Lung cancer (LC) is one of the leading causes of cancer occurrence and mortality worldwide. Treatment of patients with advanced and metastatic LC presents a significant challenge, as malignant cells use different mechanisms to resist chemotherapy. Drug resistance (DR) is a complex process that occurs due to a variety of genetic and acquired factors. Identifying the mechanisms underlying DR in LC patients and possible therapeutic alternatives for more efficient therapy is a central goal of LC research. Advances in nanotechnology resulted in the development of targeted and multifunctional nanoscale drug constructs. The possible modulation of the components of nanomedicine, their surface functionalization, and the encapsulation of various active therapeutics provide promising tools to bypass crucial biological barriers. These attributes enhance the delivery of multiple therapeutic agents directly to the tumor microenvironment (TME), resulting in reversal of LC resistance to anticancer treatment. This review provides a broad framework for understanding the different molecular mechanisms of DR in lung cancer, presents novel nanomedicine therapeutics aimed at improving the efficacy of treatment of various forms of resistant LC; outlines current challenges in using nanotechnology for reversing DR; and discusses the future directions for the clinical application of nanomedicine in the management of LC resistance.

Enhanced permeation retention (EPR) was a significant milestone discovery by Maeda et al. paving the path for the emerging field of nanomedicine to become a powerful tool in the fight against cancer. Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE-5) used for the treatment of erectile dysfunction (ED) through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. Overexpression of PDE-5 has been reported in lung, colon, metastatic breast cancers, and bladder squamous carcinoma. Moreover, sildenafil has been reported to increase the sensitivity of tumor cells of different origins to the cytotoxic effect of chemotherapeutic agents with augmented apoptosis mediated through inducing the downregulation of Bcl-xL and FAP-1 expression, enhancing reactive oxygen species (ROS) generation, phosphorylating BAD and Bcl-2, upregulating caspase-3,8,9 activities, and blocking cells at G0/G1 cell cycle phase. Sildenafil has also demonstrated inhibitory effects on the efflux activity of ATP-binding cassette (ABC) transporters such as ABCC4, ABCC5, ABCB1, and ABCG2, ultimately reversing multidrug resistance. Accordingly, there has been a growing interest in using sildenafil as monotherapy or chemoadjuvant in EPR augmentation and management of different types of cancer. In this review, we critically examine the basic molecular mechanism of sildenafil related to cancer biology and discuss the overall potential of sildenafil in enhancing EPR-based anticancer drug delivery, pointing to the outcomes of the most important related preclinical and clinical studies.

The particle size (PS) and encapsulation efficiency (EE%) of drug-loaded nanoparticles (NPs) may inhibit their cellular uptake and lead to possible leakage of the drug into the systemic circulation at the tumor site. In this work, ultra-high paclitaxel-loaded poly(lactide-co-glycolide) NPs (PTX-PLGA-NPs) with ultra-small sizes were prepared and optimized by adopting the principles of quality by design (QbD) approach. The optimized PTX-PLGA-NPs showed ultra-small spherical particles of about 53 nm with EE% exceeding 90%, a relatively low polydispersity index (PDI) of 0.221, an effective surface charge of −10.1 mV, and a 10-fold increase in the in vitro drug release over 72 h relative to free drug. The cellular viability of pharynx carcinoma cells decreased by almost 50% in 24 h following treatment with optimized PTX-PLGA-NPs, compared to only 20% from the free drug. The intracellular uptake of PTX-PLGA-NPs was highly favored, and the antitumor activity of PTX was remarkably improved with a reduction in its half maximal inhibitory concentration (IC₅₀), by almost 50% relative to free drug solution. These results suggest that the optimal critical formulation parameters, guided by QbD principles, could produce PLGA-NPs with remarkably high EE% and ultra-small PS, resulting in enhanced cellular uptake and efficacy of PTX.

Messenger RNA (mRNA) technology is a potent platform for new vaccines and therapeutics. To deliver RNA medicines effectively, safe delivery vectors are crucial. Among these, poly(β-amino ester)s (PBAEs) complexes with nucleic acids have been shown as promising alternatives to conventional lipid nanoparticles, but toxicity and colloidal stability concerns still remain. Conjugation of poly(ethylene glycol) (PEG) has been used to mitigate these issues, but challenges associated with PEG-induced reactogenicity have emerged. Polysarcosine (pSar) has shown promise as a PEG alternative, demonstrating reduced reactogenicity when incorporated into lipid nanoparticles. We therefore developed a synthetic route to conjugate pSar on to PBAE end-groups, resulting in a pSar-PBAE-pSar triblock copolymer. Polyplexes containing various ratios (0, 20, 50, 80, 100% pSar) of the pSarylated and a non-pSarylated PBAE were prepared with self-amplifying messenger RNA, to examine the effect of surface pSar density. RNA encapsulation efficiencies, formulation properties and gene transfectability in vitro were then assessed indicating complete encapsulation of the cargo and sub-200 nm particle diameters in all cases. Despite high gene transfection in HEK293T cells, only the 50%-pSar displayed significantly higher expression of the reporter gene than the negative control in Caco-2. Further evaluation of 50%-pSar was conducted using 3D human colorectal cancer organoids, which displayed high transfection ability within the core of the organoid indicating high penetration of these nanoparticles. As a result, these findings indicate that pSarylated PBAEs have the potential to serve as a promising component material for enhancing delivery of nucleic acid therapeutics.

Poly(beta-amino ester) (PBAE)s are versatile polymers which can be complexed with multiple nucleic acids to modulate immune responses.