Micro/nanoparticles fabricated with triblock PLLA-based copolymers containing PEG-like subunit for controlled drug release: Effect of chemical structure and molecular architecture on drug release profile

Highlights

• PLLA-based triblock copolymers are obtained by polycondensation and ROP.

• Central blocks have different molecular architecture: block and random.

• Flexibility, crystallinity degree and wettability depend on molecular architecture.

• Dexamethasone-containing micro- and nanoparticles were prepared by miniemulsion.

• Drug release can be tuned by varying molecular architecture and particle size.

Abstract

Novel A-B-A triblock copolymers based on poly(l-lactic acid) (PLLA) were designed with an ad hoc chemical structure to prepare micro- and nanoparticles for controlled drug delivery. A block is formed by PLLA, while central B block is a copolymeric system based on poly(butylene succinate) and poly(triethylene succinate): more specifically, two copolymers with fix composition (50:50 mol:mol) and different molecular architecture were synthesized. One of them is characterized by a block architecture, i.e. long butylene succinate and triethylene succinate sequences form the macromolecular chains, the other being on the contrary a random copolymer with short sequences. The so-obtained materials were characterized from the molecular and thermal point of view. Moreover, to investigate the effect of both chemical structure and molecular architecture of the polymers synthesized on drug release kinetics, Dexamethasone-encapsulated micro- and nanoparticles were prepared by oil-in-water miniemulsion technique. These particles were subjected to thermal and morphological characterization. After that, drug release studies were carried out, and the effect of chemical composition, sequence distribution and particle size on release profile was evaluated.

Introduction

Controlled drug delivery (CDD) systems undoubtedly represent one of the most important challenges in the world of nanomedicine and pharmacokinetics. Conversely from traditional drug administration, they can guarantee a constant concentration of therapeutic agents without any relevant fluctuations, a predictable release over long time, together with a better patient compliance and protection of bioactive compounds with a short half-life. In such a way, it is possible to limit typical side effects of conventional administration, such as waste of drug and frequent dosing, with peaks even above toxic threshold or below the effective therapeutic one [1,2]. According to all these benefits, it is not surprising that the global CDD market size was valued at about 37.8 billion dollars in 2019 and it is predicted to witness a further increase, of about 7.8% by 2027, as recently reported by Grand View Research, Inc [3].

Several drug delivery technologies, i.e. long acting injectable, transdermal and transmucosal systems, nasal and oral sprays, soft gels, implantable and stimuli-responsive devices [[4], [5], [6]] have been developed to obtain a targeted release at a controlled and constant rate. In particular, micro- and nanocarriers (i.e. particles) represent a simple and cost-effective way to encapsulate both hydrophilic and hydrophobic drugs, like anti-tumoral and gene therapies, radiotherapy, proteins, antibiotics, vaccines, etc. Indeed, they can be easily prepared, using different methods (like miniemulsion and solvent evaporation, solvent displacement or salting out), making it possible to satisfy precise requirements, such as encapsulation efficiency, load and release profile, with the maximum surface/volume ratio [7]. Moreover, by tuning the carrier size, they can bring drugs in proximity to the desired target site. In case of nanoparticles, these ones can cross even physiological barriers like the blood-brain and the ocular ones. Conversely, microparticles can release drugs with predetermined kinetics and unaltered bioactivity in blood circulation [4,8], thus opening new forefront scenarios in the field of nanomedicine [9].

Among the wide plethora of micro- and nanometric CDD systems, those based on both natural and synthetic polymers represent one of the most important class. Natural polymers, such as proteins like albumin and gelatine, polysaccharides, etc, are characterized by high biocompatibility thanks to the high affinity with human tissues. On the contrary, synthetic polymers can be ad hoc designed and engineered in relation to the intended use and to the desired release profile, simply changing chemical composition, molecular architecture and synthetic strategy [9]. In fact, the correct choice of materials, together with an appropriate design of the delivery system itself, are the key to obtain an accurate and predictable administration [10].

Among synthetic polymers, biodegradable polyesters deserve particular attention, since they can be reabsorbed in the physiological environment, avoiding any surgery for the removal of the implant. The degradation by-products can be easily excreted by the human body through kidneys or eliminated in the form of CO₂ and water through metabolic processes, without any side-effect [11].

Poly(lactic acid) PLA, poly(glicolyc acid) PGA, poly(lactic-co-glycolic acid) PLGA and poly(ε-caprolactone) PCL are some of the most successful examples of polyesters employed for nanomedicine purposes, thanks to their degradability due to the presence of ester bonds, biocompatibility, low toxicity of degradation by-products and easy encapsulation of drugs. In addition, in these cases, the release of incapsulated drug can be obtained by diffusion through polymeric matrix, erosion or swelling of polymeric device, or after some predetermined stimuli [7,12].

As to PLA, the hydrophobicity and the low biodegradation rate represent its main drawbacks, the former limiting the interactions with biological structures, like extracellular matrix and cell membrane, the latter reducing the range of applications of PLA-based systems only to therapeutics with a long-term release. In order to overcome these limits, many different PLA-based CDD systems, obtained by copolymerization, have been investigated, as confirmed by the conspicuous literature related to this topic [6,7,11,[13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44]].

More recently, the aliphatic polyester poly(butylene succinate) (PBS) drew also attention in controlled nanodrug delivery, as testified by the growing number of articles present in the literature, reporting the employment of PBS and PBS-based copolymers in this field [[45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56]].

Some of the Authors of the present paper have started to synthesize and characterize PBS-based copolymers more than 10 years ago, providing different areas of applications for the new materials, including biomedical one. In order to improve the unsatisfactory properties of PBS on one hand, and to tune the final properties of the material on the other, the authors employed different tools, such as the use of comonomers with a particular chemical structure (containing heteroatoms, such as oxygen and sulfur, long and short branches, polar groups) and of different molecular architecture [45,46,[57], [58], [59], [60], [61], [62], [63], [64], [65], [66]].

Noteworthy is the poly(butylene/triethylene succinate) copolymeric system P(BSTES), consisting of samples with fixed equimolar composition and different molecular architecture. In this case, the Authors modulated the mechanical properties, the hydrophilic/hydrophobic ratio and the kinetics of both hydrolytic degradation and release of drug, through the control of block length [64]. In particular, the results obtained from this previous study evidenced the PEG-like glycol subunit (triethylene moiety) determined an increase of polymer hydrophilic character that in turn affected both hydrolytic degradation and drug kinetic release. The entity of such effect besides the composition was also related to the different block length.

In light of the results obtained so far, we thought to synthesize new A-B-A triblock copolymers of PLLA (PLLA forms the A blocks), with B central block represented by the previously investigated P(BSTES) copolymers, to prepare micro- and nanoparticles for controlled drug delivery. Many ABA PLLA-based triblock copolymers are reported in the literature, containing central B blocks with different chemico-physical characteristics, i.e. crystallinity degree, melting point, hydrophilicity and amorphous phase mobility [6,[67], [68], [69], [70]]. With the aim of properly tuning chemico-physical behaviour, in the present study, the central B block was ad hoc synthesized to provide a finer property modulation. In particular, the PBS-based copolymers have been prepared by reactive blending equimolar amounts of PBS and poly(triethylene succinate) (PTES) for different times, according to the conditions previously described [64]. In such a way, the block length could be properly controlled. The effect of both chemical structure and molecular architecture as well as of particles size on drug release kinetics was evaluated, in order to investigate the possible application of these new materials for the manufacture of micro- and nanodevices for CDD. We loaded the micro- and nanoparticles with dexamethasone, a synthetic corticosteroid functionally analogous to the endogenous hormones cortisol and cortisone, but characterized by more targeted pharmacokinetic and therapeutic properties, and by more modest side effects due to its rapid gastro-intestinal absorption.