Biodegradable and Self-Immolative Block Copolymers for Drug Delivery to Tumor Xenograft

Abstract

Effective cancer therapy is the one of the major challenges in human healthcare owing to poor efficacy and severity of side effects of conventional chemotherapy. Small molecules chemotherapeutic exhibits severe toxicities such as cardiotoxicity, nephrotoxicity neurotoxicity due to lack of targeting abilities and poor solubility. Moreover, therapeutics delivery to brain is the most challenging because of tightly packed nature blood brain barrier (BBB) which results in limited success in brain related disease treatments. To circumvent these limitations, polymeric nanocarrier mediated drug delivery strategies have been emerging and proven to improve efficacies, increase blood circulation time, accumulation at targeting side by passive targeting (EPR effect) and reduced toxicities. Unfortunately, most of the nanocarriers reported are mostly designed based on non-biodegradable polymers or inorganic nanoparticles and their fate is not clearly understood yet, which eventually can lead to longer accumulation and toxicity in body. Consequently, nanocarriers derived from biodegradable polymers urgently needs to be addressed in terms of their design, self-assembly, stabilities, efficacies and target specificity. To address this, biodegradable polymers based on aliphatic polyester backbone (PCL) has been designed using ring opening polymerization strategy. We investigated the importance of the architecture by designing 6-arm star-shaped copolymers and role of amphiphilicity by tuning shell of the star-shaped copolymer. These polymers were self-assembled in aqueous medium to form nanoparticles (NP) rages from 200 nm to 20nm. Their drug encapsulation, esterase enzyme-biodegradation in lysosome, in-vitro delivery capabilities and in-vivo tumor targeting and tumor suppression in xenograft mouse model were investigated in detail. In addition to that, performance of aggregated micelles was compared with unimolecular micellar NP. Succeeding, the surface charges of these star-shaped copolymers were fine tuned to achieve anionic, cationic and neutral nanoparticle to understand the critical role of surface charges and sizes in self-assembly and in-vitro and in-vivo brain specific delivery. Furthermore, the new generation of smart polymeric nanomaterials were engineered by combining enzymatic biodegradable PCL and self-immolative PAEs having zwitterionic properties and dual responsiveness. PAEs are excellent material of choice due to their auto-degradation into small units under physiological pH. However, their drug delivery applications are greatly limited because of instability of their drug formulations in, blood (pH 7.4). To mitigate these problems, we incorporated enzymatic biodegradable anionic PCL units along with self-immolative PAE in triblock architecture to design zwitterionic polymers. These zwitterions stabilized the unstable PAE units due to electrostatic interaction between anionic pendent of PCL and cationic units of PAE under physiological pH. These zwitterions exhibited excellent drug loading capabilities, and their lysosomal biodegradation, in-vitro and in-vivo drug delivery applications investigated. Efforts have been taken to further understand deeply about role of the topology and architecture of the star zwitterionic and star anionic polymers in encapsulation abilities for Doxorubicin (Dox) and delivery to solid tumors. These drugs loaded NP demonstrated longer blood circulation time and better tumor accumulation and tumor suppression in pancreatic cancer tumor mice model. Thus, currently designed polymers are superior in drug loading (~15 wt.%) and fully biodegradable, non-toxic with better efficacies for in-vivo tumor drug delivery.