pH-responsive high stability polymeric nanoparticles for targeted delivery of anticancer therapeutics

Abstract

The practical application of nanoparticles (NPs) as chemotherapeutic drug delivery systems is often hampered by issues such as poor circulation stability and targeting inefficiency. Here, we have utilized a simple approach to prepare biocompatible and biodegradable pHresponsive hybrid NPs that overcome these issues. The NPs consist of a drug-loaded polylactic-co-glycolic acid (PLGA) core covalently 'wrapped' with a crosslinked bovine serum albumin (BSA) shell designed to minimize interactions with serum proteins and macrophages that inhibit target recognition. The shell is functionalized with the acidity-triggered rational membrane (ATRAM) peptide to facilitate internalization specifically into cancer cells within the acidic tumor microenvironment. Following uptake, the unique intracellular conditions of cancer cells degrade the NPs, thereby releasing the chemotherapeutic cargo. The drugloaded NPs showed potent anticancer activity in vitro and in vivo while exhibiting no toxicity to healthy tissue. Our results demonstrate that the ATRAM-BSA-PLGA NPs are a promising targeted cancer drug delivery platform.

Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

“…Peptides possess a number of pharmaceutically desirable properties, including the ability to selectively bind to specific targets with high potency, thereby minimizing off-target interactions and reducing the potential for toxicity 87 . However, a major disadvantage of peptides is their low in vivo stability 73 . Small molecules, with their constrained backbone, are inherently more stable than peptides 24,88 , which is reflected in the substantially longer in vivo circulation half-life and prolonged presence in the bloodstream of ADH-6 relative to ReACp53.…”

“…Following intraperitoneal injection, ADH-6 quickly entered circulation, with the peak concentration in serum mice (~21 µg/mL) occurring at 2 h post-injection ( Figure 8a). The in vivo circulation half-life 72 of ADH-6 (t1/2 = ~3.6 h) was much longer than that of ReACp53 (t1/2 ~1.5 h) 14 , or other chemotherapeutics of a comparable size, such as doxorubicin (t1/2 < 30 min) 73 or paclitaxel (t1/2 ~1.7 h) 74 . Moreover, ADH-6 was detected in the plasma up to 48 h after administration, whereas ReACp53 was eliminated from the bloodstream in 24 h 14 .…”

“…Cell viability/toxicity was measured using two complementary assays as previously described 73 : i) CellTiter 96 AQueous One Solution (MTS) assay, which measures reduction of the tetrazolium compound MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4sulfophenyl)-2H-tetrazolium, inner salt) to soluble formazan, by mitochondrial NAD(P)H-dependent dehydrogenase enzymes, in living cells 110,111 ; and ii) Dead Cell Apoptosis assay, in which Alexa 488conjugated annexin V is used a sensitive probe for detecting exposed phosphatidylserine in apoptotic cells 112 , and red-fluorescent PI, a membrane impermeant nucleic acid binding dye, assesses plasma membrane integrity and distinguishes between apoptosis and necrosis 113 .…”

Recent Advances in Bioplastics: Application and Biodegradation

“…These biodegradable polymeric DDS should fulfil two major requirements: performance and safety. In addition, the DDS have to be capable of maximum encapsulation efficiency of the target drug [84] have increased residence time in the target tissue, maximum bioavailability to achieve a therapeutic effect, and biodegradation in a timeframe compatible with the healing of the target tissue [85]. At the same time these biodegradable polymers should be safe; i.e., not inducing in vivo toxicity and not promoting an inflammatory response by the immunological system [86].…”

Setting out on a fantastic voyage to advance nanomedicine

“…These different translocation types depend on synergism between nanoparticle size, surface charge and ligand chemistry. In another study, Prof Magzoub and his group prepared pH-responsive nanoparticles with a drug-loaded PLGA core with a cross-linked BSA corona (to avoid opsonisation) 4 . By functionalising with an ATRAM peptide that binds the cell membrane at low pH-such as tumour microenvironment-these nanoparticles display excellent in vitro and in vivo efficacy while evading recognition by macrophages.…”