Dendritic cells (DCs) are antigen-presenting cells with a unique ability to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.

Immunobiology of Dendritic Cells

Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications

Spurred by recent progress in materials chemistry and drug delivery, stimuli-responsive devices that deliver a drug in spatial-, temporal- and dosage-controlled fashions have become possible. Implementation of such devices requires the use of biocompatible materials that are susceptible to a specific physical incitement or that, in response to a specific stimulus, undergo a protonation, a hydrolytic cleavage or a (supra)molecular conformational change. In this Review, we discuss recent advances in the design of nanoscale stimuli-responsive systems that are able to control drug biodistribution in response to specific stimuli, either exogenous (variations in temperature, magnetic field, ultrasound intensity, light or electric pulses) or endogenous (changes in pH, enzyme concentration or redox gradients).

Stimuli-responsive nanocarriers for drug delivery

CA : A Cancer Journal for Clinicians

Photodynamic therapy involves administration of a tumor-localizing photosensitizing agent, which may require metabolic synthesis (i.e., a prodrug), followed by activation of the agent by light of a specific wavelength. This therapy results in a sequence of photochemical and photobiologic processes that cause irreversible photodamage to tumor tissues. Results from preclinical and clinical studies conducted worldwide over a 25-year period have established photodynamic therapy as a useful treatment approach for some cancers. Since 1993, regulatory approval for photodynamic therapy involving use of a partially purified, commercially available hematoporphyrin derivative compound (Photofrin) in patients with early and advanced stage cancer of the lung, digestive tract, and genitourinary tract has been obtained in Canada, The Netherlands, France, Germany, Japan, and the United States. We have attempted to conduct and present a comprehensive review of this rapidly expanding field. Mechanisms of subcellular and tumor localization of photosensitizing agents, as well as of molecular, cellular, and tumor responses associated with photodynamic therapy, are discussed. Technical issues regarding light dosimetry are also considered.

Photodynamic Therapy

Abstract Since tumor stroma poses as a barrier to achieve efficacy of nanomedicines, it is essential to evaluate nano-chemotherapeutics in stroma-mimicking 3D models that reliably predict their behavior regarding these hurdles limiting efficacy. In this study, we evaluated the effect of paclitaxel-loaded polymeric micelles (PTX-PMCs) and polymeric nanoparticles (PTX-PNPs) in a tumor stroma–mimicking 3D in vitro model. PTX-PMCs (77 nm) based on a amphiphilic block copolymer of mPEG-b-p(HPMAm-Bz) and PTX-PNPs (159 nm) based on poly(lactic-co-glycolic acid) were prepared, which had an encapsulation efficiency (EE%) of 81 ± 15% and 45 ± 8%, respectively. 3D homospheroids of mouse 4T1 breast cancer cells and heterospheroids of NIH3T3 fibroblasts and 4T1 (5:1 ratio) were prepared and characterized with high content two-photon microscopy and immunostaining. Data showed an induction of epithelial-mesenchymal transition (α-SMA) in both homo- and heterospheroids, while ECM (collagen) deposition only in heterospheroids. Two-photon imaging revealed that both fluorescently labeled PMCs and PNPs penetrated into the core of homospheroids and only PMCs penetrated into heterospheroids. Furthermore, PTX-PMCs, PTX-PNPs, and free PTX induced cytotoxicity in tumor cells and fibroblasts grown as monolayer, but these effects were substantially reduced in 3D models, in particular in heterospheroids. Gene expression analysis showed that heterospheroids had a significant increase of drug resistance markers (Bcl2, Abgc2) compared to 2D or 3D monocultures. Altogether, this study shows that the efficacy of nanotherapeutics is challenged by stroma-induced poor penetration and development of resistant phenotype. Therefore, this tumor stroma–mimicking 3D model can provide an excellent platform to study penetration and effects of nanotherapeutics before in vivo studies. Graphical Abstract 

https://link.springer.com/content/pdf/10.1007/s13346-023-01310-1.pdf

Evaluation of paclitaxel-loaded polymeric nanoparticles in 3D tumor model: impact of tumor stroma on penetration and efficacy

Complement activation-related pseudoallergy (CARPA) is a hypersensitivity reaction occurring upon intravenous administration of numerous liposomal therapeutics, other nonbiological complex drugs and biologicals. It has a complex molecular and cellular mechanism that involves the production, actions and interactions of numerous vasoactive mediators in blood, including thromboxane A2 (TXA2). This short review focuses on the latter eicosanoid: Its role in CARPA, effects underlying some of the symptoms and experimental evidence for its rate-limiting role in pulmonary hypertension in pigs. Animal experiments and recent clinical observations suggest that the cyclooxygenase blocker indomethacin may represent an effective new approach to prevent liposome-induced CARPA, lending clinical relevance to better understand the involvement of TXA2 and other eicosanoids in this adverse immune effect.

The role of thromboxane A2 in complement activation-related pseudoallergy

Drug delivery to the retina is one of the major challenges in ophthalmology due to the biological barriers that protect it from harmful substances in the body. Despite the advancement in ocular therapeutics, there are many unmet needs for the treatment of retinal diseases. Ultrasound combined with microbubbles (USMB) was proposed as a minimally invasive method for improving delivery of drugs in the retina from the blood circulation. This study aimed to investigate the applicability of USMB for the delivery of model drugs (molecular weight varying from 600 Da to 20 kDa) in the retina of ex vivo porcine eyes. A clinical ultrasound system, in combination with microbubbles approved for clinical ultrasound imaging, was used for the treatment. Intracellular accumulation of model drugs was observed in the cells lining blood vessels in the retina and choroid of eyes treated with USMB but not in eyes that received ultrasound only. Specifically, 25.6 ± 2.9% of cells had intracellular uptake at mechanical index (MI) 0.2 and 34.5 ± 6.0% at MI 0.4. Histological examination of retinal and choroid tissues revealed that at these USMB conditions, no irreversible alterations were induced at the USMB conditions used. These results indicate that USMB can be used as a minimally invasive targeted means to induce intracellular accumulation of drugs for the treatment of retinal diseases.

/pdf/microbubble-assisted-ultrasound-for-drug-delivery-to-the-vs2m5gyn.pdf

Microbubble-Assisted Ultrasound for Drug Delivery to the Retina in an Ex Vivo Eye Model

introduction Since the 1950s glucocorticoids (GC) have emerged as one of the main treatments in inflammatory diseases.[1] Their immunosuppressive and antiinflammatory effects are primarily caused by binding of GC with their cytosolic receptors and subsequent DNA transcription modulation in the nucleus.[2] Additionally, GC are able to exert a number of direct effects outside the nucleus, such as interaction with specific membrane-bound receptors, inhibition of arachidonic acid release and alteration of cationic transport through the plasma membrane.[3] Along with the high potency, GC have an unfavorable toxicity profile though this has not prevented their widespread use [1] Severe side effects include immunosuppression (and related increased risk of infection), osteoporosis, hypertension, peptic ulcer disease and a number of dermatological effects such as thinning of the skin and purpura.[4, 5] Additional symptoms include rapid weight gain and fat deposition around abdomen and face, fatigue, weak muscles and excessive hair growth. Furthermore, it is known that administration of exogenous GC suppresses the hypothalamus–pituitary– adrenal (HPA) axis, a neuroendocrine system involved in stress-response, leading to deregulation of physiological corticosteroid levels.[6] Full recovery of the HPA axis after cessation of GC therapy might take months, with the patient being at risk to develop symptomatic adrenal insufficiency or even stress-induced adrenal crisis.[7] In clinical practice, high-dose intravenous GC therapy is being applied as firstline treatment in several situations. In addition to the potential occurrence of severe side effects, GC have highly unfavorable pharmacokinetic properties (rapid clearance and a large volume of distribution), which necessitates high and frequent dosing to maintain therapeutic levels at sites of inflammation.[4, 5] To circumvent the drawbacks of conventional therapy, described above, advanced drug delivery systems have been applied to administer GC in an efficient and safe way. Liposomes have prevailed in this regard and have been studied extensively in preclinical and clinical settings since the late 1980s.[8] After local administration, e.g. intra-articular or intra-corneal injection, they induce prolonged drug levels at the inflamed sites, resulting in improved therapeutic effects and less systemic adverse effects, when compared to local administration of free GC (i.e. not incorporated in liposomes). After intravenous administration, liposomes benefit from the locally enhanced permeability of the vasculature allowing extravasation of circulating liposome nanoparticles at inflamed areas. [9] To obtain sufficient extravasation at the pathological sites, prolonged blood circulation is required. Shielding of the liposome surface by means of a hydrophilic polymer, e.g. polyethylene glycol (PEG), showed to be extremely effective in extending the circulation time of i.v. administered liposomes by reducing hepatosplenic uptake of the liposomes by the mononuclear and phagocyte system (MPS).[10] Nanocort is a long-circulating liposomal formulation of prednisolone phosphate (PLP), consisting of vesicles of ~ 100-150 nm, with a PEGylated lipid bilayer comprising phospholipids and cholesterol, and an aqueous core in which the hydrophilic drug PLP (a derivative of prednisolone) is entrapped. The corticosteroid is used as a phosphate derivative in order to achieve stable retention of the drug within the liposomes. PEG-liposomal PLP (referred to as LCL-PLP throughout this contribution) has been studied extensively over the past 5-10 years.[11, 12] The next sections address preclinical studies that have been conducted with Nanocort, both in the field of chronic inflammatory diseases and more recently also in cancer.

https://www.degruyter.com/view/j/ejnm.2008.1.1/ejnm.2008.1.1.15/ejnm.2008.1.1.15.pdf

Therapeutic nanomedicine: Liposomal corticosteroid as targeted antiinflammatory nanomedicine

The first part of the lecture will be focused on the targeted delivery of glucocorticoids. Glucocorticoids are highly effective anti-inflammatory drugs, but have also been investigated as anti-angiogenic agents in the early '80s. Antitumor activity was observed in experimental animals, but only when the corticosteroids were administered frequently and in high doses. The need for such an intensive treatment schedule is associated with side effects, which has precluded further clinical development of corticocosteroids as anti-angiogenic agents. As long-circulating liposomes can passively accumulate at sites of malignancy, their potential usefulness for the targeted delivery of glucocorticoids will be highlighted. The results obtained in a variety of animal models of cancer are promising and warrant further investigation of liposomal glucocorticoids as novel antitumor agents [Schiffelers, R.M. et al. Neoplasia 7 (2005) 118]. Vascular targeting offers therapeutic promise for the delivery of a broad spectrum of agents. An RDG peptide that targets alpha v beta 3 integrins overexpressed on angiogenic endothelial cells was coupled to the surface of poly (ethylene glycol) (PEG)-coated liposomes. We aimed at obtaining a stable multivalent nanoparticulate delivery system with a favorable pharmacokinetic profile and high drug payload capacity functioning as a platform for display of RGD peptides. Specific binding of the RGD-targeted liposomes to angiogenic endothelial cells was demonstrated in vivo in several animal models of cancer. Marked therapeutic effects were observed when the anthracycline doxorubicin or the corticosteroid prednisolone phosphate (PP) were encapsulated [Schiffelers, R.M. et al.peptide was coupled to the cationic polymer poly(ethylene) imine (PEI) via a PEG spacer. In the presence of siRNA, the RGD-PEG-PEI self-assembles into a nanoparticle with a core formed by an electrostatic complex between siRNA and PEI exposing RGD-peptide on the surface. Incorporated siRNA was specific for silencing of reporter genes or vascular endothelial growth factor receptor 2 (VEGFR2). Specific silencing effects and therapeutic efficacy mediated by this polymeric vascular targeting system were achieved in vivo [Schiffelers, R.M. et al.

Gert Storm

Papers

Evaluation of paclitaxel-loaded polymeric nanoparticles in 3D tumor model: impact of tumor stroma on penetration and efficacy

The role of thromboxane A2 in complement activation-related pseudoallergy

Microbubble-Assisted Ultrasound for Drug Delivery to the Retina in an Ex Vivo Eye Model

Therapeutic nanomedicine: Liposomal corticosteroid as targeted antiinflammatory nanomedicine

Nanoparticles for targeted delivery of anticancer agents