Synthesis of multifunctional poly(l-histidine) containing polypeptides and hybrid polymers for controlled drug delivery applications.

No abstract

A novel, multifunctional hydrogel that exhibits a unique set of properties for the effective treatment of pancreatic cancer (PC) is presented. The material is composed of a pentablock terpolypeptide of the type PLys- b-(PHIS- co-PBLG)-PLys- b-(PHIS- co-PBLG)- b-PLys, which is a noncytotoxic polypeptide. It can be implanted via the least invasive route and selectively delivers gemcitabine to efficiently treat PC. Simply mixing the novel terpolypeptide with an aqueous solution of gemcitabine within a syringe results in the facile formation of a hydrogel that has the ability to become liquid under the shear rate of the plunger. Upon injection in the vicinity of cancer tissue, it immediately reforms into a hydrogel due to the unique combination of its macromolecular architecture and secondary structure. Because of its pH responsiveness, the hydrogel only melts close to PC; thus, the drug can be delivered directionally toward the cancerous rather than healthy tissues in a targeted, controlled, and sustained manner. The efficacy of the hydrogel was tested in vivo on human to mouse xenografts using the drug gemcitabine. It was found that the efficacy of the hydrogel loaded with only 40% of the drug delivered in one dose was equal to or slightly better than the peritumoral injection of 100% of the free drug delivered in two doses, the typical chemotherapy used in clinics so far. This result suggests that the hydrogel can direct the delivery of the encapsulated drug effectively in the tumor tissue. Enzymes lead to its biodegradation, avoiding removal by resection of the polypeptidic carrier after cargo delivery. The unique properties of the hydrogel formed can be predetermined through its molecular characteristics, rendering it a promising modular material for many biological applications.

Mucosal delivery across the gastrointestinal (GI) tract, airways, and buccal epithelia is an attractive mode of therapeutic administration, but the challenge is to overcome the mucus and epithelial barriers. Here, we present degradable star polypept­(o)­ides capable of permeating both barriers as a promising biomaterial platform for mucosal delivery. Star polypept­(o)­ides were obtained by the initiation of benzyl-l-glutamate N-carboxyanhydride (NCA) from an 8-arm poly­(propyleneimine) (PPI) dendrimer, with subsequent chain extension with sarcosine NCA. The hydrophobic poly­(benzyl-l-glutamate) (PBLG) block length was maintained at 20 monomers, while the length of the hydrophilic poly­(sarcosine) (PSar) block ranged from 20–640 monomers to produce star polypept­(o)­ides with increasing hydrophilic: hydrophobic ratios. Transmission electron microscopy (TEM) images revealed elongated particles of ∼120 nm length, while dynamic light scattering (DLS) provided evidence of a decrease in the size of polymer aggregates in water with increasing poly­(sarcosine) block length, with the smallest size obtained for the star PBLG20-b-PSar640. Fluorescein isothiocyanate (FITC)-conjugated PBLG20-b-PSar640 permeated artificial mucus and isolated rat mucus, as well as rat intestinal jejunal tissue mounted in Franz diffusion chambers. An apparent permeability coefficient (P app) of 15.4 ± 3.1 ×10–6 cm/s for FITC-PBLG20-b-PSar640 was calculated from the transepithelial flux obtained with the apical-side addition of 7.5 mg polypept­(o)­ide to jejunal tissue over 2 h. This P app could not be accounted for by flux of unconjugated FITC. Resistance to trypsin demonstrated the stability of FITC-labeled polypept­(o)­ide over 2 h, but enzymatic degradation at the mucus-epithelial interface or during flux could not be ruled out as contributing to the P app. The absence of any histological damage to the jejunal tissue during the 2 h exposure suggests that the flux was not associated with overt toxicity.