61. “Prolonged local in vivo delivery of stimuli-responsive nanogels that rapidly release doxorubicin in triple-negative breast cancer cells”
Y. Zhang, P. Dosta, João Conde, N. Oliva, M. Wang and N. Artzi
Advanced Healthcare Materials (2019)
Triple negative breast cancer patients remain with chemotherapy as their only viable therapeutic option. However, the toxicity of available anticancer drugs and their inefficient delivery have limited the development of effective chemotherapy administration protocols and combination therapies. Drug delivery devices that can properly target chemotherapy to the right cells with efficient cancer-cell killing may play a vital role in eliminating triple-negative breast cancer. While systemic delivery results in low drug accumulation at the tumor site and for a short period of time, local delivery enables sustained drug release. However, a system that is able to provide rapid, yet prolonged action, would enable efficient tumor elimination. Herein, we describe the development of dual-sensitive nanogels designed to rapidly dislodge the chemotherapy drug, doxorubicin, inside cancer cells through dual-sensitive action—pH and Redox sensitivities— enabling efficient cancer-cell killing while eliminating systemic side effects. Their embedment within a hydrogel injected next to a tumor in a triple-negative breast-cancer mouse model enables prolonged release of the drug with instantaneous action when inside the cells resulting in efficacious tumor elimination compared to sustained local delivery only. This technology can be used for the delivery of combination therapies and for the treatment of other solid tumors.
C. Baker*, T. Rodrigues*, R.A. Pumroy*, João Conde*, D. Picard, M.C. Marques, B.P. de Almeida, A. Samanta, F. Sieglitz, M. Langini, M. Remke, R. Roque, F. Corzana, C.C. Faria, T. Carvalho, N.L. Barbosa-Morais, V.Y. Moiseenkova-Bell, G.J.L. Bernardes
Cell Sneak Peek (2019)
The use of machine learning to identify biological targets for natural products with anticancer properties and unknown modes of action is gaining momentum. We used machine intelligence to deconvolute the phenotypic effects of Piperlongumine (PL) and establish a link to allosteric modulation of the human transient receptor potential vanilloid 2 (hTRPV2) channel. The structure of the PL-bound full-length rat TRPV2 channel was determined by cryo-EM. PL binds to an allosteric pocket responsible for a new mode of anticancer activity against glioblastoma (GBM) in which hTRPV2 is overexpressed. Downregulation of hTRPV2 reduces sensitivity to PL and decreases ROS production. Analysis of GBM patient samples associates hTRPV2 overexpression with tumor grade, disease progression and poor prognosis. We obtained tumor remission in a murine model of orthotopic GBM by formulating PL for sustained local therapy. Our strategy is broadly applicable and leverages data-motivated research hypotheses for the discovery of new biology and therapeutics.
B. Stenton, B. Oliveira, João Conde, M. Negrão, M. Godinho Ferreira, R. Fior, G. Bernardes
ChemRxiv. Preprint (2019)
Creating ways to control drug activation at specific tissues while sparing healthy tissues remains a major challenge. The administration of exogenous triggers offers the possibility for precise and traceless drug activation. However, ensuring localization of the trigger as well as the prodrug at the diseased tissue is complex while essential for therapeutic efficacy and to avoid side-toxicity. Cisplatin remains a first line option to treat 20% of all cancer patients and while clearing after 30 min from blood it concentrates in tumor tissues. Here, we demonstrate the use of the platinum-mediated bond cleavage of protected tertiary amides, which can occur in a catalytic manner under bioorthogonal conditions. Protected analogues of cytotoxic drugs 5-fluorouracil (5-FU) and monomethyl auristatin E (MMAE) were successfully activated using non-toxic amounts of platinum salts in cells. An otherwise fully stable and non-internalizing ADC built using a bifunctional linker featuring a tertiary amide protected MMAE was also bioorthogonally decaged in the presence of platinum salts for extracellular drug release. Finally, cisplatin-mediated activation of a prodrug 5-FU was shown in a colorectal zebrafish xenograft model leading to a significant tumor reduction. Considering cisplatin’s continued use as a first-choice treatment for many solid cancers and especially in colorectal cancer, we anticipate that our platinum-mediated decaging strategy will enhance cancer therapy by allowing tumor specific prodrug activation.
X. Zhi, Y. Liu, L. Lin, M. Yang, L. Zhang, L. Zhang, Y. Liu, G. Alfranca, L. Ma, Q. Zhang, H. Fu, João Conde, X. Di, J. Ni, J. Song, D. Cui
Nanomedicine: Nanotechnology, Biology and Medicine (2019)
How to eradicate Helicobacter pylori (H. pylori) in vivo with antibiotic resistance owns tremendous clinical requirement. Herein, gold nanostars were conjugated with acid-sensitive cis-aconitic anhydride modified anti-H. pylori polyclonal antibodies, resultant pH sensitive gold nanostars@H. pylori-antibodies nanoprobes (GNS@Ab) were employed for the theranostics of H. pylori in vivo. Photoacoustic imaging confirmed that prepared GNS@Ab could target actively H. pylori in the stomach. GNS@Ab nanoprobes could kill H. pylori in vivo in model animals under NIR laser irradiation, all GNS@Ab nanoprobes could be excreted out of gut within 7 days after oral administration. Gastric local lesion caused by H. pylori restored to normal status within one month. GNS@Ab nanoprobes within therapeutic doses did not damage intestinal bacteria imbalance. 40 clinical specimens of H. pylori with antibiotic resistance were verified validity of GNS@Ab nanoprobes. Prepared oral pH-sensitive GNS@Ab nanoprobes own clinical translational potential in the theranostics of H. pylori in near future.
Y. Liu, K. Liu, M. Yang, Y. Han, Q. Zhang, João Conde, Y. Yang, Y. Han, G. Alfranca, Y. Wang, J. Song, Y. Zhang, J. Ni, J.M. de la Fuente, D. Cui
Nanoscale Research Letters (2019)
Up to date the way in which metal nanoparticles are cleared in vivo has yet to be properly elucidated. Herein we report for the first time a novel intestinal goblet cell-mediated in vivo clearance pathway to remove metal nanoparticles. Typical metal nanoparticles such as triangular silver nanoplates, magnetic nanoparticles, gold nanorods and gold nanoclusters were selected as representative examples. These metal nanoparticles were prepared and characterized, and injected via tail vein into a mice model with common bile duct (CBD) ligation. The feces and urines were collected for seven days to be followed by the sacrifice of the mice and collection of the intestinal and gastric tissues for further analysis. The results showed that all four selected metal nanoparticles were located inside the goblet cells (GCs) of the whole intestinal tissue and were excreted into the gut lumen through the secretion of intestinal GC. Moreover, triangular silver nanoplates and gold nanorods were located inside the gastric parietal cells (PCs). Importantly, nanoparticles did not cause pathological changes of intestinal tissues. In this study, we confirmed that the blood corpuscles are involved in the GCs secretion pathway. Furthermore, we found that the secretion of nanoparticles from intestinal GCs and PCs is accelerated by diarrhea. In conclusion, metal nanoparticles such as triangular silver nanoplates, magnetic nanoparticles, gold nanorods and gold nanoclusters can be cleaned away by intestinal GCs and PCs. This novel pathway of in vivo clearance of metal nanoparticles has a great potential for future applications such as new drug design and development, nanoparticle-based labeling and in vivo tracking, and biosafety evaluation of in vivo nanoparticles.