PLGA-Based Strategies for Intranasal and Pulmonary Applications

Abstract

Poly(D,L-lactide-co-glycolide) (PLGA) has emerged as a cornerstone in the development of advanced drug delivery systems, particularly for intranasal and pulmonary routes. Its biodegradability, biocompatibility, and adaptability make it an ideal platform for addressing challenges associated with conventional therapies. By enabling sustained and controlled drug release, PLGA formulations reduce dosing frequency, improve patient compliance, and enhance therapeutic efficacy. These systems demonstrate versatility, accommodating hydrophilic and hydrophobic drugs, biological molecules, and co-delivery of synergistic agents. Moreover, surface modifications and advanced preparation techniques enhance targeting, bioavailability, and stability, expanding PLGA’s applications to treat complex diseases such as tuberculosis, cancer, pulmonary fibrosis, and CNS disorders. This manuscript provides an in-depth review of PLGA’s materials, properties, preparation methods, and therapeutic applications, alongside a critical evaluation of challenges and future opportunities in this field.

1. The Role of PLGA in Enhancing Nasal and Pulmonary Drug Delivery Systems

The development of effective drug delivery systems remains a cornerstone of modern pharmaceutical science, particularly for challenging administration routes like nasal and pulmonary pathways. These routes offer significant therapeutic potential, providing direct access to systemic circulation or target sites such as the central nervous system (CNS) and respiratory tract while bypassing barriers like first-pass metabolism or the blood–brain barrier. The application of PLGA, a biodegradable and biocompatible polymer, has transformed intranasal and pulmonary drug delivery by enabling sustained release, enhanced targeting, and reduced systemic toxicity [1,2,3,4].

PLGA’s unique properties, including its ability to degrade into non-toxic byproducts such as lactic and glycolic acids, make it a safe and versatile material for long-term applications in sensitive tissues like the nasal mucosa and lungs [1,5,6,7]. Moreover, its adaptability to a wide range of preparation techniques, such as emulsification, Flow Focusing® technology, spray drying, and supercritical fluid processing, allows for the tailored design of drug delivery systems to meet specific therapeutic requirements [2,5,8,9,10].

Intranasal delivery using PLGA offers a non-invasive approach to accessing the CNS, leveraging the olfactory and trigeminal pathways for effective treatment of neurodegenerative disorders and brain cancers [11,12,13]. Similarly, pulmonary delivery systems using PLGA enable deep lung deposition and retention, which are crucial for treating diseases such as tuberculosis, asthma, and pulmonary hypertension [5,14,15,16]. The ability of PLGA to encapsulate a wide range of drugs, including hydrophilic, hydrophobic, and biological molecules, further underscores its versatility and relevance in modern drug delivery [10,17,18,19].

Additionally, PLGA-based systems have demonstrated compatibility with advanced surface modifications, such as ligand conjugation and chitosan coating, to enhance targeting, mucoadhesion, and bioavailability for both systemic and localized therapies [3,12,20,21,22]. The incorporation of cryoprotectants and stabilizers ensures the long-term stability of these formulations, enabling practical storage and transportation for commercial use [23,24,25]. Furthermore, the ability to co-deliver multiple therapeutic agents expands the potential of PLGA in treating complex diseases like cancer and cystic fibrosis through synergistic effects [15,26,27].

The application of PLGA in intranasal and pulmonary drug delivery presents a promising strategy to overcome the limitations of conventional therapies by enabling targeted, sustained, and innovative solutions for localized, systemic, and CNS-directed treatments. Its biocompatibility, adaptability across diverse drug formulations, and potential to address challenges such as poor bioavailability and rapid clearance have made PLGA an essential platform for treating CNS disorders, respiratory diseases, and other complex conditions. However, issues such as inconsistent drug release, physiological variability, and safety concerns related to functionalized particles underscore the need for further innovation in polymer modification, surface engineering, and production standardization. Refining formulation stability and ensuring long-term safety are critical to achieving successful clinical translation.

2. Therapeutic Applications of PLGA in Nasal and Pulmonary Route

2.1. Enhancing Antibiotic Therapies for Respiratory Infections

PLGA-based formulations are highly effective in enhancing antibiotic therapies for respiratory infections, providing prolonged release and reducing dosing frequency. Levofloxacin and tobramycin are examples of antibiotics designed for sustained pulmonary release, extending therapeutic action and providing ongoing protection against bacterial pathogens in chronic respiratory conditions [28,29]. Importantly, safety studies have shown that celecoxib-loaded PLGA microparticles caused no pulmonary toxicity during extended evaluations, as confirmed by histological and biochemical analyses over 21 days [8]. Similarly, testing on lung cell lines exposed to PLGA at concentrations as high as 10 mg/mL demonstrated no cytotoxicity, further validating its suitability for antibiotic delivery in respiratory therapies [4].

Similarly, ethionamide and ciprofloxacin, encapsulated in PLGA for inhalation, deliver extended antimicrobial effects, which is particularly valuable in managing persistent and severe respiratory infections [30,31]. Cryoprotectants like sucrose are often employed during the freeze-drying of PLGA nanoparticles, reducing aggregation and maintaining the stability of these antibiotic formulations, thus preserving their physicochemical properties [32]. This sustained-release approach not only maintains consistent therapeutic levels but also improves patient adherence, potentially reducing the risk of antibiotic resistance.

2.2. Anti-Inflammatory and Anti-Fibrotic Applications

PLGA-based systems are also used for delivering anti-inflammatory and anti-fibrotic drugs, particularly in treating chronic lung diseases. Encapsulation of alpha-mangostin, an anti-inflammatory compound, in PLGA nanoparticles ensures prolonged pulmonary delivery, making it suitable for managing inflammation in chronic respiratory conditions [17]. Drugs like celecoxib, nintedanib, and pirfenidone, often formulated in PLGA nanoparticles or combined with liposomes, provide targeted therapy for pulmonary fibrosis, where fibrotic lung tissue necessitates extended and controlled drug release [8,33]. Importantly, advanced formulations such as porous PLGA microparticles have been engineered to evade macrophage uptake, minimizing off-target effects and increasing local lung retention [34]. These biocompatibility improvements ensure that PLGA-based systems deliver anti-inflammatory and anti-fibrotic drugs effectively without triggering significant adverse effects.

2.3. Combination Therapies for Complex Respiratory Conditions

In complex respiratory conditions, combination therapies using PLGA are particularly advantageous. For example, a formulation combining tobramycin, ciprofloxacin, azithromycin, N-acetylcysteine (NAC), and curcumin addresses infections, mucus buildup, and inflammation simultaneously, highlighting PLGA’s versatility in multimodal respiratory treatment (Figure 1) [15]. In addition to their therapeutic benefits, PLGA nanoparticles demonstrate excellent safety in combination therapy contexts, with minimal oxidative stress or hemolysis observed in preclinical studies [13].

Figure 1. Shows the morphology of multidrug inhalable microparticles using confocal laser scanning microscopy (CLSM):

2.4. PLGA-Based Pulmonary Delivery of Peptides and Proteins

Peptide and protein drugs, traditionally challenging to administer, also benefit from PLGA-based pulmonary and systemic delivery systems. Insulin, developed for pulmonary delivery using PLGA, presents a promising non-invasive option for diabetes management with extended-release profiles [35,36]. Similarly, respiratory therapies leverage PLGA for delivering therapeutic proteins like Deoxyribonuclease I (DNaseI), which breaks down extracellular DNA in lung secretions to improve respiratory function in cystic fibrosis by enhancing mucus clearance [37]. Proteins such as alpha-1 antitrypsin and somatropin (r-hGH) are also formulated with PLGA for targeting inflammatory and degenerative lung conditions, providing protein stability and controlled release for chronic treatments requiring long-term efficacy [38]. Figure 2 shows a schematic preparation of large, porous, biodegradable, aerodynamically light microparticles as tunable carriers for pulmonary r-hGH delivery [6]. These formulations have been tested for biocompatibility, demonstrating no significant cytotoxicity or inflammatory reactions, which is crucial for maintaining the safety of prolonged protein therapies.

2.5. Innovations in Nanoparticle Design for Biologics

The FDA’s regulatory approval of PLGA has also enabled innovation in nanoparticle design for biologics. For example, recombinant human interleukin-2 (rhIL-2)-loaded PLGA microparticles for pulmonary administration demonstrated high encapsulation efficiency and retained biological activity post-encapsulation [39]. These findings further underscore PLGA’s potential as an effective carrier for biologics, expanding its therapeutic applications while leveraging its established safety profile.

2.6. Intranasal PLGA-Based Formulations for CNS Drug Delivery

Intranasal PLGA-based formulations have shown significant potential in delivering neurological drugs directly to the brain, bypassing the blood–brain barrier and enabling rapid therapeutic action. Chlorpromazine hydrochloride, for instance, is formulated for CNS applications via nasal administration, with PLGA supporting controlled drug delivery and efficient brain targeting [20]. Dopamine agonists such as rotigotine and ropinirole hydrochloride, used in Parkinson’s disease treatment, are encapsulated in PLGA for intranasal delivery, enabling precise brain targeting and controlled drug release [12,13]. These formulations benefit from PLGA’s proven safety profile in the CNS context, as evidenced by studies where lactoferrin-modified PLGA nanoparticles showed enhanced brain targeting without inducing toxicity or systemic side effects [40]. Similarly, antiepileptic drugs like oxcarbazepine and thyrotropin-releasing hormone analogs (NP-355, NP-647) are effectively delivered through the nose-to-brain route, leveraging PLGA’s capabilities for localized delivery, minimal systemic exposure, and rapid onset of therapeutic effects [41,42].

2.7. Oncology Applications of PLGA in Lung and Brain Cancers

The role of PLGA in oncology highlights its effectiveness in achieving targeted delivery and reducing adverse systemic effects, particularly for lung and brain cancers. For lung cancer, anticancer agents like doxorubicin (DOX), cisplatin, and docetaxel are incorporated into PLGA formulations for controlled pulmonary delivery, enhancing drug targeting to tumor sites and reducing systemic toxicity [26,43]. Artesunate-loaded PLGA microparticles, for example, demonstrated excellent safety profiles while inducing apoptosis and inhibiting cancer cell migration and invasion [43]. In CNS applications, intranasal PLGA-based formulations for drugs like docetaxel and curcumin target brain tumors such as glioblastoma, achieving localized therapeutic action, reducing side effects, and potentially increasing efficacy in aggressive brain cancers [32,44].

PLGA-based formulations have demonstrated remarkable versatility in advancing therapeutic applications through nasal and pulmonary routes, addressing critical challenges such as sustained drug release, patient adherence, and targeted delivery. However, limitations including burst-release effects, protein instability, macrophage clearance, and challenges in multi-drug encapsulation must be systematically addressed to fully exploit the potential of PLGA systems. Regulatory approval of PLGA provides a solid foundation for clinical translation, but precise optimization of manufacturing processes, drug loading, and stability remains pivotal. With advancements in surface functionalization, cryoprotectant utilization, and scalable techniques, PLGA formulations are poised to transform the management of complex diseases such as chronic respiratory infections, CNS disorders, and cancers.

Table 1 explores the therapeutic applications of various drugs encapsulated in PLGA formulations, focusing on pulmonary, CNS, and systemic delivery. It highlights key drug groups and their roles in treating infections, cancer, fibrosis, and neurodegenerative diseases, showcasing the versatility of PLGA-based systems. PLGA formulations enable a broad spectrum of therapeutic uses, including sustained drug delivery for chronic infections, tumor targeting for lung and CNS cancers, and enhanced brain targeting for neurodegenerative diseases. The versatility of PLGA systems supports tailored treatments for diseases like pulmonary fibrosis, tuberculosis, and hypertension. Synergistic drug combinations (e.g., docetaxel and celecoxib) improve efficacy and reduce side effects. Advanced delivery mechanisms for hormonal, protein, and gene therapies indicate the potential of PLGA for precision medicine.

Table 1. Therapeutic agents delivered via PLGA systems: indications and benefits.

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Omidian, H.; Wilson, R.L. PLGA-Based Strategies for Intranasal and Pulmonary Applications. Pharmaceutics 2025, 17, 207. https://doi.org/10.3390/pharmaceutics17020207