Chemotherapy is almost exclusively administered via the
intravenous
(IV) route, which has serious limitations (e.g., patient discomfort,
long hospital stays, need for trained staff, high cost, catheter failures,
infections). Therefore, the development of effective and less costly
chemotherapy that is more comfortable for the patient would revolutionize
cancer therapy. While subcutaneous (SC) administration has the potential
to meet these criteria, it is extremely restrictive as it cannot be
applied to most anticancer drugs, such as irritant or vesicant ones,
for local toxicity reasons. Herein, we report a facile, general, and
scalable approach for the SC administration of anticancer drugs through
the design of well-defined hydrophilic polymer prodrugs. This was
applied to the anticancer drug paclitaxel (Ptx) as a worst-case scenario
due to its high hydrophobicity and vesicant properties (two factors
promoting necrosis at the injection site). After a preliminary screening
of well-established polymers used in nanomedicine, polyacrylamide
(PAAm) was chosen as a hydrophilic polymer owing to its greater physicochemical,
pharmacokinetic, and tumor accumulation properties. A small library
of Ptx-based polymer prodrugs was designed by adjusting the nature
of the linker (ester, diglycolate, and carbonate) and then evaluated
in terms of rheological/viscosity properties in aqueous solutions,
drug release kinetics in PBS and in murine plasma, cytotoxicity on
two different cancer cell lines, acute local and systemic toxicity,
pharmacokinetics and biodistribution, and finally their anticancer
efficacy. We demonstrated that Ptx-PAAm polymer prodrugs could be
safely injected subcutaneously without inducing local toxicity while
outperforming Taxol, the commercial formulation of Ptx, thus opening
the door to the safe transposition from IV to SC chemotherapy.
