Drug delivery systems, particularly nanomaterial-based drug delivery systems, possess a tremendous amount of potential to improve diagnostic and therapeutic effects of drugs. Controlled drug delivery targeted to a specific disease is designed to significantly improve the pharmaceutical effects of drugs and reduce their side effects. Unfortunately, only a few targeted drug delivery systems can achieve high targeting efficiency after intravenous injection, even with the development of numerous surface markers and targeting modalities. Thus, alternative drug and nanomedicine targeting approaches are desired. Circulating cells, such as erythrocytes, leukocytes, and stem cells, present innate disease sensing and homing properties. Hence, using living cells as drug delivery carriers has gained increasing interest in recent years. This review highlights the recent advances in the design of cell-mediated drug delivery systems and targeting mechanisms. The approaches of drug encapsulation/conjugation to cell-carriers, cell-mediated targeting mechanisms, and the methods of controlled drug release are elaborated here. Cell-based “live” targeting and delivery could be used to facilitate a more specific, robust, and smart payload distribution for the next-generation drug delivery systems.
Although tremendous efforts have been made on targeted drug delivery systems, current therapy outcomes still suffer from low circulating time and limited targeting efficiency. The integration of cell-mediated drug delivery and theranostic nanomedicine can potentially improve cancer management in both therapeutic and diagnostic applications. By taking advantage of innate immune cell’s ability to target tumor cells, we developed a novel drug delivery system by using macrophages as both nanoparticle-carriers and navigators to achieve cancer-specific drug delivery. Theranostic nanoparticles were fabricated from a unique polymer, biodegradable photoluminescent poly (lactic acid) (BPLP-PLA), which possesses strong fluorescence, biodegradability, and cytocompatibility. In order to minimize the toxicity of cancer drugs to immune cells and other healthy cells, an anti-BRAF V600E mutant melanoma specific drug (PLX4032) was loaded into BPLP-PLA nanoparticles. Muramyl tripeptide (MTP) was also conjugated onto the nanoparticles to improve the nanoparticle loading efficiency. The resulting nanoparticles were internalized within macrophages, which were tracked via the intrinsic fluorescence of BPLP-PLA. Macrophages carrying nanoparticles delivered drugs to melanoma cells via cell-cell binding. Pharmacological studies also indicated that the PLX4032 loaded nanoparticles effectively killed melanoma cells. Our “self-powered” immune cell-mediated drug delivery system demonstrates a potentially significant advancement in targeted theranostic cancer nanotechnologies.
Novel citric acid based photoluminescent dyes and degradable polymers are synthesized via a facile “one-pot” reaction. A comprehensive understanding of the fluorescence mechanisms of the resulting citric acid-based fluorophores is reported. Two distinct types of fluorophores are identified: a thiozolopyridine family with high quantum yield, long lifetime, and exceptional photostability, and a dioxopyridine family with relatively lower quantum yield, multiple lifetimes, and solvent-dependent band shifting behavior. Applications in molecule labeling and cell imaging were demonstrated. The above discoveries contribute to the field of fluorescence chemistry and have laid a solid foundation for further development of new fluorophores and materials that show promise in a diversity of fluorescence-based applications.
Sustained reliance on androgen receptor (AR) after failure of AR-targeting androgen deprivation therapy (ADT) prevents effective treatment of castration-recurrent (CR) prostate cancer (CaP). Interfering with the molecular machinery by which AR drives CaP progression may be an alternative therapeutic strategy but its feasibility remains to be tested. Here, we explore targeting the mechanism by which AR, via RhoA, conveys androgen-responsiveness to Serum Response Factor (SRF), which controls aggressive CaP behavior and is maintained in CR-CaP. Following a siRNA screen and candidate gene approach, RNA-Seq studies confirmed that the RhoA effector Protein Kinase N1 (PKN1) transduces androgen-responsiveness to SRF. Androgen treatment induced SRF-PKN1 interaction, and PKN1 knockdown or overexpression severely impaired or stimulated, respectively, androgen regulation of SRF target genes. PKN1 overexpression occurred during clinical CR-CaP progression, and hastened CaP growth and shortened CR-CaP survival in orthotopic CaP xenografts. PKN1’s effects on SRF relied on its kinase domain. The multikinase inhibitor lestaurtinib inhibited PKN1 action and preferentially affected androgen regulation of SRF over direct AR target genes. In a CR-CaP patient-derived xenograft, expression of SRF target genes was maintained while AR target gene expression declined and proliferative gene expression increased. PKN1 inhibition decreased viability of CaP cells before and after ADT. In patient-derived CaP explants, lestaurtinib increased AR target gene expression but did not significantly alter SRF target gene or proliferative gene expression. These results provide proof-of-principle for selective forms of ADT that preferentially target different fractions of AR’s transcriptional output to inhibit CaP growth.
A major limitation in the management of castration-recurrent prostate cancer (CR-CaP) is the lack of treatments to inhibit androgen receptor (AR) action that is driving CaP growth when androgen-deprivation therapy (ADT) has failed. AR action breaks down in fractions that are regulated differently at the molecular level, control diverse aspects of CaP biology and contribute differentially to CaP progression. Blocking a specific fraction(s) of AR action that mediates CaP progression may serve as alternative treatment strategy, yet evidence for such an approach and drugs that render this approach feasible are not known. Our laboratory has identified a mechanism of AR action in which AR conveys androgen-responsiveness to Serum Response Factor (SRF) target genes via androgen activation of RhoA. Androgen-responsive SRF action mediates cell migration and is associated with aggressive CaP behavior and recurrence. Importantly, control of AR over RhoA-SRF action is maintained in CR-CaP, which renders this signaling a potentially attractive novel therapeutic target. Using an siRNA screen, we identified Protein Kinase N1 (PKN1) as the Rho effector that transduces androgen-responsiveness from RhoA to SRF. In promoter-reporter, qRT-PCR and oligoarray assays, knockdown of PKN1 severely impaired the androgen-regulation of SRF target genes, but affected androgen response of only a few (12 of 452) direct AR target genes. In contrast, transient overexpression of PKN1 preferentially stimulated androgen-responsive SRF target gene expression. Stable overexpression of PKN1 hastened growth and shortened survival in CaP orthotopic xenografts. Site-directed mutagenesis showed that the effect of PKN1 on SRF target genes relied on its kinase activity. Treatment with lestaurtinib, a multikinase inhibitor that is also a potent inhibitor of PKN1, mimicked the effects of PKN1 knockdown on expression of SRF and AR target genes in several CaP cell lines and ex vivo CaP explants. Lestaurtinib also inhibited the proliferation of CaP cells that are either ADT-naïve or -resistant, express only the constitutively active AR variant ARv567es, or are growth-stimulated by the AR-activating ADT drug metabolite 5α-abiraterone. RNA-Seq followed by MSigDB analyses confirmed that lestaurtinib impairs androgen-dependent PKN1 activity and revealed that 100 of the 127 MgSigDB gene sets isolated after PKN1 silencing overlapped with 123 gene sets derived after lestaurtinib treatment. Overlapping gene sets included several related to hormonal carcinogenesis and cancer progression, prostate development, signaling cascades that have been implicated in SRF and RhoA function and/or are relevant to CaP. PKN1 inhibition via lestaurtinib, which is used already to treat human hematologic malignancies and is well tolerated by carcinoma patients, may thus serve as novel alternative treatment strategy to target AR-dependent SRF action in CR-CaP. Citation Format: Varadha Balaji Venkadarkrishnan, Adam DePriest, Yixue Su, Giridhar Mudduluru, Salma Ben-Salem, Sangeeta Kumari, Qiang Hu, Eduardo Cortes, Scott Dehm, Cristina Magi-Galluzzi, Eric Klein, Nima Sharifi, Song Liu, Hannelore Heemers. Inhibition of Protein Kinase N1 prevents control of AR over SRF action in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3745.
By taking advantage of the innate ability of the immune cells to target tumor cells, in article number 1603121, Cheng Dong, Jian Yang, and co‐workers develop a selfpowered immune cell‐mediated theranostic biodegradable photoluminescent poly (lactic acid) (BPLP‐PLA) nanoparticle‐based drug delivery system for melanoma targeting and drug delivery.
Androgen receptor (AR) is the major driver of prostate cancer (CaP) progression. Despite initially inducing remissions, androgen deprivation therapy (ADT) does not cure CaP and the majority of CaP that recurs under ADT continues to rely on AR. In a subset of patients, administration of novel, more potent ADT drugs leads to emergence of a neuroendocrine (NE) CaP phenotype that is AR-indifferent and even harder to treat. The molecular mechanisms by which AR regulates cell cycle progression and that can be developed into alternative targets to inhibit CaP growth, overcome acquired resistance to ADT, or prevent NE progression, however, remain largely unknown. Here, we identify citron kinase (CIT), which controls cell division, as a novel drugabble target that acts downstream of AR. In multiple CaP models, CIT protein expression was stimulated selectively by low doses of androgens that promote CaP cell proliferation and decreased by AR silencing or short-term administration of AR-antagonist enzalutamide, confirming its AR dependence. Silencing of CIT significantly reduced CaP cell viability and cell proliferation, delayed cell progression, increased the number of multinucleated cells in ADT-naïve and -recurrent CaP cells, and attenuated CaP growth in xenograft models. Overexpression of CIT, transiently or stably, stimulated CaP cell proliferation in androgen-supplemented conditions and under ADT, and this depended entirely on an intact CIT kinase domain. In 2 independent clinical CaP datasets, CIT mRNA levels increased during CaP progression and higher CIT expression correlated with shorter disease-free and overall survival. Using CaP tissue microarrays that contain more than 200 patient specimens, CIT protein expression was significantly higher in primary CaP when compared to adjacent non-neoplastic prostate tissues and correlated with increasing Gleason scores, validating the relevance of CIT overexpression to CaP aggressiveness. Integrated RNA-Seq, MSigDB and GSEA analyses confirmed that the AR- and CIT-dependent transcriptome preferentially controlled CaP cell cycle progression and proliferation. Mechanistically, the use of inhibitors of gene transcription, mRNA translation and proteasome indicated that the androgen-dependence of CIT expression is regulated at the post-transcriptional level. Specifically, CIT protein expression was controlled by the E2F family of cell cycle regulators, with androgen-responsive E2F2 as the major determinant of CaP CIT expression. Our work, thus, isolated a novel role for the mitotic kinase CIT in AR-dependent CaP cell proliferation and clinical progression and identified CIT’s kinase moiety as a novel target for CaP therapy. Funding: NIH/NCI, Case Comprehensive Cancer Center Pilot Research Award Citation Format: Salma Ben-Salem, Salam Bachour, Varadha Balaji Venkadakrishnan, Yixue Su, Eduardo Cortes Gomez, Qiang Hu, Eric Klein, Nicolas Marlo, Cristina Magi-Galluzzi, Liu Song, Hannelore V. Heemers. Prostate cancer progression depends on the activity of the mitotic kinase citron kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 390.
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