Precision nanoparticles for prognosis-based early intervention of COPD-emphysema

KEYWORDS:

• Drug delivery
• COPD
• emphysema
• lung diseases
• prognosis
• intervention
• therapeutics
• nanoparticles
• precision nanomedicine

1. Introduction

Chronic obstructive pulmonary disease (COPD) is a fatal lung condition, where prognosis-based early intervention of emphysema is critical for limiting its progression to severe emphysema [1]. We and others recently elucidated the challenges of targeted intervention(s) in COPD that can be circumvented by nano-based targeted drug delivery to the airway or a specific cell type [2–4]. We also demonstrated for the first time the efficacy of targeted nano-drug delivery systems in rescuing inflammatory lung disease and controlling COPD-emphysema progression that has been since verified in various disease models [3,5].

Several nano-pharmaceuticals are FDA approved since 1990 for variety of conditions that have potential for facilitating targeted delivery to COPD airway for improving outcomes, limiting side effects, inhibiting lung function decline and preventing recurring exacerbations [5]. As a proof of concept, some of the recent FDA approved nano-pharmaceutical drugs have shown efficacy in sustained airway delivery, targeting inflammation and controlling lung disease progression as recently reviewed [5]. The classical methods for pulmonary drug delivery includes dry powder inhalers (DPI), soft mist or aerosolized inhalers, metered dose inhalers (MDI) or nebulizers, although nanoparticle (polymer, lipid, inorganic or dendrimer)-based drug delivery systems have several advantages such as providing targeted intervention or modulation of a disease biomarker, specific cell type etc., thus facilitating rapid and sustained effect onsite at a significantly lower dose, limiting toxicity or side effects and facilitating rapid metabolism [6].

Hence, we discuss here current advances and strategies for enabling bench to bedside translation of nano-pharmaceuticals for targeted prognosis-based early intervention of COPD-emphysema for delivering on the promise of precision medicine.

2. Advances in precision nanoparticles and airway applications

Targeted drug delivery systems or precision nanoparticles significantly improve the therapeutic efficacy by providing sustained localized effect at lower doses as compared to systemic, inhaler (DPI/MDI) or nebulizer based classical delivery methods. Moreover, it helps in reducing side effects, toxicity etc., by reducing systemic interference of vital homeostatic processes. Key advantages of nano-systems include increased bioavailability and stability [6–9] of the drug as nano-carriers significantly improve drug solubility while reducing its metabolism or degradation [7,10,11].

The nano-based targeted airway delivery using FDA approved polymeric nanoparticles such as PLGA (Poly lactic-co-glycolic acid), PEG (Polyethylene glycol) etc., or liposomes and lipid-based nano-carriers that were recently demonstrated to be effective in controlling airway inflammation, infection and COPD-emphysema progression in pre-clinical models, provide an effective strategy for prognosis-based targeted intervention. Thus, these precision nano-systems are novel tools for enabling targeted efficacy of therapeutics for reducing inflammation, recurring exacerbations and declining lung function in COPD-emphysema [3], warranting further clinical safety and efficacy evaluation. Moreover, they can facilitate theranostic application by allowing monitoring of prognostic or inflammatory marker(s) for an effective intervention at a targeted site [12,13].

3. FDA approved drug delivery systems for airway applications

As discussed above, nano-formulations such as the PEGylated drugs have been FDA approved since 1990 for clinical application(s), although first nano-formulation for airway application was not FDA approved until 1999, when for the first-time pulmonary surfactant nano-formulations that are Liposome-based, SP-B and SP-C (Curosurf/Poractant Alpha), were approved for clinical use for the treatment of respiratory distress. Lately, such precision nano-systems have been developed for COPD, where higher drug efficacy in the lungs and targeted delivery for controlling obstructive lung disease has been demonstrated [3,4,7] in pre-clinical studies. Moreover, airway applications of precision nano-formulations have been demonstrated in other airway conditions such as asthma, cystic fibrosis, lung fibrosis, lung inflammation, lung infection and lung cancer [7].

Although several nano-formulations have been FDA-approved for variety of diseases but only few are either approved or in clinical trials for respiratory conditions. As an example, PEGylate liposome or other nano-formulations are in clinical use for variety of conditions, including nano-delivery of bronchodilators for the respiratory conditions [7]. In addition, variety of such nano-formulations or nano-systems are FDA approved for clinical use in gene, biological therapies etc., and/or for theranostic applications, as recently reviewed [5,7].

4. Novel applications of nano-delivery in chronic obstructive lung diseases

Typical methods for nano-delivery to airway includes intra-tracheal or intra-nasal delivery and/or may involve an inhaler, nebulizer etc., for clinical application, although it involves several challenges such as need for circumventing mucus barrier in chronic obstructive lung diseases, as recently demonstrated and extensively reviewed [5,14,15]. Despite these challenges, effort has been made to develop nano-formulations specifically to circumvent mucus obstruction in obstructive lung diseases that includes COPD, CF and Asthma [5,14,15]. As an example, PLGA and/or PEG (PLGA, PLGA-PEG, PEG), liposomes and solid lipid nanoparticles are developed for targeted cell or airway delivery for COPD, CF and Asthma [3,4,7], where bench to bedside translation will facilitate prognosis-based targeted and timely intervention to limit disease progression, recurring exacerbations and lung function decline, as a potential cure.

Moreover, common drugs used for COPD such as inhaled corticosteroids, bronchodilators and antibiotics increase the risk of developing resistance, pneumonia or other side effects, where use of precision nano-systems can provide sustained site directed effect at lot lower doses to circumvent these risks. In addition, limiting recurring exacerbation and its impact, requires targeted delivery to inflammatory cells or airway to achieve an optimal immune or homeostatic response in these subjects. Thus, targeted delivery systems will not only help with reducing risks of current symptomatic long-term interventions but also facilitate targeted intervention of disease-causing homeostatic processes to control progressive lung function decline and recurring exacerbations as a potential cure.

5. Expert opinion

In summary, precision nano-systems have shown promise in targeted delivery for COPD, where safety and efficacy of these systems have been demonstrated. Although, limited progress is made in clinical translation of these novel systems for COPD and other respiratory conditions. Moreover, current COPD therapies are primarily focused on symptomatic relief, primarily due to their inability in achieving targeted intervention of prognostic disease-causing processes, where prognosis-based intervention can now be achieved by the use of the novel precision nano-systems and effort needs to be made to not only treat the symptoms but to cure the disease.

Moreover, theranostic application of novel targeted nano-systems allows real-time evaluation of targeted delivery and its efficacy for prognosis-based intervention, and provide a noninvasive method for early diagnosis and timely intervention [1,13]. Specially, the key to cure COPD as recently discussed [1] requires early diagnosis of both COPD and its exacerbations, where proposed targeted nano-based intervention strategy can not only facilitate early diagnosis but also support prognosis-based intervention to potentially cure COPD. To conclude, since clinical safety and efficacy for these nano-systems are demonstrated in variety of conditions, including some of the respiratory diseases as discussed above, further clinical development of precision nano-pharmaceuticals and theranostics will pave the way for achieving the potential cure for COPD.

Declaration of interest

N Vij is a CEO of PRECISION THERANOSTICS INC focused on developing strategies for early diagnosis and prognosis-based targeted interventions. The author has no other 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.