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Engineered Nanoparticles for Drug Delivery in Cancer Therapy *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Tianmeng Sun, Yu Shrike Zhang, Pang Bo, Dong Choon Hyun, Miaoxin Yang, Younan Xia
Liposomes can be stabilized sterically by reinforcing the bilayer with an amphiphilic, long-chain polymer containing PEG at one end, which can concurrently reduce opsonization and prolong the plasma circulation time. Polymers with proper end groups for conjugation with antibodies or ligands can also be inserted into the lipid bilayer, thus making targeted delivery possible. Despite the apparent simplicity in the functionalization, the most interesting feature of liposomes, which differentiates them from other nanoparticle-based drug delivery systems, is their mechanism of intracellular delivery. As the bilayers of liposomes closely mimic those of cells, they can be directly fused with the plasma membrane. If they are internalized by cells through endocytosis, the lipid bilayer will be disrupted because of the acidic environment of certain intracellular compartments (e.g., endosomes and lysosomes), or the bilayer can be fused with the membranes of intracellular compartments. The fusion process may not occur if the liposomes are functionalized with certain compounds to eliminate a direct contact between the bilayer of a liposome and that of a cell, prompting the need for additional endosomal escape mechanisms.
Application of Bioresponsive Polymers in Drug Delivery
Published in Deepa H. Patel, Bioresponsive Polymers, 2020
Manisha Lalan, Deepti Jani, Pratiksha Trivedi, Deepa H. Patel
Zhou et al. formulated the conjugates of a PEG polymer backbone with multiple DOX molecules linked to it. The conjugates have shown a significantly faster drug release at pH 6.0 than at pH 7.4. This is particularly useful for intracellular delivery. The cellular release of DOX was brought about by the cleavage of the hydrazone linkages. This allowed the drug to be accumulated in the nuclear compartment. The in-vivo studies on the conjugates confirmed a longer plasma half-life and tumor accumulation with intravenous administration [147].
Genome Editing for Genetic Lung Diseases
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Based on the successful results that adenoviral vectors were able to transfect human bronchial epithelial cells in vitro, a clinical trial to transfer CFTR gene to the lung started in early 90s.91 To date, more than 25 gene therapy trials for cystic fibrosis have been completed.42,91 CFTR gene delivery was generally tolerated, but limited efficiency was observed.42,91 Numerous challenges remain for delivery of genetic materials to the lung. Although CFTR gene can be transferred into lung cells, the percentage of transduced cells and the expression level need to be further improved.47,57,64,65,77,78 Moreover, studies to characterize the transduced cells and to understand the fate of those cells could provide the key information for improving intracellular delivery. Results from linage tracing studies indicate that airway epithelial cells of mice have a half-life of 17 months.92 However, those animals were under clean air environment, and the turnover rate of these cells in human is not exactly known.92 To maintain the persistent expression in the right cell type, either repeated injection or targeting the lung progenitor cells are preferred.70,93 However, immune responses are likely induced by repeated administration, and it is not clear that “local” delivery via the airway could efficiently transduce the lung progenitor cells.40,94
State-of-the-art of ultrasound-triggered drug delivery from ultrasound-responsive drug carriers
Published in Expert Opinion on Drug Delivery, 2022
Ching-Hsiang Fan, Yi-Ju Ho, Chia-Wei Lin, Nan Wu, Pei-Hua Chiang, Chih-Kuang Yeh
Cell therapy shows high potential in regenerative medicine and cancer immunotherapy. The specific cells are collected for ex vivo activation for the regulation of cell proliferation, differentiation, secretion, or expression, and then the activated cells are reinjected into the host for therapy to accomplish precise personalized medicine. US-triggered ex vivo intracellular delivery promotes the uptake of antigens, DNA, or RNA to activate dendritic cells, natural killer cells, or T cells [54]. The activated immune cells are IV injected into the host and migrate into tumor tissue for anti-tumor immunotherapy. Since stem cells, macrophages, and other immune cells demonstrate tumor tropism, use of these cells as drug carriers in a tumor delivery system has been proposed [55,56]. In this approach, US is used to trigger ex vivo cell uptake of NPs via sonoporation [57]. After IV injection, the NP-loaded cells would automatically migrate into the tumor tissue. When the cavitation of intracellular US-responsive NPs is induced by US stimulation, the cells are disrupted to release drugs into the tumor tissue for treatment [58,59]. Possible concerns related to a cell delivery system include uptake efficiency, cytotoxicity, and migration ability of NP-loaded cells. The biosafety of sonoporation induced by US mechanical effects allows intracellular delivery of NPs, antigens, or DNA without cell damage [60].
A cationic cyclodextrin derivative-lipid hybrid nanoparticles for gene delivery effectively promotes stability and transfection efficiency
Published in Drug Development and Industrial Pharmacy, 2022
Zhongjuan Wang, Shaobin Xu, Hongying Xia, Yanqiu Liu, Bin Li, Yueqin Liang, Zhongkun Li
Genetic medicines are genetic materials including messenger RNA (mRNA), short interfering RNA (siRNA), and plasmid DNA (pDNA) delivered into the body as a therapeutic, and capable of preventing and treating diseases by addressing the root cause [1]. Moreover, the recent advent of genome editing techniques utilize clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein (Cas9) that allows virtually any desired wild-type sequence to replace a lack-of-function gene for direct correction of altered genomic DNA sequences. Thus, genetic medicines hold great promise for treatment of a number of diseases such as inherited disorders, viral infection, and cancers [2]. To date, the FDA has more than 900 investigational new drug applications for ongoing clinical studies related to gene therapy. However, only a limited number of genetic medicines have been approved. One of the challenges in successfully implementing gene therapies in real-life clinical practice is the lack of effective intracellular delivery into host cells.
Targeting the undruggable: emerging technologies in antibody delivery against intracellular targets
Published in Expert Opinion on Drug Delivery, 2020
Suchada Niamsuphap, Christian Fercher, Sumukh Kumble, Pie Huda, Stephen M Mahler, Christopher B Howard
Despite continuous development in intracellular delivery systems for biopharmaceuticals, low efficiency of intracellular release mechanisms remains a major issue. This is primarily due to entrapment of cargos in endosomes where they are either degraded by proteolytic enzymes upon lysosome conversion or recycled back to the cell surface [132]. Moreover, nonspecific interactions between payloads and endosomal lipid components may lead to prolonged association of cargos with endocytic organelles even after lysis has occurred [138,139]. Consequently, implementing a method that promotes endosomal escape upon translocation of antibodies to the cytoplasm is crucial. In the following sections, an overview of three major endosomal escape mechanisms described for antibodies is presented (Figure 4) together with exemplary strategies for enhancing endosomal escape.