Smart Polymeric Delivery System for Antitumor and Antimicrobial Photodynamic Therapy

Photodynamic therapy (PDT) has attracted tremendous attention in the antitumor and antimicrobial areas. To enhance the water solubility of photosensitizers and facilitate their accumulation in the tumor/infection site, polymeric materials are frequently explored as delivery systems, which are expected to show target and controllable activation of photosensitizers. This review introduces the smart polymeric delivery systems for the PDT of tumor and bacterial infections. In particular, strategies that are tumor/bacteria targeted or activatable by the tumor/bacteria microenvironment such as enzyme/pH/reactive oxygen species (ROS) are summarized. The similarities and differences of polymeric delivery systems in antitumor and antimicrobial PDT are compared. Finally, the potential challenges and perspectives of those polymeric delivery systems are discussed.

Therapeutic delivery of siRNA with polymeric carriers to down-regulate STAT5A expression in high-risk B-cell acute lymphoblastic leukemia (B-ALL)

Overexpression and persistent activation of STAT5 play an important role in the development and progression of acute lymphoblastic leukemia (ALL), the most common pediatric cancer. Small interfering RNA (siRNA)-mediated downregulation of STAT5 represents a promising therapeutic approach for ALL to overcome the limitations of current treatment modalities such as high relapse rates and poor prognosis. However, to effectively transport siRNA molecules to target cells, development of potent carriers is of utmost importance to surpass hurdles of delivery. In this study, we investigated the use of lipopolymers as non-viral delivery systems derived from low molecular weight polyethylenimines (PEI) substituted with lauric acid (Lau), linoleic acid (LA) and stearic acid (StA) to deliver siRNA molecules to ALL cell lines and primary samples. Among the lipid-substituted polymers explored, Lau- and LA-substituted PEI displayed excellent siRNA delivery to SUP-B15 and RS4;11 cells. STAT5A gene expression was downregulated (36–92%) in SUP-B15 and (32%) in RS4;11 cells using the polymeric delivery systems, which consequently reduced cell growth and inhibited the formation of colonies in ALL cells. With regard to ALL primary cells, siRNA-mediated STAT5A gene silencing was observed in four of eight patient cells using our leading polymeric delivery system, 1.2PEI-Lau8, accompanied by the significant reduction in colony formation in three of eight patients. In both BCR-ABL positive and negative groups, three of five patients demonstrated marked cell growth inhibition in both MTT and trypan blue exclusion assays using 1.2PEI-Lau8/siRNA complexes in comparison with their control siRNA groups. Three patient samples did not show any positive results with our delivery systems. Differential therapeutic responses to siRNA therapy observed in different patients could result from variable genetic profiles and patient-to-patient variability in delivery. This study supports the potential of siRNA therapy and the designed lipopolymers as a delivery system in ALL therapy.

Ghatti gum-base graft copolymer: a plausible platform for pH-controlled delivery of antidiabetic drugs

In the present study, we aimed to develop a novel pH-sensitive polymeric delivery system (GG-g-PMMA) for antidiabetic therapy via grafting ghatti gum (GG) with methyl methacrylate (MMA) chains.

Formaldehyde-Doxorubicin Dual Polymeric Drug Delivery System for Higher Efficacy and Limited Cardiotoxicity of Anthracyclines

<p>We report the synthesis of a dual delivery system composed of a chemically bound pH-responsive formaldehyde polymer prodrug and pH-responsive doxorubicin loaded nanoparticles to increase the therapeutic index of anthracyclines by limiting the cardiotoxicity of doxocrubicin by working in synergy with formaldehyde to enable the formation of DOX-DNA adducts. Polyacrylates bearing 1,2- and 1,3- pendant diols were synthesized via reversible addition fragmentation chain transfer (RAFT) polymerization to conjugate formaldehyde, forming 5- or 6-membered acetal rings with tunable conjugation percentages (1.5 – 10 wt%) for controlled release in acidic environments of the tumor extracellular matrix. The formaldehyde-conjugated prodrugs are then combined with polyester nanoparticles formed by intermolecular crosslinking via oxime click chemistry of less than 200 nm in size containing 14 wt% encapsulated Doxorubicin (DOX). Release kinetics show a sustained release of both DOX and formaldehyde at pH 5.0, mimicking the low pH of the tumor environment whereas insignificant release was recorded at physiological pH. The cell viability of the dual delivery system combination was evaluated in 4 T1 breast cancer cells resulting in a considerably increase of cell death of about 4-fold compared to free DOX alone. The resulting polymeric delivery system is the first example reported of a DOX and formaldehyde co-administration, demonstrating the potential significant effect of formaldehyde for an improved anti-cancer efficacy of DOX and towards a reduced cardiotoxicity of DOX.</p>

Formaldehyde-Doxorubicin Dual Polymeric Drug Delivery System for Higher Efficacy and Limited Cardiotoxicity of Anthracyclines

<p>We report the synthesis of a dual delivery system composed of a chemically bound pH-responsive formaldehyde polymer prodrug and pH-responsive doxorubicin loaded nanoparticles to increase the therapeutic index of anthracyclines by limiting the cardiotoxicity of doxocrubicin by working in synergy with formaldehyde to enable the formation of DOX-DNA adducts. Polyacrylates bearing 1,2- and 1,3- pendant diols were synthesized via reversible addition fragmentation chain transfer (RAFT) polymerization to conjugate formaldehyde, forming 5- or 6-membered acetal rings with tunable conjugation percentages (1.5 – 10 wt%) for controlled release in acidic environments of the tumor extracellular matrix. The formaldehyde-conjugated prodrugs are then combined with polyester nanoparticles formed by intermolecular crosslinking via oxime click chemistry of less than 200 nm in size containing 14 wt% encapsulated Doxorubicin (DOX). Release kinetics show a sustained release of both DOX and formaldehyde at pH 5.0, mimicking the low pH of the tumor environment whereas insignificant release was recorded at physiological pH. The cell viability of the dual delivery system combination was evaluated in 4 T1 breast cancer cells resulting in a considerably increase of cell death of about 4-fold compared to free DOX alone. The resulting polymeric delivery system is the first example reported of a DOX and formaldehyde co-administration, demonstrating the potential significant effect of formaldehyde for an improved anti-cancer efficacy of DOX and towards a reduced cardiotoxicity of DOX.</p>