Prospective nanoparticle treatments for lymphangioleiomyomatosis

ABSTRACT

Introduction

Lymphangioleiomyomatosis (LAM) is a rare lung disease that is characterized by smooth muscle-like cell growth in the lungs. The current available oral treatment rapamycin slows down the disease progression but does not result in a cure. Rapamycin is also limited by its low bioavailability and dose-related adverse side effects. New treatments are, therefore, underway to investigate alternative targets and combination therapies for LAM. In recent years, much focus has been on the development of therapies based on inhaled nanotechnology using carriers to deliver drugs, as it is shown to improve drug solubility, local targeted treatment, and bioavailability.

Areas covered

This review, therefore, focuses on future prospective treatments for LAM using nanoparticles and lipid-based nanocarriers, including liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. It also investigates how nanoparticles’ physicochemical factors such as size and charge can affect the treatment of both pulmonary and extrapulmonary LAM.

Expert opinion

Advanced clinical research is still needed to demonstrate the full potential and drive future commercialization of LAM treatments delivered via inhaled lipid nanobased formulations. If successful, the resultant effects will be seen in the improvement in the life expectancy and life quality of LAM patients.

KEYWORDS:

• Lymphangioleiomyomatosisi
• inhalation
• nanoparticles
• lymphatic system

Article highlights

• LAM is caused by constitutive activation of the mTOR pathways, downstream of tuberous sclerosis complexes 1 and 2, resulting in increased proliferation, migration, and reduced autophagy, as well as increased lymphangiogenesis.

• The current approved LAM therapy is limited to oral rapamycin, which has greatly improved the quality of life and survival rate of LAM patients, yet it is limited by its low oral bioavailability, associated adverse side effects, and importantly only acting on part of the mTOR pathway to reduce proliferation and slow down the progression of the disease.

• There is an imperative need for new treatments that can target the entire dysregulated intracellular pathway including targeting extrapulmonary LAM and reducing lymphangiogenesis.

• Recent advances in nanoparticle technology using a variety of lipid-based carriers allow prospective LAM therapies to be incorporated into nanocarrier-based formulations that would improve drug solubility, reduce local toxicity, protect the drugs from enzymatic degradation, and provide a more sustained drug release.

• In vitro and in vivo studies show that nanoparticle formulations with negative surface charge and a size range below 500 nm result in improved lymphatic uptake and lymph node localization, and thus, developing LAM therapies with similar characteristics would potentially allow drugs to access extrapulmonary LAM cells that could spread to other organs via the lymphatic system.

• Inhaled delivery of nano-based therapies, as opposed to oral delivery, may further improve LAM treatment as it allows direct delivery of the drug to the main growth area of LAM cells in the lungs, bypassing first-pass metabolism and resulting in improved bioavailability.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.