An exploratory study of a new PH-responsive, ionizable hybrid nanocarrier for enchancing drug accumulation in bacterial biofilms

Temple University received a $158,500 Project Grant from the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855), effective August 1, 2025, through July 31, 2027. The award supports an exploratory study to develop and validate a novel pH-responsive, ionizable hybrid nanocarrier system designed to enhance therapeutic drug delivery to bacterial biofilms. The research focuses on creating a poly(lactic-co-glycolic acid) (PLGA) core nanocarrier coated with pH-responsive ionizable lipids that become cationic in the acidic microenvironment of biofilms while remaining neutral in surrounding host tissues, thereby improving drug accumulation and bacterial targeting while minimizing off-target binding.

The deliverables include the development of efficient, stable ionizable hybrid nanocarriers capable of entrapping diverse therapeutic agents for anti-biofilm therapy, verification of the nanocarrier's pH-responsiveness and biofilm retention properties, and characterization of the system's efficacy in delivering anti-biofilm treatments. This research addresses a critical clinical need, as bacterial biofilms are a primary cause of chronic wound infections and are highly resistant to conventional antibiotics due to their protective matrix structure, requiring substantially higher drug concentrations for effective treatment compared to planktonic bacterial states.

Abstract

Description. Our goal is to study the feasibility of a newer, potentially safer and better nanocarrier design for enhancing the delivery of a variety of therapeutic agents to bacterial biofilms. Biofilms are the main culprit causing the majority of chronic wounds. Once established, biofilms can protect the encased bacteria against immune system and most antibiotics, thus rendering the biofilm-associated infections very difficult to treat. Despite the advance of antibiotics and development of new anti-biofilm agents, the first and foremost challenge remains to be delivering enough drugs into the biofilms. This is a realistic need as much higher drug concentrations are needed for effective treatment of the bacteria in biofilms than in their planktonic state. Considering that many mature biofilms produce a microenvironment more acidic than the surrounding host tissues, in this application we propose to exploit this biofilm characteristic by developing a new hybrid nanocarrier design with a poly(lactic-CO-glycolic acid) (plga) core coated with PH-responsive, ionizable lipids. We hypothesize that: (1) by decorating plga with ionizable lipids that turn cationic in an acidic microenvironment, the resulting "hybrid" nanocarrier will be well-retained in a biofilm, yet stay nearly neutral outside to avoid excessive binding to the negatively charged host cell surfaces, and (2) with the lipid coating, the plga core will still preserve its proven capability to encapsulate a wide range of different drugs. Moreover, this nanocarrier may also have enhanced interaction with the negatively charged bacteria cell surface. Driven by these hypotheses, the following aims are developed: (1) develop efficient, stable ionizable hybrid nanocarriers capable of entrapping diverse therapeutic agents for anti-biofilm therapy. (2) verify and optimize the impact of decorating nanocarriers with PH-responsive, ionizable lipids on their distribution and retention in biofilms. (3) evaluate the feasibility to enhance anti-biofilm activities of antibiotics and quorum sensing inhibitors with PH-responsive, ionizable hybrid nanocarriers. Relevance to public health. Biofilms are nearly ubiquitous and can form on the surfaces of most medical devices and host tissues, resulting in a high incidence of device-related infections and tissue-related infections. They are a critical barrier against effective drug treatment of many chronic infections such as delayed wound healing, cystic fibrosis, endocarditis, urinary tract infections, etc, and are also responsible for bacteria dissemination through the biofilm dispersal mechanism, as well as promoting other diseases including cancer. However, up to date there is no drug officially approved for biofilm eradication. Successful completion of this project will validate the feasibility of a new nanotherapy that can increase the selectivity of antibiotics and antibiofilm compounds for biofilms, prolong their retention there and avoid excessive distribution to the host tissues. Consequently, the effectiveness and safety of biofilm therapy can be significantly enhanced.