PHB‐Based Gels as Delivery Agents of Chemotherapeutics for the Effective Shrinkage of Tumors

Abstract

Injectable thermogel to deliver chemotherapeutics in a minimally invasive manner and to achieve their long term sustained release at tumor sites to minimize side effects is attractive for chemotherapy and precision medicine, but its rational design remains a challenge. In this work, a copolymer with natural biodegradable poly[(R)-3-hydroxybutyrate] (PHB), hydrophilic poly(ethylene glycol), and temperature sensitive poly(propylene glycol) blocks linked by urethane linkages is designed to show thermogelling characteristics which are beneficial for minimally invasive injection and safe degradation. This thermogelling polymer possesses in vitro biocompatibility with very low cyto-toxicity in HEK293 cells. Furthermore, it is able to form the gel to achieve the controllable release of paclitaxel (PTX) and doxorubicin (DOX) by adjusting polymer concentrations. A rodent model of hepatocarcinoma has been performed to demonstrate the in vivo applications of this PHB-based thermogel. The drug-loaded thermogel has been intratumorally injected and both PTX-loaded and DOX-loaded thermogel have significantly slowed down tumor growth. This work represents the first time that injectable PHB thermogels have possessed good controllable release effect of chemotherapeutics against the in vivo model of tumors and will benefit various applications, including on-demand drug delivery and personalized medicine.

New Poly[(R )-3-hydroxybutyrate-co -4-hydroxybutyrate] (P3HB4HB)-Based Thermogels

“…P3HB has a stereoregular structure and is biodegradable and biocompatible with the human body due to lack of toxicity, compatibility with blood and surrounding tissues . Upon degradation, it degrades into a nontoxic product in the human blood plasma known as d ‐3‐hydroxybutyrate . P3HB is highly hydrophobic and this attribute gives it a slow degradation rate and hence exhibits good hydrolytic stability.…”

How Can We fine-tune Nanoparticles to Improve Drug delivery?

“…These changes are manipulated in vivo to stimulate a trigger for drug release [15]. For example, pH in tumorous tissues are lower than health tissues [16,17]. The acidic environment in vivo can be exploited internally to stimulate a trigger release of a pH-sensitive drug.…”

Biodegradable Thermogelling Polymers

“…Examples of common/commercial biodegradable thermogelling polymers are: Pluronic‐based triblock copolymers (PEG–X–PEG being the most common form due to their hydrophilicity and biocompatibility; ABA or BAB type), chitosan‐based copolymers, hyaluronic acid, chitosan and poly(N‐isopropylacrylamide)‐based copolymers. These thermosensitive copolymers have been grafted with a variety of biocompatible and biodegradable components containing hydrolysable backbones or easily oxidized side groups, such as poly(D,L‐lactic acid‐co‐glycolic acid) (PLGA), poly(L‐lactic acid) (PLLA), poly(ε‐carprolactone) (PCL) or polycaprolactone diol, poly([R]‐3‐hydroxybutyrate) (PHB), poly(organophosphazene), poly(propylene phosphate), polyacetal, and poly(ortho ester) . Polypeptides with unique biodegradability, thermosensitivity due to self‐assembled secondary or tertiary structures and ionic side groups for customizability, such as poly(L‐alanine) and poly(L‐alanine‐co‐L‐phenyl alanine), are also excellent alternatives.…”