Tumor cells develop resistance to chemotherapeutic drugs through multiple mechanisms. Overexpression of efflux transporters is an important source of drug resistance. Efflux transporters such as P-glycoprotein reduce intracellular drug accumulation and compromise drug efficacy. Various nanoparticle-based approaches have been investigated to overcome efflux-mediated resistance. These include the use of formulation excipients that inhibit transporter activity and co-delivery of the anticancer drug with a specific inhibitor of transporter function or expression. However, the effectiveness of nanoparticles can be diminished by poor transport in the tumor tissue. Hence, adjunct therapies that improve the intratumoral distribution of nanoparticles may be vital to the successful application of nanotechnology to overcome tumor drug resistance. This review discusses the mechanisms of tumor drug resistance and highlights the opportunities and challenges in the use of nanoparticles to improve the efficacy of anticancer drugs against resistant tumors.

The oral absorption of drugs that have poor bioavailability can be enhanced by encapsulation in polymeric nanoparticles. Transcellular transport of nanoparticle-encapsulated drug, possibly through transcytosis, is likely the major mechanism through which nanoparticles improve drug absorption. We hypothesized that the cellular uptake and transport of nanoparticles can be further increased by targeting the folate receptors expressed on the intestinal epithelial cells. The objective of this research was to study the effect of folic acid functionalization on transcellular transport of nanoparticle-encapsulated paclitaxel, a chemotherapeutic with poor oral bioavailability. Surface-functionalized poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles loaded with paclitaxel were prepared by the interfacial activity assisted surface functionalization technique. Transport of paclitaxel-loaded nanoparticles was investigated using Caco-2 cell monolayers as an in vitro model. Caco-2 cells were found to express folate receptor and the drug efflux protein, p-glycoprotein, to high levels. Encapsulation of paclitaxel in PLGA nanoparticles resulted in a 5-fold increase in apparent permeability (Papp) across Caco-2 cells. Functionalization of nanoparticles with folic acid further increased the transport (8-fold higher transport compared to free paclitaxel). Confocal microscopic studies showed that folic acid-functionalized nanoparticles were internalized by the cells and that nanoparticles did not have any gross effects on tight junction integrity. In conclusion, our studies indicate that folic acid functionalized nanoparticles have the potential to enhance the oral absorption of drugs with poor oral bioavailability.

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent pulmonary carcinogen in rats and is believed to be one cause of lung cancer in smokers. NNK is metabolized to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) which is also a strong lung carcinogen in rats and has a chiral center at its 1-carbon. Previous studies have demonstrated that cytochrome P450-catalyzed α-hydroxylation of NNK in the lung leading to the formation of methyl and pyridyloxobutyl (POB)-DNA adducts is critical for its carcinogenicity. α-Hydroxylation of NNAL would similarly produce pyridylhydroxybutyl (PHB)-DNA adducts, but these have not been previously investigated in vivo. POB-and PHB-DNA adduct levels can indicate the amounts of pyridyloxobutylating and pyridylhydroxybutylating agents present in tissues of NNK or NNAL treated rats at any given point. Therefore, in this study, we developed a sensitive and quantitative liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring method to determine levels of the PHB-DNA adducts , 11b), and 7-[4-(3-pyridyl)-4-hydroxybut-1-yl]-2′-deoxyguanosine (7-PHB-dGuo, 12b), the latter as the corresponding base 7-[4-(3-pyridyl)-4-hydroxybut-1-yl]-Gua (7-PHB-Gua, 14b) in DNA isolated from liver and lung of rats treated with 10 ppm NNK, (S)-NNAL, or (R)-NNAL in the drinking water for 20 weeks, and sacrificed at 1, 2, 5, 10, 16, and 20 weeks. PHB-DNA adduct levels were higher in lung than in liver at each time point, consistent with previous studies of POB-DNA adducts in rats treated with NNK and NNAL in the drinking water. The results showed that NNK and (S)-NNAL behaved in a similar fashion while (R)-NNAL was strikingly different. In the rats treated with NNK or (S)-NNAL, levels of each adduct at each time point were remarkably similar in lung, and levels of O 2 -PHB-dThd were generally > than 7-PHB-Gua > O 6 -PHB-dGuo. The highest PHB-DNA adduct levels were found in lung and liver of rats treated with (R)-NNAL, suggesting that there are cytochrome P450s that efficiently catalyze the α-methyl hydroxylation of this compound. The results of this study provide further support for our hypothesis that (S)-NNAL is rapidly formed from NNK, sequestered at an unknown site in the lung, then released and reoxidized to NNK with consequent DNA adduct formation resulting in lung carcinogenicity.

While numerous microRNAs (miRNAs) have been reported to alter their expression levels in human lung cancer tissues compared with normal tissues, the function of these miRNAs and their contribution to the long process of lung cancer development remains largely unknown. We applied a tobacco-specific carcinogen-induced cancer model to investigate the involvement of miRNAs in early lung cancer development, which could also provide information on potential, early biomarkers of lung cancers. Male F344 rats were first chronically treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a carcinogen present in tobacco products, for up to 20 weeks. The expression profiles of miRNAs in rat lungs were then determined. As measured by miRNA microarrays and confirmed by Northern blot and real-time polymerase chain reaction analyses, NNK treatment reduced the expression of a number of miRNAs, such as miR-101, miR-126*, miR-199 and miR-34. Significantly, these miRNAs overlap with previously published reports on altered miRNA expression in human lung cancer samples. These miRNAs might, therefore, represent early-response miRNAs that signify the molecular changes associated with pulmonary tumorigenesis. Moreover, we identified cytochrome P450 (CYP) 2A3, a critical enzyme in rat lungs that activates NNK to render it carcinogenic, as a potential target of miR-126*. NNK treatment in rats repressed miR-126* but induced CYP2A3 expression, a mechanism that may potentiate the oncogenic effects of NNK.

We report here the synthesis and selected properties of various silicate ester derivatives (tetraalkoxysilanes) of the taxanes paclitaxel (PTX) and docetaxel (DTX) [i.e., PTX-OSi(OR)3 and DTX-OSi(OR)3]. Both the hydrophobicity and hydrolytic lability of these silicates can be (independently) controlled by choice of the alkyl group (R). The synthesis, structural characterization, hydrolytic reactivity, and in vitro cytotoxicity against the MDA-MB-231 breast cancer cell line of most of these derivatives are described. We envision that the greater hydrophobicity of these silicates (vis-à-vis PTX or DTX itself) should be advantageous from the perspective of preparation of stable aqueous dispersions of amphiphilic block-copolymer-based nanoparticle formulations.