Oral Nonviral Gene Delivery for Chronic Protein Replacement Therapy

Lin, Po‐Yen; Chiu, Ya Ling; Huang, Jing Huei; Chuang, Er Yuan; Mi, Fwu Long; Lin, Kun; Juang, Jyuhn Huarng; Sung, Hsing‐Wen; Leong, Kam W.

doi:10.1002/advs.201701079

Cited by 31 publications

(28 citation statements)

References 41 publications

(55 reference statements)

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“…However, oral drug delivery faces several challenges, such as the poor solubility of drugs, the complex gastrointestinal environment, and nonspecific drug distribution in the gastrointestinal tract 17 . With the recent developments in nanomedicine, nanoparticle-based oral drug delivery systems are now possible, providing the potential to enhance permeation through intestinal barrier, alleviate adverse systemic effects, and improve treatment efficiency [18][19][20] . In addition, targeting ligand-modified drug delivery systems aimed at improving therapeutic outcomes of gastrointestinal tract diseases have been developed [21][22][23][24] .…”

Section: Introductionmentioning

confidence: 99%

Reversing tumor stemness via orally targeted nanoparticles achieves efficient colon cancer treatment

Zhang

et al. 2019

Biomaterials

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The acquisition of stemness in colorectal cancer (CRC) attributed to the recurrence and metastasis in CRC treatment. Therefore, targeting the stemness of CRC forms a basis for the development of novel therapeutic approaches. However, the pain and systemic side effect from long-term of venipuncture injection remain great challenges to neoplastic treatment. Here, we introduce an oral drug delivery system for sustained release of BMI-1 inhibitor (PTC209) that reverse the stemness of CRC to overcome these obstacles. In this system, nanoparticles modified with hyaluronic acid (HA) showed high-affinity to CD44 / CD168 overexpressed-CRC cells, and efficiently targeted to tumor site in a metastatic orthotropic colon cancer mouse model by oral administration. Significantly, the observed tumor growth inhibition is accompanied by decreased expression of stemness markers in the tumor tissues. Furthermore, HA-NPs-PTC209 also significantly prevented metastasis to the gastrointestinal system, while failing to exhibit acute side effects. In summary, we have developed an orally active, easily synthesized nanomedicine that shows promise for the treatment of colon cancer.

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Section: Introductionmentioning

confidence: 99%

Reversing tumor stemness via orally targeted nanoparticles achieves efficient colon cancer treatment

Zhang

et al. 2019

Biomaterials

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“…Furthermore, the transepithelial electrical resistance (TEER) was measured, which could reflect the ion permeability of the monolayer. As the tight junctions open, the TEER would be reduced due to the ion passages through the paracellular route 10 . There was a progressive decrease of TEER with PCB/INS particles incubation ( Figure 3 E ).…”

Section: Resultsmentioning

confidence: 99%

“…However, the subcutaneous injection results in low patient compliance and safety issues 8 , 9 . In comparison, oral administration is considered to be the most convenient and safe choice for patients because of high patient compliance and repeatable administration 10 . Additionally, the oral insulin formulation can provide a better glucose homeostasis in the body as it more closely mimics the endogenous insulin pathway 11 , 12 .…”

Section: Introductionmentioning

confidence: 99%

Charge-switchable zwitterionic polycarboxybetaine particle as an intestinal permeation enhancer for efficient oral insulin delivery

Li¹,

Ji²,

Peng³

et al. 2021

Theranostics

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Insulin, a peptide hormone, is one of the most common and effective antidiabetic drugs. Although oral administration is considered to be the most convenient and safe choice for patients, the oral bioavailability of insulin is very low due to the poor oral absorption into blood circulation. Intestinal epithelium is a major barrier for the oral absorption of insulin. Therefore, it is vital to develop intestinal permeation enhancer to increase the antidiabetic efficacy of insulin after oral administration. Methods: Charge-switchable zwitterionic polycarboxybetaine (PCB) was used to load insulin to form PCB/insulin (PCB/INS) particles through the electrostatic interaction between positively charged PCB in pH 5.0 and negatively charged insulin in 0.01 M NaOH. The opening effect of PCB/INS particles on intestinal epithelium was evaluated by detecting the changes of claudin-4 (CLDN4) protein and transepithelial electrical resistance (TEER) after incubation or removal. The mechanism was further elucidated based on the results of Western blot and fluorescence images. The PCB/INS particles were then used for type 1 diabetes mellitus therapy after oral administration. Results: PCB could load insulin with the loading efficiency above 86% at weight ratio of 8:1. PCB/INS particles achieved sustained release of insulin at pH 7.4 due to their charge-switchable ability. Surprisingly, PCB/INS particles induced the open of the tight junctions of intestinal epithelium in endocytosis-mediated lysosomal degradation pathway, which resulted in increased intestinal permeability of insulin. Additionally, the opening effect of PCB/INS particles was reversible, and the decreased expression of CLDN4 protein and TEER values were gradually recovered after particles removal. In streptozotocin-induced type 1 diabetic rats, oral administration of PCB/INS particles with diameter sub-200 nm, especially in capsules, significantly enhanced the bioavailability of insulin and achieved longer duration of hypoglycemic effect than the subcutaneously injected insulin. Importantly, there was no endotoxin and pathological change during treatment, indicating that PCB/INS particles were safe enough for in vivo application. Conclusion: These findings indicate that this system can provide a platform for oral insulin and other protein drugs delivery.

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“…Nanoparticles are the most prevalent approach to circumvent the delivery problem. They are also being widely investigated for oral delivery with the goal to protect gene vectors from gastric acid degradation and to facilitate its transport across the intestinal epithelium [ 109 ]. Despite the fact that oral administration of gene therapies has not yet reached the clinic, multiple studies have validated its potential in preclinical studies [ 109 , 110 , 111 , 112 , 113 ].…”

Section: Gene Therapy In Dermatologymentioning

confidence: 99%

Future Perspectives of Oral Delivery of Next Generation Therapies for Treatment of Skin Diseases

et al. 2021

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Gene therapies have conspicuously bloomed in recent years as evidenced by the increasing number of cell-, gene-, and oligo-based approved therapies. These therapies hold great promise for dermatological disorders with high unmet need, for example, epidermolysis bullosa or pachyonychia congenita. Furthermore, the recent clinical success of clustered regularly interspaced short palindromic repeats (CRISPR) for genome editing in humans will undoubtedly contribute to defining a new wave of therapies. Like biologics, naked nucleic acids are denatured inside the gastrointestinal tract and need to be administered via injections. For a treatment to be effective, a sufficient amount of a given regimen needs to reach systemic circulation. Multiple companies are racing to develop novel oral drug delivery approaches to circumvent the proteolytic and acidic milieu of the gastrointestinal tract. In this review, we provide an overview of the evolution of the gene therapy landscape, with a deep focus on gene and oligonucleotide therapies in clinical trials aimed at treating skin diseases. We then examine the progress made in drug delivery, with particular attention on the peptide field and drug-device combinations that deliver macromolecules into the gastrointestinal tract. Such novel devices could potentially be applied to administer other therapeutics including genes and CRISPR-based systems.

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Oral Nonviral Gene Delivery for Chronic Protein Replacement Therapy

Cited by 31 publications

References 41 publications

Reversing tumor stemness via orally targeted nanoparticles achieves efficient colon cancer treatment

Reversing tumor stemness via orally targeted nanoparticles achieves efficient colon cancer treatment

Charge-switchable zwitterionic polycarboxybetaine particle as an intestinal permeation enhancer for efficient oral insulin delivery

Future Perspectives of Oral Delivery of Next Generation Therapies for Treatment of Skin Diseases

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