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Fluorescence microscopy studies using 4-morpholinoscriptaid (4MS) demonstrated rapid cellular uptake of this scriptaid analogue into the cytoplasm but no nuclear penetration. As 4MS and scriptaid have the same in vitro activity against HDACs and KASUMI-1 cells; 4MS exemplifies a rational approach to subtly modify ‘profluorogenic’ substrates for intracellular studies.

Docetaxel (Taxotere®) and cabazitaxel (Jevtana®) are mitotic inhibitors that function as effective cytotoxic agents and are widely used in many chemotherapy regimens. However, treatment with taxanes is limited by serious adverse toxicities, notably bone marrow toxicity (neutropenia, leukopenia and anemia) and hepatotoxicity. Taxanes are poorly water soluble and must be formulated with surfactants such as polysorbate, which can cause systemic adverse events (e.g. anaphylaxis and fluid retention) requiring predosing with corticosteroids. These combined drug and excipient toxicities limit clinical use and make them ideal candidates for improvement using dendrimer technology. Starpharma's novel dendrimer nanoparticle DEP platform has broad applicability in drug delivery through improved drug solubility, efficacy and pharmacokinetics, reductions in certain toxicities (e.g. bone marrow toxicity) and generation of intellectual property. The DEP platform has shown reproducible benefits across a wide range of drug classes including small molecules, peptides and proteins. Currently there are three DEP candidates in the clinic; DEP docetaxel (DEP DTX), DEP cabazitaxel (DEP CTX), and DEP irinotecan. The fourth DEP candidate, AZD0466, is a promising Bcl-2/Bcl-xL inhibitor, partnered with AstraZeneca, and is currently transitioning into clinical trials in the US. Starpharma's DEP DTX and DEP CTX are both PEGylated polylysine dendrimers with the drug conjugated to the surface via a hydrolytically labile linker. Both products have demonstrated superior efficacy and survival compared to the standard drug formulations in a range of xenograft cancer models in immunocompromised mice: breast (MDA-MB-2231), prostate (DU145), and pancreatic (CAPAN-1). In the CAPAN-1 pancreatic xenograft model, the DEP taxanes were superior to Nab paclitaxel (Abraxane®) when dosed either as monotherapy or in combination with gemcitabine. Abraxane inhibited tumor growth by 85% (monotherapy) and 81% (combination with gemcitabine) compared to complete inhibition for DEP CTX and DEP DTX treated groups (at day 37). DEP CTX induced complete regression of tumors over the duration of the study. Treatment with DEP taxanes significantly extended survival compared to Abraxane as monotherapy (P= 0.004, DEP DTX; P <0.0001, DEP CTX), and in combination with gemcitabine (P<0.0001, DEP DTX; P<0.0001, DEP CTX). In summary, both DEP taxanes are well tolerated and show significant efficacy and survival benefits compared to current standard of care therapies when used either as a monotherapy or in combination. DEP CTX and DEP DTX are two of four clinical stage products from Starpharma's DEP platform. DEP DTX is currently in a P2 clinical trial at Guy's and St Thomas', NUTH, The Leeds Teaching Hospital, UCLH, The Christies and The Beatson while DEP CTX is in a phase 1/2 adaptive trial at Guy's and St Thomas', UCLH, Velindre Cancer Centre and ICLH. Citation Format: Brian D. Kelly, Victoria McLeod, Rachael Walker, Jeannette Schreuders, Susan Jackson, Michael Giannis, Christine Dietinger, Pauline Reitano, Rashmi Pathak, Shirley Xia, Anne Cargill, Aynaz Seta, Richard Hufton, Graham Heery, Carleen Cullinane, David J. Owen. Anticancer activity of the taxane nanoparticles, DEP® docetaxel and DEP® cabazitaxel [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1716.

Irinotecan (Camptosar®) is a water-soluble prodrug of the potent topoisomerase I inhibitor SN-38 used clinically to treat multiple cancers. Irinotecan must be metabolized to its active metabolite SN-38 by carboxylesterases in hepatic and tumor cells. This metabolism in humans is inefficient with significant interpatient variability and leads to serious toxicities, notably diarrhea and myelosuppression. The narrow therapeutic window of irinotecan makes it an ideal candidate for improvement using dendrimer nanomedicine delivery. Starpharma's novel dendrimer nanoparticle DEP® platform has broad applicability in drug delivery, enhancing the therapeutic utility of drugs through improved solubility, efficacy and pharmacokinetics, reductions in certain toxicities (e.g. bone marrow toxicity) and providing novel intellectual property. The DEP platform has shown reproducible advantages across a wide range of drug classes including small molecule, peptides and proteins. Starpharma's DEP irinotecan is a PEGylated polylysine dendrimer with SN-38 conjugated to the surface via a hydrolytically labile linker. The incorporation of the active metabolite, SN-38 avoids the need for hepatic conversion and thereby minimizes variability in SN-38 levels. In preclinical studies, DEP irinotecan has shown to be well tolerated in animals. Efficacy assessments have been conducted, using a range of xenograft cancer models [SW620 (colon), HT-29 (colon), MDA-MB-231 (Breast) and CAPAN-1 (pancreatic)]. These studies demonstrated significant efficacy and survival benefits of DEP irinotecan compared to standard irinotecan. DEP irinotecan also showed significant benefit when dosed in combination with current standard of care therapies such as the anti-EGFR antibody, cetuximab, and the PARP inhibitor, olaparib. DEP irinotecan in combination with olaparib, significantly improved anti-tumor efficacy leading to tumor regression and extended median survival by 28 days compared to DEP irinotecan alone (P<0.0001, Mantel Cox Log rank test) whereas olaparib alone had minimal activity. This result highlights the synergistic combination benefits that can be achieved using DEP technology. DEP irinotecan is Starpharma's third internal DEP candidate to enter the clinic. The fourth DEP candidate, AZD0466 is a promising Bcl-2/Bcl-xL inhibitor and is partnered with AstraZeneca. AZD0466, is currently transitioning into clinical trials in the US. In summary, DEP irinotecan is well tolerated and allows for the delivery of SN-38 by successfully utilizing dendrimer drug delivery technology. The dendrimer nanoparticle shows significant efficacy and survival benefits compared to current standard of care therapies when used either as a monotherapy or in combination. DEP irinotecan is currently in a phase 1 / 2 adaptive trial at leading UK hospitals; The Christie, The Royal Marsden and The Newcastle Upon Tyne. Citation Format: Brian D. Kelly, Victoria McLeod, Rachael Walker, Jeannette Schreuders, Susan Jackson, Michael Giannis, Christine Dietinger, Shirley Xia, Anne Cargill, Aynaz Seta, Richard Hufton, Graham Heery, Carleen Cullinane, David J. Owen. Anti-cancer activity of a SN-38 nanoparticle, DEP® irinotecan, in human colon cancer xenograft models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1715.

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