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Orally Administrable Therapeutic Nanoparticles for the Treatment of Colorectal Cancer.

ABSTRACT: Colorectal cancer (CRC) is one of the most common and lethal human malignancies worldwide; however, the therapeutic outcomes in the clinic still are unsatisfactory due to the lack of effective and safe therapeutic regimens. Orally administrable and CRC-targetable drug delivery is an attractive approach for CRC therapy as it improves the efficacy by local drug delivery and reduces systemic toxicity. Currently, chemotherapy remains the mainstay modality for CRC therapy; however, most of chemo drugs have low water solubility and are unstable in the gastrointestinal tract (GIT), poor intestinal permeability, and are susceptible to P-glycoprotein (P-gp) efflux, resulting in limited therapeutic outcomes. Orally administrable nanoformulations hold the great potential for improving the bioavailability of poorly permeable and poorly soluble therapeutics, but there are still limitations associated with these regimes. This review focuses on the barriers for oral drug delivery and various oral therapeutic nanoparticles for the management of CRC.

SUBMITTER: Ying K

PROVIDER: S-EPMC8293278 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Orally Administrable Therapeutic Nanoparticles for the Treatment of Colorectal Cancer.

Ying Kangkang K Bai Bingjun B Gao Xing X Xu Yuzi Y Wang Hangxiang H Xie Binbin B

Frontiers in bioengineering and biotechnology 20210707

Colorectal cancer (CRC) is one of the most common and lethal human malignancies worldwide; however, the therapeutic outcomes in the clinic still are unsatisfactory due to the lack of effective and safe therapeutic regimens. Orally administrable and CRC-targetable drug delivery is an attractive approach for CRC therapy as it improves the efficacy by local drug delivery and reduces systemic toxicity. Currently, chemotherapy remains the mainstay modality for CRC therapy; however, most of chemo drug ...[more]

PMID: 34307319

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Project description:The spread of Zika virus (ZIKV) infection across the USA and various countries in the last three years will not only have a direct impact on the U.S. health care system but has caused international concerns as well. The ultimate impact of ZIKV infection remains to be understood. Currently, there are no therapeutic or vaccine options available to protect those infected by ZIKV. The drug ivermectin (IVM) was found to be a viable agent for the prevention of transmission of ZIKV. Ivermectin is unstable in the presence of water and does not remain in adequate concentration in the human bloodstream to be effective in treatment for ZIKV. Biodegradable nanoparticles would aid in the delivery of ivermectin by providing a high enough concentration of drug and ensuring the drug is gradually released to maintain an appropriate level in the body. The overall goal of this study was to develop and optimize an orally administrable nanoformulation of IVM which can circulate in the blood for a long period for efficient delivery. To achieve the goal, we synthesized and optimized a synthetic nanoformulation of IVM for oral use which can cross the intestinal epithelial barrier to enter the bloodstream. Our studies documented that when delivered with the synthetic nanoparticle (NP), IVM can be accumulated in the blood at a higher concentration and preliminary studies highlighted that NP delivered IVM has the ability to target nonstructural 1 protein of ZIKV. For potential clinical relevance, long-term storable formulation of IVM-nanoparticle in dry powder state for inclusion in a capsule form and cryoprotectant containing frozen forms revealed promising findings. Further, our preliminary in vitro studies documented that ivermectin crosses the placental barrier, thus making it unsafe for the pregnant ZIKV population, whereas the ivermectin-loaded nanoparticle did not show any significant placental barrier crossing, thus indicating its potential suitability for such population. We envision that this work will fill a great unmet need by developing safer and more effective therapies for the treatment of viral infections, including ZIKV.

Project description:Purpose: Colitis-associated colorectal cancer (CAC) poses substantial challenges for effective treatment. Currently, there is a considerable need for the development of orally bioavailable dosage forms that enable the safe and effective delivery of therapeutic drugs to local diseased lesions in the gastrointestinal tract. Experimental Design: In this study, we developed orally deliverable nanotherapeutics for the synergistic treatment of inflammatory bowel diseases (IBDs) and CAC. Water-insoluble curcumin (CUR) and 7-ethyl-10-hydroxycamptothecin (SN38), which served as anti-inflammatory and cytotoxic agents, respectively, were chemically engineered into hydrophilic mucoadhesive chitosan for the generation of chitosan-drug amphiphiles. Results: The resulting amphiphilic constructs formed core-shell nanostructures in aqueous solutions and were orally administered for in vivo therapeutic studies. Using a preclinical CAC mouse model, we showed that the orally delivered nanotherapeutics locally accumulated in inflamed intestinal regions and tumor tissues. Furthermore, the therapeutic synergy of the combined nanotherapeutics in CAC mice was evaluated. Compared with their individual drug forms, combined CUR and SN38 nanoparticles yielded synergistic effects to alleviate intestinal inflammation and protect mice from ulcerative colitis. Notably, the combinatorial therapy demonstrated a remarkable tumor shrinkage with only ~6% of the total tumors exceeding 4 mm in diameter, whereas ~35% of tumors were observed to exceed a diameter of 4 mm in the saline-treated CAC mice. These data suggest a new and reliable approach for improving the treatment of IBD and CAC. Conclusions: Our results showed that bioadhesive chitosan materials can be used to produce colloidal-stable nanotherapeutics that are suitable for oral delivery. Both nanotherapeutics exhibited substantial accumulation in inflamed intestinal regions and tumor tissues and showed good synergy for treating CAC, warranting further clinical translation.

Project description:IntroductionAging, genetic mutations, and other pathological conditions cause impairment of skeletal growth and bone metabolism, which affect activities of daily living and quality of life in all life stages. Although several drugs have been used in clinical settings and new drugs have been developed for the treatment of skeletal degenerative disorders such as osteoporosis and genetic disorders such as osteogenesis imperfecta (OI), there is clear demand for development of new drugs, especially orally available anabolic drugs that are applicable for a wide range of skeletal disorders.MethodsTo identify therapeutic candidates for skeletal disorders, peptide screening was performed. To validate the identified peptides, we performed a bone histomorphometric analysis with rat bone tissues and in vitro cell proliferation assays of skeletal cells. To understand the metabolism of the peptides, we performed a biochemical analysis, followed by in vitro assays for proliferation and differentiation of skeletal cells. We examined the therapeutic efficacy of the identified peptides with several mouse models representing skeletal disorders including bone fracture, osteoporosis, and osteogenesis imperfecta. In vivo therapeutic effects of the candidate were assessed with radiological analysis and mechanical property tests.ResultsWe identified the egg yolk-derived functional peptide PF201. PF201 promoted in vivo bone formation in rodents and enhanced proliferation of osteoblasts and chondrocytes in vitro. D2, a metabolite of PF201, was present and circulated after digestion and absorption in the digestive tract. D2 had positive impacts on the proliferation and differentiation of mesenchymal stem cells and preosteoblasts. Oral administration of D2 accelerated bone healing in a mouse fracture model. D2 also improved bone strength and fracture healing under ovariectomy-induced osteoporotic conditions in mice, and D2 showed a therapeutic effect in a mouse OI model.ConclusionD2 is likely to be a candidate for an orally available therapeutic for a range of skeletal disorders.

Dataset Information

Orally Administrable Therapeutic Nanoparticles for the Treatment of Colorectal Cancer.

Publications

Orally Administrable Therapeutic Nanoparticles for the Treatment of Colorectal Cancer.

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