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AssigneeFidia Farmaceutici S.P.A.
InventorsMonica Campisi, Davide Renier, Pasquale Pierimarchi, Annalucia Serafino
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The present invention describes the new use in the oncologic field of bioconjugates as differentiating agents obtained by the conjugation between hyaluronic acid (HA) and a chemotherapeutic product (identified hereafter with the trade-name ONCOFID®) among which, in particular, Irinotecan, Doxorubicin, Paclitaxel, Cis-platinum and 5-Fluorouracyl (5-FU) for treating primary tumors and metastasis. In particular, the biological behavior is described in terms of action mechanism, efficacy and tolerability of pharmaceutical preparations of derivative of ONCOFID® soluble in water. More specifically, the invention relates to the surprising biological and pharmacological effect demonstrated by formulations based on ONCOFID-S (HA-SN38 conjugates) and ONCOFID-D (HA-Doxorubicin conjugates) in promoting the differentiation of tumoral cells towards a untransformed phenotype, compared with the reference drug Irinotecan (or CPT11 whose active form is represented by SN38) and Doxorubicin.
A method for differentiating a neoplastic cell towards a non tumoral untransformed phenotype which comprises exposing a neoplastic cell to at least one bioconjugate consisting of hyaluronic acid bound to an antitumoral drug for differentiating a neoplastic cell towards a non-tumoral untransformed phenotype, wherein said method avoid the nuclear accumulation of β-catenin protein and activates the APC-GSK-3β protein complex, and wherein the drug is doxorubicin, covalently bound through a spacer selected from bromobutanol or bromopropanol, with a substitution degree of doxorubicin at carboxyl of hyaluronic acid ranging from 3 to 20%, wherein said hyaluronic acid is bound to said spacer via an ester bond with the carboxyl moiety in said hyaluronic acid and said spacer is bound to said doxorubicin via a carbamic bond.
A pharmaceutical formulation containing at least one bioconjugate consisting of hyaluronic acid bound to an antitumoral drug together with one or more pharmacologically acceptable adjuvant and/or excipient for differentiating a neoplastic cell towards a non-tumoral, untransformed phenotype, wherein the drug is doxorubicin, covalently bound through a spacer selected from bromobutanol or bromopropanol, with a substitution degree of doxorubicin at carboxyl of hyaluronic acid ranging from 3 to 20%.
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