery of mirtazapine via lipid nanocapsules: Preparation, statistical optimization, radiolabeling, in vivo biodistribution and pharmacokinetic study
https://link.springer.com/article/10.1007/s13346-024-01528-7
Mirtazapine (MZP) is an FDA-approved antidepressant drug but suffer from low bioavailability, which is only 50% despite its rapid absorption after oral administration. This study seeks to deliver MZP intranasally to the brain via lipid nanocapsules (LNCs). MZP-LNCs were constructed by solvent-free phase inversion temperature technique applying D-Optimal mixture design to study the impact of formulation variables, including percentage of Labrafac oil, Solutol, and water, on the characterization of the formulated nanocapsules. The optimized MZP-LNCs exhibited spherical morphology, particle diameter of 20.59 nm, z-potential of -5.71 mV, PDI of 0.223, and solubilization capacity of 7.21 mg/g. The in vivo pharmacokinetics of the intranasally administered MZP-LNCs in brain and blood were correlated with intravenously and intranasally administered MZP solution in mice. In vivo biodistribution analysis revealed that MZP-LNCs were able to deliver greater MZP amount to the brain, with lesser blood MZP levels, compared to MZP solution. Overall, MZP-LNCs showed greater nose-to-brain delivery compared to MZP solution.
The selection of animal models influences the assessment of anti-tumor efficacy:
promising sialic acid-conjugate modified liposomes demonstrate remarkable therapeutic
effects in diverse mouse strains
https://link.springer.com/article/10.1007/s13346-023-01502-9
Mouse models serves as a crucial tool for preclinical assessment of antineoplastic agents, but
the impact of physiological differences among mouse strains on in vivo antitumor efficacy has
been overlooked. Mononuclear phagocyte system (MPS) is the major player in clearance in
vivo, and differences in MPS among different strains may potentially impact the effectiveness of
antitumor preparations. We thus employed conventional liposomes (CL-EPI) and sialic acid-
octadecamine-modified liposomes (SAL-EPI) as model preparations to compare the therapeutic
effects in tumor-bearing KM, BALB/c, and C57BL/6 mice. The results demonstrated significant
variability in the efficacy of CL-EPI for tumor treatment across different mouse strains,
necessitating careful selection of animal models. SAL-EPI effectively targeted tumor sites by
binding to Siglec-1 on the surface of peripheral blood monocytes (PBMs) and achieved
uniformly improved therapeutic effect in different mouse strains. The sialic acid-modified
preparation is therefore expected to achieve a favorable therapeutic effect in tumor patients with
different immune states through PBMs delivery (Siglec-1 was expressed in both mice and
humans), thereby possessing clinical translational value and promising development prospects.
The Innovation of Microneedle Technologies for Drug Delivery Applications:
November 2023 Issue
Intravenous injection of cyclosporin A loaded lipid nanocapsules fights inflammation and immune system activation in a mouse model of diabetic retinopathy).
https://link.springer.com/article/10.1007/s13346-023-01350-7
Summary:
Inflammation and immune system activation are key pathologic events in the onset and
escalation of diabetic retinopathy (DR). Both are driven by cytokines and complement
originating from the retinal pigment epithelium (RPE). Despite the RPE’s pivotal role, there is no
therapeutic tool to specifically interfere with the RPE-mediated pathology of DR. Here, we
utilized lipoprotein-mimetic lipid nanocapsules to deliver the anti-inflammatory and
immunosuppressive drug cyclosporin A (CsA) to RPE cells. Using a mouse model of DR that
mirrors all pathologic aspects of human DR, we demonstrate that intravenously applied CsA-
loaded lipid nanocapsules comprehensively counteract inflammation and immune system
activation. One single injection suppressed the expression of pro-inflammatory cytokines,
dampened macrophage infiltration, and prevented macrophage and microglia activation in eyes
with DR. This work shows that CsA-loaded lipid nanocapsules can offer new avenues for the
treatment of DR.
Nebulizers effectiveness on pulmonary delivery of alpha1 antitrypsin
https://link.springer.com/article/10.1007/s13346-023-01346-3
Summary:
The administration of nebulized alpha-1 antitrypsin (AAT) to the lung represents an interesting
alternative to parenteral infusion for patients suffering from AAT genetic deficiency (AATD).
However, nebulization of proteins can have a dramatic effect on their activity. In this paper, a
formulation of AAT for infusion was nebulized with a jet or a mesh vibrating system, whose
performance was compared in terms of aerosolization efficiency and preservation of AAT function.
The two nebulizers allowed a satisfactory preservation of protein activity and provided equivalent
aerosolization performances, while the delivered dose was higher with the mesh vibrating system.
Nebulization of AAT proved to be a suitable administration strategy ready to be translated to the
clinical practice for direct lung delivery of the protein in AATD patients, either as a support therapy
to parenteral administration or, for subjects with a precocious diagnosis, as a means to prevent the
onset of pulmonary symptoms.
Neuronal differentiation and functional maturation of neurons from neural stem cells
induced by bFGF-chitosan controlled release system
https://link.springer.com/article/10.1007/s13346-023-01322-x
Summary:
Available methods for differentiating stem cells into functional neurons require numerous
cytokines and neurotrophic factors, and the process is highly complex, slow, inefficient, and
costly for clinical implementation. Here, we demonstrate a bioactive material, basic fibroblast
growth factor (bFGF)-chitosan controlled release system, facilitates neuronal differentiation from
neural stem cells (NSCs) and the functional maturation of the induced neurons with high
efficiency. Immunostaining revealed that the neurons derived from NSCs expressed mature
immunomarkers of interneurons and excitatory neurons. We also found by patch-clamp that the
induced neurons exhibited diverse electrophysiological properties as well as functional
synapses. In vivo, we implanted bFGF-chitosan into lesion area in traumatic brain injury mice
and observed abundance of neuroblasts in subventricular zone and the presence of newborn
functional neurons in injury area, which integrated into synaptic networks. Taken together, our
efficient and rapid tissue engineering approach provides a means to generate functional
neuronal lineage cells from stem cells and potentially to treat brain injury and diseases.
Drug Delivery and Translational Research – Best Paper August 2023 Issue
Summary:
https://link.springer.com/article/10.1007/s13346-022-01190-x
The discovery of proteins that neutralize vascular endothelial growth factors can inhibit the
process of angiogenesis to restore eyesight in individuals with retinal vascular disorders.
However, a safe and effective means to deliver these protein drugs to the target posterior
segment is currently lacking. To this end, we developed dissolving bilayer microneedles (MNs)
possessing the potential to deliver proteins to the back of the eye in an efficient and minimally
invasive manner. A model protein, ovalbumin (OVA), was incorporated into MNs fabricated from
different polymers, including hyaluronic acid, polyvinyl alcohol (PVA) and polyvinylpyrrolidone
(PVP). Optimized PVA/PVP MNs demonstrated robust permeation of porcine sclera with > 75%
of the needle length penetrating the sclera while dissolving within 150 s. SDS-PAGE and OVA-
specific ELISA revealed that the bioactivity of OVA was retained during the manufacture of MNs.
In hen’s egg-chorioallantoic membrane test, MNs fabricated from all chosen polymers were
classified as non-irritants. Furthermore, ex vivo permeation studies showed that optimized MNs
mediated the penetration of 86.99 ± 7.37% of OVA through the sclera, twice that of the needle-
free patch (42.16 ± 3.95%), highlighting the capability of MNs to circumvent physical barriers
and promote protein delivery to the posterior segment of the eye. Overall, a novel, efficient, and
safe intraocular protein delivery system was successfully established.
Drug Delivery and Translational Research – Best Paper July 2023 Issue
Summary:
https://link.springer.com/article/10.1007/s13346-023-01319-6
Despite recent clinical successes of the chimeric antigen receptor T cell therapy in treating liquid
cancers, numerous challenges hamper its broader translation. Macrophage has been proposed
as an alternative given its abilities in promoting tumor infiltration, acquiring diverse antigens, and
continuously stimulating adaptive responses. However, poor survival of transplanted
macrophages and transient retention of anti-tumor phenotype have been major obstacles.
Leveraging on recent discoveries of nanoparticle strategies addressing these limitations, we
herein report enhanced survival and phenotypic retention of macrophage transplants in murine
lungs by pre-treatment with nanoparticles of varying degradation rates. Poly(ethylene glycol)
diacrylate nanoparticles prolonged the survival of transplanted macrophages over untreated cells,
where nanoparticles increased the retention of transplanted cell counts by over 50%.
Furthermore, pre-treated macrophages more efficiently retained the pro-inflammatory-like
polarization state compared to macrophages pre-treated with a classical pro-inflammatory
stimulus, interferon-gamma, where CD86 costimulatory molecule expression was over 150%
greater in pre-treated macrophage transplants compared to untreated counterparts. These
findings provide an avenue for a major improvement in the lifespan and efficacy of macrophage-
based therapies and thus their broader therapeutic implementation.
Drug Delivery and Translational Research – Best Paper June 2023 Issue
Summary:
Sustained antigens delivery using composite microneedles for effective
epicutaneous immunotherapy Allergen-specific immunotherapy is an efficacious therapy for various allergic diseases such as
food allergy (FA). However, frequent clinical visits and potential adverse effects often hinder
patient compliance. Here, we proposed an implantable microneedle (MN) system composed of
OVA (antigen)-loaded silk MNs and a dissolvable, flexible polyvinyl alcohol (PVA) pedestal.
Once MNs are inserted into the skin, the PVA pedestal can quickly dissolve in the interstitial
fluid of the excised skin and implant the OVA-loaded silk MN tips in dermal layer as a sustained
antigen depot, thus inducing a long-lasting immune response. After receiving 3 doses of MN-
based immunotherapy, the immune response in OVA-sensitized mice was successfully
suppressed, with no apparent side effects. Compared to conventional subcutaneous
immunotherapy, MN immunotherapy ameliorated systemic anaphylaxis more effectively even at
a lower dose, demonstrating the antigen dose-sparing potential of the proposed MNs. Moreover,
due to the prolonged release effect of silk-PVA composite MNs, the frequency of
immunotherapy can be significantly reduced. Overall, through prolonged skin exposure to
antigen, this implantable designed MN may offer a new therapeutic strategy for FA treatment
with significant improvements in efficacy and convenience.
Drug Delivery and Translational Research – Best Paper May 2023 Issue
Summary:
Preterm-born infants are often susceptible to necrotizing enterocolitis (NEC), a terrible disease associated with impaired intestinal barrier properties, and are often empirically treated with intravenous broad-spectrum antibiotics. Yet, it is unclear how this antibiotic exposure, as well as the way they are dosed, affects the intestinal barrier and minimizes the risk of developing NEC. We show that permeability rates through intestinal mucosa from piglets dosed with the combination of enteral and parenteral antibiotics were comparable to the rates in untreated piglets, whereas the piglets dosed with parenteral antibiotics had lower permeability rates. Interestingly, decreased permeability rates through the mucus alone were evident, suggesting that the change in the mucosa permeability to a large extent was caused by altered mucus permeability. Mixing the antibiotics with untreated mucus had no effect, suggesting that the altered properties of mucus were caused by other associated events induced by the antibiotics.
Drug Delivery and Translational Research – Best Paper April 2023 Issue
Summary:
The analysis of gastrointestinal cellular permeation in pre-clinical drug development is widely
conducted, however the permeation of the overlying mucus layer is often overlooked. This is
attributed to a lack of understanding of the complexity of this layer, coupled with minimal
availability of experimental tools to quantify permeation through the turbid, viscous solution. Here,
a novel microfluidic device facilitates the observation of interactions between physicochemically
diverse nanocarriers and the mucin protein on a microscopic scale. This approach provides key
information on mucin-binding which may be lost with traditional methods and allows the
quantification of mucoadhesive as well as mucopermeating formulations. In addition, utilising a
complex biomimetic solution of proteins, lipids and salts which accurately mimics the chemistry and
rheology of native mucus within the device resulted in a 5.5-fold reduced permeation and 1.4-fold
reduced diffusivity of PLGA nanoparticles, compared to a more prevalent, simple mucus mimic.
Summary: Circular RNAs (circRNAs) are a class of highly stable and closed-loop noncoding RNA that are
involved in the occurrence and development of hepatocellular carcinoma (HCC). We found that
high circ_0058051 expression was negatively correlated with the prognosis of HCC patients.
We also showed here that circ_0058051 knockdown attenuated the proliferation and colony
formation, while inhibited migration of HCC cells. The findings underscore the potential of
circ_0058051 as a therapeutic target for HCC. We synthesized a novel small interfering RNA
(siRNA) delivery system, PEG-PCL-PEI-C14-SPIONs (PPPCSs), based on superparamagnetic
iron oxide nanoparticles (SPIONs). PPPCSs protected the siRNA of circ_0058051 from
degradation in serum and effectively delivered siRNA into SMMC-7721 cells. Meanwhile,
intravenous injection of the PPPCSs/siRNA complex could inhibit tumor growth in the
subcutaneous tumor model. In addition, the nanocomposite was not toxic to the organs of nude
mice. Collectively, PPPCSs/si-circ_0058051 complex may provide a novel and promising
method of HCC treatment.
Best Papers of the February 2023 Issue of DDTR (listed by corresponding authors):
Summary: Thymoquinone (TQ) is a quinone-based phenolic compound with antioxidant and anti-
inflammatory activities, but its therapeutic utility has been underexplored due to inadequate
biological stability, short half-life, low hydrophilicity, and poor systemic bioavailability.
Tamanu oil-stabilized nanostructured lipid carriers (TQ-NLCs) enriched with TQ were
prepared and optimized using Box-Behnken design with the size of 153.9 ± 0.5 nm and
surface charge of -30.7 mV. The encapsulation efficiency and drug loading density were
found to be 84.6 ± 0.5 % and 14.8 ± 0.5 %, respectively. The TQ-NLCs assayed for skin
permeation for transdermal delivery where TQ-NLC provided roughly 15 times greater
permeation compared to aqueous solution of TQ. Tamanu oil displayed a synergistic anti-
inflammatory potential with TQ in comparison to TQ alone in carrageenan-induced paw
oedema model and Freund's adjuvant-induced arthritic model. The arthritic and X-ray scores
significantly reduced in TQ-NLC-treated and standard formulation-treated groups. Moreover,
serum pro-inflammatory TNF-α and IL-6 levels were significantly reduced in TQ-NLC-treated
group compared to the arthritic control group.
Best Papers of the December 2022 Issue of DDTR (listed by corresponding authors):
Summary: We introduce a novel antiviral nano-drug called SNAT (Smart Nano-Enabled
Antiviral Therapeutic) composed of taxoid (Tx)-decorated amino (NH 2 )-functionalized silver
nanoparticles (Tx–[NH 2 -AgNPs]). The particles are around 5 nm in diameter, positively charged
and stable for over three years at room temperature. We assessed the preclinical efficacy of
inhaled SNAT where we found that SNAP significantly reversed the body weight loss, reduced
the virus load in oral swabs, and improved lung health of hamsters infected with SARS-CoV-2.
Further, SNAT was found to be noncytotoxic and antioxidant, potentially quenching lipid
peroxidation, in human lung epithelial cells and dermal fibroblasts. Overall, our study
collectively highlights SNAT as a safe and potent antiviral platform against SARS-CoV-2
infection and potentially other respiratory viruses of epidemic and pandemic potential.
Summary: A potent therapeutic option is sorely needed for triple negative breast cancer (TNBC) due to its clinical concerns, such as poor prognosis, drug resistance, and tumor recurrence. We here explored anti-cancer potential of synthetic cannabidiol (CBD; GLP grade) as a monotherapy or a chemosensitizer for doxorubicin (DOX) in TNBC (i.e., MDA-MB-231 and MDA-MB-468) cells. In comparison to 2D cultures, CBD showed greater IC 50 values in hydrogel-based 3D cultures of MDA-MB-231 and MDA-MB-468 cells. Next-generation RNA sequencing revealed GADD45A, GADD45G, FASN, LOX, and integrin (i.e., -α5, -β5) genes to be novelly altered by CBD in MDA-MB-231 cells. CIM-16 plate-based migration assay and western blotting analysis disclosed that CBD induced anti-migratory effects in TNBC cells. Western blotting, RT-qPCR, and immunocytochemistry revealed that CBD inhibited autophagy of TNBC cells. CBD pre-treatment increased DOX sensitivity in TNBC cells. CBD pre-treatment accompanied by DOX treatment decreased LOX, integrin-α5, and increased caspase 9 respectively in MDA-MB-468 cells.
Maria Jose Alonso: Quantification of the actual composition of polymeric nanocapsules: a quality control analysis
Summary: The exact compositions of nanocarriers are rarely described in the literature. However, this information is critical for understanding and/or predicting the biological behaviors of the nanocarriers. This paper describes for the first time the exact composition of polymeric nanocapsules using liquid chromatography-mass spectrometry methodology and the results shows that actual composition is significantly different from the theoretical one. While the work focuses on polymeric nanocapsules, this methodology can be broadly applicable to other nanosystems and would be crucial for understating protein corona formation and targeting capability of functionalized nanocarriers.
Perspective
Role of drug delivery technologies in the success of COVID-19 vaccines: a perspective
This newly published DDTR “Perspective” article discusses the roles of drug delivery technologies in developing safe and efficacious vaccines. We thank Drs. Robert Langer, Pieter Cullis, Olivia Merkel and Mark Prausnitz for sharing their perspectives and insights on this important topic.
DDTR Videos
Editor-in-Chief María José Alonso, PhD talks about DDTR, an official journal of the CRS.
Prof. Ben Boyd, President of the CRS and Editor of DDTR, talks about his experience with the DDTR, an official journal of the CRS.
Inspirational Note
This newly released Inspirational Note discusses critical considerations for the clinical implementation of nanomedicine.
Inspirational note by Martin J. Whitaker, Hiep Huatan and Richard J. Ross
The newly published Inspirational Note features innovative drug delivery technology that replicates the physiological cortisol diurnal rhythm for chronotherapy.
Inspirational note by James Goodson and Dr. Paul Rota
In this inspirational note, James Goodson and Dr. Paul Rota provide insightful and timely perspective and discussion regarding the importance of vaccine delivery technology and multidisciplinary efforts to achieve global vaccination and ultimately well-being.
Inspirational note by Dr. Andrew L. Lewis
Development and approval of rybelsus (oral semaglutide): ushering in a new era in peptide delivery
In this Inspirational Note, Dr. Andrew Lewis and coauthors feature an amazing and innovative discovery that is changing the paradigm of oral peptide delivery.
2020 DDTR Best Paper of the Year: Translational studies of intravenous and intracerebroventricular routes of administration for CNS cellular biodistribution for BMN 250, an enzyme replacement therapy for the treatment of Sanfilippo type B.
2019 DDTR Best Paper of the Year: Depletion of collagen by losartan to improve tumor accumulation and therapeutic efficacy of photodynamic nanoplatforms
2019 CRS Nanomedicine and Nanoscale Delivery (NND) Best Paper of the Year: Tumor growth inhibition by mSTEAP peptide nanovaccine inducing augmented CD8+ T cell immune responses
2019 DDTR CRS Oral Drug Delivery Focus Group Paper of the Year Award: Loratadine self-microemulsifying drug delivery systems (SMEDDS) in combination with sulforaphane for the synergistic chemoprevention of pancreatic cancer
Read DDTR's First Inspirational Note: Contraceptive technologies for global health: ethically getting to safe, effective and acceptable options for women and men
ISSN: 2190-3948
Editor-in-Chief:
Maria José Alonso, PhD - University of Santiago de Complotela, Spain
