Microparticle compositions for controlled delivery of telmisartan and actinomycin D
Inventors
Mohapatra, Subhra • Mohapatra, Shyam S. • Markoutsa, Eleni • Gonzalez, Alejandro J. • Jadhav, Heta N.
Assignees
US Department of Veterans Affairs • University of South Florida St Petersburg
Publication Number
US-11951152-B1
Publication Date
2024-04-09
Expiration Date
2040-09-18
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Abstract
This disclosure is directed to therapeutic compositions, and more particularly to microparticle compositions for the controlled delivery of telmisartan and actinomycin D.
Core Innovation
This disclosure provides therapeutic compositions comprising liposomal microparticles encapsulating two different types of crosslinked chitosan nanoparticles, enabling controlled and differential release of telmisartan and actinomycin D for cancer treatment. The therapeutic composition includes terephthalaldehyde (TPA)-crosslinked chitosan nanoparticles loaded with actinomycin D, which release rapidly in acidic environments such as tumor sites, and tripolyphosphate (TPP)-crosslinked chitosan nanoparticles loaded with telmisartan, which provide sustained drug release.
A key feature of the invention is the pH-dependent release mechanism achieved through TPA-crosslinking that forms Schiff bases susceptible to hydrolysis under acidic conditions, allowing rapid payload release in tumors. Concurrently, TPP-crosslinked nanoparticles maintain stability across pH levels, enabling sustained delivery of telmisartan. The compositions may further include acetazolamide conjugated to nanoparticle surfaces as a hypoxia-targeting moiety to enhance tumoral accumulation and therapeutic effectiveness.
The problem addressed is the poor survival rate of lung cancer patients, largely due to drug resistance in metastatic tumors, highlighting a need for improved treatment options. This disclosure aims to meet this need by delivering two anticancer agents in a controlled and targeted fashion to tumors, particularly in the lung, leveraging the differential release profiles of the dual nanoparticle system within liposomal microparticles for enhanced delivery and efficacy with reduced systemic toxicity.
Claims Coverage
The patent includes two independent claims related to a therapeutic composition and its method of use in treating lung cancer. These claims cover the composition's core structural features and specific release properties of the nanoparticles.
Therapeutic composition comprising liposomal microparticles encapsulating two types of crosslinked chitosan nanoparticles
The composition includes a plurality of liposomal microparticles encapsulating (1) TPA-crosslinked chitosan nanoparticles loaded with actinomycin D and (2) TPP-crosslinked chitosan nanoparticles loaded with telmisartan.
Controlled release properties of TPA- and TPP-crosslinked chitosan nanoparticles
TPA-crosslinked nanoparticles release actinomycin D rapidly at pH less than about 7 with increased particle diameter and zeta potential, releasing at least 25% of drug within 30 minutes. TPP-crosslinked nanoparticles provide sustained release of telmisartan and are stable across pH ranges.
Conjugation of acetazolamide for hypoxia targeting
Acetazolamide is conjugated to the surface of TPA-crosslinked nanoparticles, TPP-crosslinked nanoparticles, or both to enable targeting to hypoxic tumor environments.
Formulation characteristics and administration method
Liposomal microparticles have average diameters from about 25 to 55 microns and may comprise dipalmitoylphosphatidylcholine (DPPC). The compositions can be formulated for delivery to the lung. A method of treating lung cancer involves administering a therapeutically effective amount of the described composition to a subject, including administration directly to the lung.
The claims collectively cover a dual nanoparticle-in-liposome therapeutic composition with differential pH-responsive and sustained drug release for cancer therapy, the use of hypoxia-targeting acetazolamide conjugation, and methods of treatment with lung delivery.
Stated Advantages
Allows differential, controlled release of therapeutic agents, enabling rapid release of actinomycin D in acidic tumor environments while sustaining telmisartan release.
Improves targeting to hypoxic tumor tissue via acetazolamide conjugation, enhancing drug accumulation and effectiveness.
Utilizes biocompatible and FDA Generally Recognized As Safe (GRAS) materials such as chitosan nanoparticles and liposomal microparticles for safe and effective delivery.
Facilitates delivery to the lung, including deep lung regions, potentially improving treatment of lung cancers.
Documented Applications
Treatment of cancer in a subject, particularly lung cancer.
Use of the composition formulated for delivery to the lung, including intravenous and inhalation routes.
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