Paper on Topic Pub­lished in Cancer Gene Therapy

North­eastern Uni­ver­sity pro­fessor Man­soor Amiji and grad­uate stu­dent Sushma Kom­mareddy have pub­lished a new paper that exam­ines the poten­tial of engi­neered gelatin-​​based nanopar­ti­cles to deliver ther­a­peutic genes to human breast cancer tumors implanted in mice. Their research shows that these nanopar­ti­cles – or nanovec­tors – can serve as a safe and effec­tive gene delivery vehicle to inhibit solid tumor growth. The paper is pub­lished in the most recent issue of Cancer Gene Therapy, avail­able at: http://​www​.nature​.com/​c​g​t​/​i​n​d​e​x​.​h​tml.

In the exper­i­ment, the nanopar­ti­cles were injected into the blood stream, and 15% of the dose found its way into the tumor, where it pro­duced a pro­tein, sFlt-​​1 or sol­uble receptor for an angio­genic factor, that cut off blood supply to the tumor.

Essen­tially, what this treat­ment does,” says Amiji, “is make the tumor a fac­tory for its own destruc­tion. The treat­ment shuts off the blood supply to a tumor – thereby effec­tively closing down the ‘road’ for oxygen and nutri­ents to travel to the tumor and for can­cerous cells to escape from the tumor and spread throughout the rest of the body.”

In the past, this kind of gene delivery system had been attempted, but with viral vec­tors, which, although effec­tive, are in many cases toxic to the recip­ient. Non-​​viral vec­tors for gene delivery appli­ca­tions are becoming increas­ingly pop­ular owing to sev­eral advan­tages, which include lack of tox­i­city, no upper limit on the plasmid DNA size, and ease of manufacture.

Non-​​viral gene therapy has tremen­dous promise when it comes to treating and curing dis­eases,” says Amiji, “because you avoid the issues of tox­i­city that arise any time you intro­duce a viral ele­ment into the human body.”

The researchers chose to work with gelatin in making the nanopar­ti­cles because it has a long his­tory of safe use in the human body. In order to enhance the intra­cel­lular delivery poten­tial of the gelatin, North­eastern researchers syn­the­sized thi­o­lated gelatin by cova­lent mod­i­fi­ca­tion of the epsilon-​​amino groups of gelatin with 2-​​iminothiolane. Nanopar­ti­cles were then pre­pared with thi­o­lated gelatin using a mild sol­vent exchange method that has been opti­mized in North­eastern laboratories.

In this study, the sur­face of both gelatin and thi­o­lated gelatin nanopar­ti­cles was mod­i­fied by reacting with methoxy-poly(ethylene glycol) (PEG)-succinimidyl glu­tarate to pro­long in vivo cir­cu­la­tion time – enabling the med­ica­tion to stay in the body for up to 15 hours, a sig­nif­i­cant increase from just three hours with unmod­i­fied nanopar­ti­cles. PEG mod­i­fi­ca­tion also enhanced tumor uptake and reten­tion of the nanopar­ti­cles after administration.

Amiji notes that they are seeing pos­i­tive results in pre-​​clinical studies and hope to begin clin­ical trials in the near future.

We believe there are appli­ca­tions for this system of drug delivery in other dis­eases besides just cancer,” said Amiji. “From heart dis­ease and dia­betes to glau­coma and mac­ular degen­er­a­tion, this is a ver­sa­tile plat­form solu­tion that could prove suc­cessful in a variety of applications.”

When I look at all of the drugs that are in clin­ical trials and some of the hor­rible side affects that patients must endure, all I can think is: We can do better – we must do better,” says Amiji.

This study was sup­ported by a grant from the National Cancer Insti­tute of the National Insti­tutes of Health (NIH).

For more infor­ma­tion, please con­tact Laura Shea at 617–373-5427 or l.​shea@​neu.​edu.