Engineering nanoparticles for targeted delivery of nucleic acid therapeutics in tumor

We previously found that a polymer conjugated to the anticancer protein neocarzinostatin, named smancs, accumulated more in tumor tissues than did neocarzinostatin. To determine the general mechanism of this tumoritropic accumulation of smancs and other proteins, we used radioactive (51Cr-labeled) proteins of various molecular sizes (Mr 12,000 to 160,000) and other properties. In addition, we used dye-complexed serum albumin to visualize the accumulation in tumors of tumor-bearing mice. Many proteins progressively accumulated in the tumor tissues of these mice, and a ratio of the protein concentration in the tumor to that in the blood of 5 was obtained within 19 to 72 h. A large protein like immunoglobulin G required a longer time to reach this value of 5. The protein concentration ratio in the tumor to that in the blood of neither 1 nor 5 was achieved with neocarzinostatin, a representative of a small protein (Mr 12,000) in all time. We speculate that the tumoritropic accumulation of these proteins resulted because of the hypervasculature, an enhanced permeability to even macromolecules, and little recovery through either blood vessels or lymphatic vessels. This accumulation of macromolecules in the tumor was also found after i.v. injection of an albumin-dye complex (Mr 69,000), as well as after injection into normal and tumor tissues. The complex was retained only by tumor tissue for prolonged periods. There was little lymphatic recovery of macromolecules from tumor tissue. The present finding is of potential value in macromolecular tumor therapeutics and diagnosis.

Tumor targeting by nanomedicine-based therapeutics has emerged as a promising approach to overcome the lack of specificity of conventional chemotherapeutic agents and to provide clinicians the ability to overcome shortcomings of current cancer treatment. The major underlying mechanism of the design of nanomedicines was the Enhanced Permeability and Retention (EPR) effect, considered as the "royal gate" in the drug delivery field. However, after the publication of thousands of research papers, the verdict has been handed down: the EPR effect works in rodents but not in humans! Thus the basic rationale of the design and development of nanomedicines in cancer therapy is failing making it necessary to stop claiming efficacy gains via the EPR effect, while tumor targeting cannot be proved in the clinic. It is probably time to dethrone the EPR effect and to ask the question: what is the future of nanomedicines without the EPR effect? The aim of this review is to provide a general overview on (i) the current state of the EPR effect, (ii) the future of nanomedicine and (iii) the strategies of modulation of the tumor microenvironment to improve the delivery of nanomedicine.