In this study, we report the in vivo anti-
lymphoma efficacy and diagnostic potential of newly designed near-infrared
fluorescent dye containing
polymer-
doxorubicin conjugates using murine models of
malignant lymphomas including one cell line-derived xenograft (RAJI) and two patient-derived
lymphoma xenografts (VFN-D1 and VFN-M2). Two types of passively targeted conjugates differing in architecture of the
polymer backbone were synthesized. One of the conjugates was designed using a single linear
polymer chain, and the second was more sophisticated with a star-shaped high-molecular-weight (HMW)
polymer employing a
dendrimer core. The linear
HPMA copolymers were linked to the
dendrimer core via a one-point attachment, thus forming a hydrophilic
polymer shell. Both
polymer-
doxorubicin conjugates were long-circulating with reduced side effects. Both
polymer prodrugs were designed as stimuli-sensitive systems in which the anti-
cancer drug
doxorubicin was attached to the hydrophilic copolymers via a pH-labile
hydrazone linkage. Such
polymer prodrugs were fairly stable in aqueous solutions at pH 7.4, and the drug was readily released in mildly
acid environments at pH 5-6.5 by hydrolysis of the
hydrazone bonds. In addition,
polymers were labelled with near-infrared
fluorescent dye enabling long term in vivo visualization.
Malignant lymphomas represent the most common type of haematological
malignancies.
Therapy for the majority of
malignant lymphomas consists of multi-agent
chemotherapy based on an
anthracycline doxorubicin, the most prominent side effect of which is
cardiotoxicity. We have demonstrated significant anti-
lymphoma efficacy of the
polymer-
doxorubicin conjugates when compared to equally toxic doses of conventional (unbound)
doxorubicin in all tested models. Favourable pharmacokinetics for carried drug and labelled
polymer carrier was observed, showing predominant uptake of the drug and
polymer itself in the tumour mass. In addition, we have observed a promising diagnostic potential of fluorescently labelled
polymer prodrugs. Dynamically analyzed fluorescence intensity over subcutaneously xenografted
lymphomas closely corresponded to changes in the
lymphoma tumour volumes, thereby enabling a non-invasive assessment of treatment efficacy.