Multidrug resistance (MDR) is a serious problem that hampers the success of cancer pharmacotherapy. A common mechanism is the overexpression of ATP-binding cassette (ABC) efflux transporters in cancer cells such as P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 1 (MRP1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2) that limit the exposure to anticancer drugs. One way to overcome MDR is to develop ABC efflux transporter inhibitors to sensitize cancer cells to chemotherapeutic drugs. The complete clinical trials thus far have showen that those tested chemosensitizers only add limited or no benefits to cancer patients. Some MDR modulators are merely toxic, and others induce unwanted drug-drug interactions. Actually, many ABC transporters are also expressed abundantly in the gastrointestinal tract, liver, kidney, brain and other normal tissues, and they largely determine drug absorption, distribution and excretion, and affect the overall pharmacokinetic properties of drugs in humans. In addition, ABC transporters such as P-gp, MRP1 and BCRP co-expressed in tumors show a broad and overlapped specificity for substrates and MDR modulators. Thus reliable preclinical assays and models are required for the assessment of transporter-mediated flux and potential effects on pharmacokinetics in drug development. In this review, we provide an overview of the role of ABC efflux transporters in MDR and pharmacokinetics. Preclinical assays for the assessment of drug transport and development of MDR modulators are also discussed.

RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery. A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets. Furthermore, guide RNAs are essential components of novel gene editing modalities, and mRNA therapeutics are under development for protein replacement therapy or vaccination, including those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or RNA motifs are highly structured to form binding pockets or clefts that are accessible by small molecules. Many natural, semisynthetic, or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of bacterial infections. Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials. Here, we review the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, with a focus on recent progresses and strategies. Challenges in the development of novel druggable RNA entities and identification of viable RNA targets and selective small-molecule binders are discussed. Significance Statement With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.

Nanomedicines have evolved into various forms including dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles since their first launch in the market. Widely highlighted benefits of nanomedicines over conventional medicines include superior efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profiles of pharmaceutical ingredients. Especially, various kinetic characteristics of nanomedicines in body are further influenced by their formulations. This review provides an updated understanding of nanomedicines with respect to delivery and pharmacokinetics. It describes the process and advantages of the nanomedicines approved by FDA and EMA. New FDA and EMA guidelines will also be discussed. Based on the analysis of recent guidelines and approved nanomedicines, key issues in the future development of nanomedicines will be addressed.

Life cycle alternation between arthropod and mammals forces the Lyme disease spirochete, Borrelia burgdorferi , to adapt to different host milieus by utilizing diverse carbohydrates. Glycerol and chitobiose are abundantly present in the Ixodes tick. B. burgdorferi can utilize glycerol as a carbohydrate source for glycolysis and chitobiose to produce N -acetylglucosamine (GlcNAc), a key component of the bacterial cell wall. A recent study reported that Rrp1, a response regulator that synthesizes cyclic diguanylate (c-di-GMP), governs glycerol utilization in B. burgdorferi . In this report, we found that the rrp1 mutant had growth defects and formed membrane blebs that led to cell lysis when GlcNAc was replaced by chitobiose in the growth medium. The gene chbC encodes a key chitobiose transporter of B. burgdorferi . We found that the expression level of chbC was significantly repressed in the mutant and that constitutive expression of chbC in the mutant successfully rescued the growth defect, indicating a regulatory role of Rrp1 in chitobiose uptake. Immunoblotting and transcriptional studies revealed that Rrp1 is required for the activation of bosR and rpoS and that its impact on chbC is most likely mediated by the BosR-RpoS regulatory pathway. Tick-mouse infection studies showed that although the rrp1 mutant failed to establish infection in mice via tick bite, exogenous supplementation of GlcNAc into unfed ticks partially rescued the infection. The finding reported here provides us with new insight into the regulatory role of Rrp1 in carbohydrate utilization and virulence of B. burgdorferi .