S. Talebian, G.G. Wallace, A. Schroeder*, F. Stellacci* and João Conde*

Nature Nanotechnology (2020) COVID-19 Special Issue

Nanotechnology-based antimicrobial and antiviral formulations can prevent SARS-CoV-2 viral dissemination, and highly sensitive biosensors and detection platforms may contribute to the detection and diagnosis of COVID-19.

H. Li, João Conde, A. Guerreiro, G.J.L. Bernardes

Angewandte Chemie International Edition (2020)

The key for improved molecular imaging and therapy is to achieve selective accumulation of the diagnostic probe or therapeutic agent at the site of interest. One of the approaches is the on-demand activation. In this context, the potency of the drug/probe is largely attenuated and upon chemical reaction or enzymatic interaction, the drug/probe will be converted to its active form at the desired site of action whilst sparing healthy tissue of adverse off-target side effect. This approach allows a precise control of the drug/probe activity and has been employed in the course of pre-targeted strategies for imaging and therapy. Bioorthogonal chemistry has become a powerful tool for on-demand activation. Notably, the inverse-electron demand Diels–Alder (IEDDA) reaction between tetrazine and trans-cyclooctene (TCO) has demonstrated its enormous potential in in vivo bioconjugation, capitalizing on the fast reactivity even at low concentrations in complex biological context and the inertness to biological functionalities. Furthermore, a ‘click-to-release’ bioorthogonal cleavage reaction that enables instantaneous release of a substance from trans-cyclooctene following tetrazine ligation was reported and has proven its great potential for prodrug activation.

65. “Localized Nanotheranostics: Recent developments in Cancer Nanomedicine”

R. Prasad, N.K. Jain, João Conde*, R. Srivastava*

Materials Today Advances (2020)

Since decades, conventional diagnosis and treatment strategies for cancer have attracted major attention despite of their expensive and time-consuming process. Moreover, conventional contrast and therapeutic agents have been suffering with various side-effects such as low radiodensity and image resolution, rapid clearance, nonspecific bio-distribution, poor tumor accumulation, heavy and multiple dose requirements, nephrotoxicity, uncontrolled exposure of high electromagnetic radiations, whole body scans etc. On the other hand, high electromagnetic radiation exposure may cause inflammation, body rashes and mutation in healthy cells leading to other diseases. Although, the technical modalities are growing fast, the progress of new cancer medicines is slow. Therefore, nanosized theranostics are gaining momentum as a concept for localized imaging and solid tumor ablation. Interestingly, nanotheranostic probes have been already recognized as clinical “weapon” for localized cancer nanomedicine. So far, numerous functional nanohybrids have been applied for targeted imaging and stimuli active therapies. Hence, nanosized diagnostics and therapeutics systems have been recognised as potential probes for combination therapies, image guided tumor regression, deep tissue visualization, localized diagnosis and tumor ablation, manipulating tumor microenvironment etc. Integration of nanodiagnostics and therapeutics within a single system represents a major achievement in cancer nanomedicine. Overall, localized and stimuli active nanosized theranostic platforms have proved its superiority over conventional therapies. This article will introduce and highlights the recent advancements of localized nanotheranostic approaches and new developments in cancer nanomedicine.

B.L. Oliveira, B.J. Stenton, Unnikrishnan V.B., C.R. Almeida, João Conde, M. Negrão, F.S.S. Schneider, C. Cordeiro, M.G. Ferreira, G.F. Caramori, J.B Domingos, R. Fior and G.J.L. Bernardes

Journal of the American Chemical Society (2020) Featured on COVER

The ability to create ways to control drug activation at specific tissues while sparing healthy tissues remains a major challenge. The administration of exogenous target-specific triggers offers the potential for traceless release of active drugs on tumor sites from antibody-drug conjugates (ADCs) and caged prodrugs. We have developed a metal-mediated bond-cleavage reaction that uses platinum complexes [K2PtCl4 or Cisplatin (CisPt)] for drug activation. Key to the success of the reaction is a water-promoted activation process that triggers the reactivity of the platinum complexes. Under these conditions the decaging of pentynoyl tertiary amides and N-propargyls occurs rap-idly in aqueous systems. In cells, the protected analogues of cytotoxic drugs 5-fluorouracil (5-FU) and monomethyl auristatin E (MMAE) are partially activated by non-toxic amounts of platinum salts. Additionally, a non-internalizing ADC built with a pentynoyl traceless linker that features a tertiary amide protected MMAE was also decaged in the presence of platinum salts for extracellular drug release in cancer cells. Finally, CisPt-mediated prodrug activation of a propargyl derivative of 5-FU was shown in a colorectal zebrafish xenograft model that led to significant reductions in tumor size. Overall, our results reveal a new metal-based cleavable reaction that expands the application of platinum complexes beyond those in catalysis and 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.

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