Search

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.

A 5-y-old female Golden Retriever was presented with a 2-wk history of hyporexia, vomiting, diarrhea, lethargy, weight loss, polyuria, and polydipsia. Clinical examination and ultrasonography revealed multiple organ enlargement with gallbladder and kidney nodules suggestive of disseminated neoplasia. Hematologic and biochemical analyses revealed pancytopenia, hypercalcemia, and monoclonal IgA gammopathy suspicious for a plasma cell neoplasm. Bone marrow and blood smear examination revealed neoplastic atypical cells highly suggestive of lymphoid origin. Autopsy confirmed the presence of homogeneous white masses and multifocal pale infiltrates in the spleen, kidney, small intestine, gallbladder, and urinary tract. Histologic features were consistent with a multicentric atypical plasma cell tumor. Tumor cells were negative for CD204, IBA-1, E-cadherin, CD3, CD5, CD79a, CD20, and PAX5, and positive for MUM1, consistent with plasma cell origin. The presence of > 20% of circulating blastic plasma cells was consistent with primary plasma cell leukemia with plasmablastic morphology, a disease rarely described in veterinary medicine.

Direct injection of naked DNA into skeletal or cardiac muscle induces detectable gene expression. Although this provides a practical system for transgene expression, the reported efficacy is too low to confer a therapeutic benefit. By following a rational strategy based on the supramolecular structures adopted by active complexes, we have discovered a novel nonionic amphiphile synthetic agent [poly(ethyleneoxide)13-poly(propyleneoxide)30-poly(ethyleneoxide)13 block copolymer; PE6400] that enables gene expression in up to 35% of muscle fibers from mouse tibial cranial muscle. PE6400 abolishes the ceiling effect on transgene expression of increasing amounts of naked DNA and permits long-term expression of the β-galactosidase reporter gene in immunologically tolerant transgenic rats. This improvement in gene expression over naked DNA was observed irrespective of the reporter gene, ranging from 0.7 to 3.4 kb, and of the animal model used. In skeletal muscle, the PE6400 formulation led to a level of transfection efficiency similar to that obtained by electrotransfer. PE6400 also promotes high transgene expression in cardiac muscle. In contrast, PE6400-DNA formulations were inefficient in vitro in established cell lines and in isolated cardiomyocytes. When microinjected into the cell cytoplasm, PE6400 promotes DNA trafficking into the nucleus and induces gene expression. PE6400 provides a simple gene delivery system for skeletal and myocardial gene transfer. We propose that the PE6400 formulation could serve for the treatment of diseases primarily affecting muscle or for the expression of therapeutic proteins for local or systemic benefit.