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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In preclinical models, the antitumor effects of cytokines are often only observed after administration via intra-tumoral or peritumoral injection, or by implantation of cytokine-expressing tumor cells. However, it is clear from these experiments that cytokines are potent modulators of the immune system, and can cause eradication of tumors if sufficiently high concentrations can be achieved at the tumor site. Unfortunately, these methods of administration are not realistic in the clinic due to the disseminated nature of most cancer types. Systemic administration is also problematic due to the poor pharmacokinetic characteristics of most cytokines and the significant dose-limiting toxicities (DLTs) at the high doses required to achieve a clinical effect. Therefore, there has been growing interest in the use of recombinant antibody–cytokine fusion proteins (i.e., immunocytokines) to enhance the therapeutic index of cytokines by targeting them to the disease site.
Organic Nanocarriers for Brain Drug Delivery
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Marlene Lúcio, Carla M. Lopes, Eduarda Fernandes, Hugo Gonẹalves, Maria Elisabete C. D. Real Oliveira
Systemic administration includes all routes which involve the passage of NCs to the blood circulation, such as classical intraperitoneal (i.p.) injections or those through the digestive tract (like oral administration), lungs or transdermal administrations [2, 23]. In such administration routes, NCs also require stealth strategies. Moreover, NCs face more off-target tissues, and if a targeted strategy is not adequate to direct NCs to the brain, they can be metabolised in the liver, thereby modifying the amount of circulating therapeutics available to the brain [23]. Furthermore, the liver, kidneys, intestine, skin, lungs and organs which separate the brain from the blood flow release enzymes which can metabolise xenobiotics and may likewise metabolise NCs [23]. Another part of the NCs can be excreted by the kidneys (especially if NC sizes are smaller than 5 nm) [24], which makes it difficult to estimate the accurate amount of the medication which finally enters the brain [2, 23].
Monographs of Topical Drugs that Have Caused Contact Allergy/Allergic Contact Dermatitis
Published in Anton C. de Groot, Monographs in Contact Allergy, 2021
Cutaneous adverse drug reactions from systemic administration of lidocaine caused by type IV (delayed-type) hypersensitivity, including extensive eczematous eruption from intravenous injection (23) and allergic reactions from intramuscular (59), intra-articular (70) or subcutaneous injections (mostly localized reactions [24-32,40,49,58,71], sometimes generalized [33,70]), are planned to be discussed in Volume IV of the Monographs in Contact Allergy series on Systemic drugs.
Cell-directed aptamer therapeutic targeting for cancers including those within the central nervous system
Published in OncoImmunology, 2022
Jun Wei, Renduo Song, Aria Sabbagh, Anantha Marisetty, Neal Shukla, Dexing Fang, Hinda Najem, Martina Ott, James Long, Lijie Zhai, Maciej S. Lesniak, Charles David James, Leonidas Platanias, Michael Curran, Amy B. Heimberger
Our proposed dual-targeting therapeutics involving direct conjugation of a siRNA molecule to a nucleic acid aptamer which reduces the complexity of manufacturing of these reagents. Systemic administration requires greater therapeutic doses (leading to higher treatment costs) and carries a greater risk for harmful side effects owing to greater exposure of non-targeted tissues. Improvements that would minimize the necessary dose of the complex would reduce both the cost of treatment and the risk for harmful side effects. To circumvent degradation by serum nuclease, a portion of the nucleotides in the siRNAs and aptamers evaluated in this study has been modified with a nuclease-resistant 2-O methyl moiety and a phosphorothioate linkage, which enhances the in vivo stability.40 Because some of the tested aptamers are species specific, human-specific aptamers will need to be synthesized and validated prior to initiating clinical trials. Future studies should also evaluate the potential of OPN targeting, using the aptamer approach, to enhance the effects of temozolomide or radiation therapy in GBM. Moreover, the overall approach may have important implications in other tumors as well, as OPN engages signaling pathways41 important for neoplastic cell survival and growth and this remains to be established in future studies.
Pharmaceutical, biomedical and ophthalmic applications of biodegradable polymers (BDPs): literature and patent review
Published in Pharmaceutical Development and Technology, 2022
Barzan Osi, Mouhamad Khoder, Ali A. Al-Kinani, Raid G. Alany
For the treatment of posterior segment disorders, either systemic or local routes of administration could be used. (Souto et al. 2019). However, systemic administration (oral or intravenous) requires higher dosage and frequent administration to achieve a therapeutic concentration, causing undesirable side effects and patient discomfort (Rupenthal and Alany 2007; Gaudana et al. 2010; Huang et al. 2018). The local ocular route is more invasive than topical and systematic ones since medicine is directly injected into the target area of the eye. Intravitreal/subconjunctival injections are an alternative strategy to deliver drugs and biologics to the posterior segment of the eye (http://fyra.io). Accordingly, the drug can be delivered directly into the target site (vitreous, mainly to reach the retina) thus allowing to bypass anatomical and physiological barriers encountered with topical and systemic administrations. However, repeated injections may be necessary to maintain a therapeutic level of the agent, which might cause haemorrhage, trauma, endophthalmitis and retinal detachment (Cañadas et al. 2016).
A review of nanocarrier-mediated drug delivery systems for posterior segment eye disease: challenges analysis and recent advances
Published in Journal of Drug Targeting, 2021
Rui Wang, Yuan Gao, Anchang Liu, Guangxi Zhai
Systemic administration means drugs are administered orally or intravenously to enable their distribution throughout the body via blood stream. However, the entry of drug molecules into the retina and vitreous humour is often limited by the BRB made up of RPE and endothelial cells [46]. As only about 2% of systemically administered dose could eventually reach the intraocular tissue, frequent systemic administrations of high doses are often required to achieve a therapeutically effective concentration, which in turn could lead to drug-related toxicities. Due to the requirement for large dose, poor safety and the limitation to large hydrophilic molecules such as bevacizumab, this route is rarely used for posterior segment disease treatment. You et al. [53] synthesised DEAE-dextran-stabilised polybutylcyanoacrylate nanoparticles with incorporated rhodamine 123 to research how the physicochemical parameters such as surface charge and size would affect the distribution of NPs in retina after rats tail vein injection. The results showed large size (300 nm) and medium surface charged (5mv) NPs were more often detected in retinal ganglion cells.