The primary goal of this project is to combine linolenic acid (a natural compound from vegetable oils) with an innovative nano-delivery technology to develop a new nanotherapeutic for eradicating Helicobacter pylori (H. pylori) infection burden. This work is driven by our recent discovery that the liposomal formulation of linolenic acid can effectively and rapidly kill both replicating (also called spiral) and dormant (also called coccoid forms of H. pylori bacteria as well as clinically isolated H. pylori strains that are normally resistant to exiting antibiotics. The current standard treatment of H. pylori infection, termed trile therapy, consists of the administration of a proton pump inhibitor (PPI) and two antibiotics (clarithromycin plus amoxicillin or metronidazole). However, the triple therapy is associated with poor compliance of patients, side effects of the antibiotics, and high cost. Moreover, the increasing emergence of H. pylori strains resistant to some of these antibiotics have resulted in a progressive decline in recent years to unacceptable low eradication rates ranging from ~60% to 75%. Herein, we aim to develop a unique and robust nanotherapeutic to treat H. pylori infection with high effectiveness and without adverse side effects. We will test the physicochemical and biological properties and working mechanism of the proposed nanotherapeutics. Using an H. pylori Sydney strain (SS1) mouse model, we will also thoroughly evaluate the antimicrobial efficacy, toxicity and pharmacokinetics of the nanotherapeutics against H. pylori infection. Overall, three specific aims will be addressed in this proposal, including: (i) to investigate the antimicrobial specificity and working mechanism of liposomal linolenic acid (LipoLLA) against H. pylori bacteria;(ii) to engineer a pH-sensitive nanoparticle-stabilized liposome system for """"""""smart"""""""" drug delivery to the stomach mucus lining;and (iii) to test the therapeutic efficacy and toxicity of nanoparticle-stabilized LipoLLA for the treatment of H. pylori infection in a mouse model. The success of this project will provide a new, effective, safe, and inexpensive medication to treat H. pylori infection that will benefit millions of patients. Thi work will also have significant impacts on advancing bioengineering and nanotechnology research by developing a unique and powerful nanoparticle-stabilized liposome system that can tolerate the acidic stomach environment and selectively deliver payloads to the stomach mucus lining. Moreover, this work will also improve the fundamental understanding of how to kill bacteria through disrupting the properties of bacterial plasma membrane and thus avoiding inducing bacterial drug resistance.

Public Health Relevance

This project is to develop a new, effective, safe and inexpensive medication for the treatment of Helicobacter pylori (H. pylori) infection that infects about half of the people in the world and is of major public health concern. The proposed medication consists of a purely natural compound (linolenic acid) from many common vegetable oils and an advanced stomach-microenvironment sensitive nano-delivery system. The success of this work will not only benefit the extremely large community of H. pylori infectious patients but also significantly advance bioengineering and nanotechnology research by providing a unique and powerful nanoparticle-stabilized liposome system for selective drug delivery to the mucus lining of the stomach.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK095168-01
Application #
8275600
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Grey, Michael J
Project Start
2012-06-01
Project End
2017-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$329,148
Indirect Cost
$111,648
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Angsantikul, Pavimol; Thamphiwatana, Soracha; Zhang, Qiangzhe et al. (2018) Coating nanoparticles with gastric epithelial cell membrane for targeted antibiotic delivery against Helicobacter pylori infection. Adv Ther (Weinh) 1:
de Ávila, Berta Esteban-Fernández; Angsantikul, Pavimol; Li, Jinxing et al. (2017) Micromotor-enabled active drug delivery for in vivo treatment of stomach infection. Nat Commun 8:272
Li, Jinxing; Angsantikul, Pavimol; Liu, Wenjuan et al. (2017) Micromotors Spontaneously Neutralize Gastric Acid for pH-Responsive Payload Release. Angew Chem Int Ed Engl 56:2156-2161
Dehaini, Diana; Fang, Ronnie H; Luk, Brian T et al. (2016) Ultra-small lipid-polymer hybrid nanoparticles for tumor-penetrating drug delivery. Nanoscale 8:14411-9
Dehaini, Diana; Fang, Ronnie H; Zhang, Liangfang (2016) Biomimetic strategies for targeted nanoparticle delivery. Bioeng Transl Med 1:30-46
Luk, Brian T; Fang, Ronnie H; Hu, Che-Ming J et al. (2016) Safe and Immunocompatible Nanocarriers Cloaked in RBC Membranes for Drug Delivery to Treat Solid Tumors. Theranostics 6:1004-11
Gao, Weiwei; Zhang, Yue; Zhang, Qiangzhe et al. (2016) Nanoparticle-Hydrogel: A Hybrid Biomaterial System for Localized Drug Delivery. Ann Biomed Eng 44:2049-61
Li, Jinxing; Thamphiwatana, Soracha; Liu, Wenjuan et al. (2016) Enteric Micromotor Can Selectively Position and Spontaneously Propel in the Gastrointestinal Tract. ACS Nano :
Wang, Fei; Fang, Ronnie H; Luk, Brian T et al. (2016) Nanoparticle-Based Antivirulence Vaccine for the Management of Methicillin-Resistant Staphylococcus aureus Skin Infection. Adv Funct Mater 26:1628-1635
Chen, Wansong; Zhang, Qiangzhe; Luk, Brian T et al. (2016) Coating nanofiber scaffolds with beta cell membrane to promote cell proliferation and function. Nanoscale 8:10364-70

Showing the most recent 10 out of 40 publications