PUBLICATIONs

63. “Stepwise Assembly of Multimode Liposomal Nanotheranostic Agent for Targeted In Vivo Bioimaging and Near‐Infrared Light Mediated Cancer Therapy”

R. Prasad, N.K. Jain, A.S. Yadav, D.S. Chauhan, J. Devrukhkar, M.K. Kumawat, S. Shinde, M. Gorain, A.S. Thakor, G.C. Kundu, João Conde*, R. Srivastava*

Nature Communications Biology (2020)

Traditionally used imaging and therapeutic probes are limited with low image resolution, toxicity, rapid clearance, poor bio-distribution and low stability, as well as low tissue penetration ability. Additionally, improving the accumulation of nanohybrids into solid tumor microenvironment is a challenging task. To resolve these limitations, multifunctional liposome based nanotheranostics loaded with gold nanoparticles (AuNPs) and emissive graphene quantum dots (GQDs) were engineered named as NFGL. In addition, an anticancer drug, doxorubicin hydrochloride, was encapsulated in NFGL to exhibit phototriggered chemotherapy and functionalized with folic acid as a targeting ligand. Encapsulated agents showed bimodal imaging for in vivo tumor diagnosis and near infrared light (NIR) mediated tumor reduction along with bio-distribution and long-time tumor binding ability. Herein, we developed a light mediated phototriggered strategy for enhanced tumor accumulation of liposomal nanohybrids for deep tissue penetration and phototherapy effect in solid tumor environment. Both in vitro and in vivo analysis of NFGL nanohybrids demonstrated enhanced uptake and significant tumor regression during NIR light (750 nm) irradiation due to generated heat. Further, Reactive Oxygen Species (ROS) were observed during NIR light exposure, which may oxidize the cellular matrix of in vitro cells and solid tumors, improving the accumulation of injected nanoparticles due to the photoionization effect. Moreover, NFGL nanohybrids demonstrated remarkable ROS scavenging ability as compared to GQDs loaded liposomes validated by antitumor study. Hence, this approach and engineered system could open new direction for targeted nanotheranostics.

João Conde*

Trends in Cancer (2020)

Considering the extensive reports of anticancer nanomedicines in preclinical studies, why is there such a paucity of clinical trials using these therapies? To date, nano-therapy studies have depended to a great extent on applying systemic routes to deliver therapeutic payloads, regardless of the low delivery efficiencies and advantages of local and continuous delivery approaches. Nanotechnology can certainly deliver, but we need to tackle the limitations that are holding back the translation of nanomedicines into the clinic and start benefiting from their full potential. Empowering a proficient systemic delivery is testing and dependent on experimental examination. There is an earnest need to form improved delivery vehicles and to establish guidelines regarding the performance metric by which we can evaluate a technology in a preclinical setting. Correlating preclinical and clinical outcomes would pave the way to generating a scoring system that would determine the probability of clinical success.

Y. Zhang, P. Dosta, João Conde, N. Oliva, M. Wang and N. Artzi

Advanced Healthcare Materials (2020) Featured on COVER

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.

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© 2020 by João Conde

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European Research Council ERC