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

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.

By combining two living polymerizations, anionic and ring opening (ROP), the following novel multiblock multicomponent linear and miktoarm star (micro-star) polymer/polypeptide hybrids (macromolecular chimeras) were synthesized: Linear, PBLL-b-PBLG-b-PS-b-PBLG-b-PBLL; 3micro-stars, (PS)2(PBLG or PBLL), (PS)(PI)(PBLG or PBLL); 4micro-stars, (PS)2[P(alpha-MeS)](PBLG or PBLL), (PS)2(PBLG or PBLL)2 [PS, polystyrene; PI, polyisoprene; P(alpha-MeS), poly(alpha-methylstyrene); PBLG, poly(gamma-benzyl-L-glutamate); and PBLL, poly(-tert-butyloxycarbonyl-L-lysine)]. The procedure involves (a) the synthesis of end- or in-chain amino-functionalized polymers, by anionic polymerization high vacuum techniques and appropriate linking chemistry and (b) the use of the amino groups for the ROP of alpha-amino acid carboxyanhydrides (NCAs). Molecular characterization revealed the high molecular weight and compositional homogeneity of the macromolecular chimeras prepared. The success of the synthesis was based mainly on the high vacuum techniques used for the ROP of NCAs, ensuring the avoidance of unwanted polymerization mechanisms and termination reactions.

Our study aimed to define the position of tamsulosin as adjunctive therapy in patients with stones of the distal ureter who had undergone extracorporeal shock wave lithotripsy (ESWL). In total, 61 consecutive patients (38 men and 23 women) with single distal radiopaque ureteral stone of > or =6 mm of diameter were enrolled. After ESWL patients were randomized in two groups. Non-steroidal anti-inflammatory drug (supp. diclofenac 50 mg) was given to both groups upon demand. In group B, all patients (30) received additionally tamsulozin 0.4 mg every day. Follow-up visits were performed 1, 2, 3 and 4 weeks after ESWL. Evaluation included a KUB plain film and an ultrasound examination. Efficacy was evaluated in terms of success rate, stone-free rate, expulsion time of the fragments and use of diclofenac. Two patients from the tamsulosin group experienced dizziness and one was withdrawn. The success rate was 58.06 and 66.66% for the control and the tamsulosin group, respectively, while the corresponding values for stone-free rate were 51.6 and 63.33%, respectively. The mean expulsion time of the fragments was 13.22 days for group A and 12.95 days for group B. These results did not achieve statistically significant difference (P > 0.05). The mean diclofenac dose was 118.9 mg in group A and 56.9 mg in group B. This difference was statistically significant (P = 0.02). Despite the relatively small number of patients, our data indicate that the use of tamsulosin after ESWL in this specific subgroup of patients does not result in improved success and stone-free rate and expulsion time. In contrast, a significantly reduced need for analgesics was found.