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Critical Review of the Article “Self-Assembled Lipid-Polymer Hybrid Nanoparticles: A Robust Drug Delivery Platform”
The primary author of this article Dr. Liangfang Zhang is currently serving as a Professor in the Department of Nanoengineering at the University of California San Diego. In UCSD the research in Dr. Zhang’s lab focuses on overcoming the therapeutic barriers in the treatment of cancer and other anti-biotic resistant bacterial infections. This research article has been published by Dr. Zhang as a part of his post-doctorate research (2008) in Prof. Robert Langer’s (one of the most widely recognized and cited researchers in the fields of drug delivery) laboratory at the Massachusetts Institute of Technology.
This article focuses on the engineering of a lipid-polymer hybrid nanoparticle that can serve as a robust drug delivery vehicle with excellent properties such as high drug loading, sustained drug release profile and good serum stability along with cellular targeting. The primary hypothesis of the article is that a drug delivery platform developed via the combination of lipids and polymeric nanoparticles can combine the advantages of polymeric nanoparticle and liposomal drug delivery platforms while overcoming the disadvantages of these systems. Moreover, these hybrid nanoparticles can be used for targeted drug delivery. The authors also hypothesize; the incorporation of a lipid monolayer at the interface of the polymeric core and polymer shell will provide two main benefits: improvement in drug encapsulation by limiting drug diffusion from core and sustained drug release by reducing the rate of hydrolysis of the core.
In order to answer the research question and test the hypothesis, a strategy has been developed using a combination of single step nanoprecipitation and self-assembly techniques to engineer lipid-polymer hybrid nanoparticles (NP) comprising of three components: (1) an ester terminated poly (D, L lactic-co -glycolic acid) (PLGA) hydrophobic core, (2) a “stealth” hydrophilic core comprising of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine- polyethylene glycol (DSPE-PEG) and (3) and a soybean lecithin lipid monolayer at the interface of the PLGA core and DSPE-PEG shell. Docetaxel (DTXL), a hydrophobic anti-cancer drug, is used as a model drug for testing drug encapsulation, drug release and serum stability of the drug delivering nanoparticles. To further test whether these nanoparticles can be used for targeted drug delivery, an A10 aptamer is conjugated to the lipid-polymer hybrid NP’s.
2. Evaluation of the Article
While writing this critique, I have followed the structure of the article and hence evaluated each section correspondingly in order. Towards the end I have connected and extended upon the concepts in the article to relate to those that we have learned in class.
The introduction first discussed about the two most popular drug carriers: polymer nanoparticles and liposomes, enumerating the various advantages that these systems offer. Successful attempts have been made to mix these two materials thereby forming lipoparticles , however these systems often require two step synthesis techniques which leads to inadequate control over structure, thereby obstructing its pathway to clinical trials. The need for developing NPs in a single step, scalable and controlled fashion is then stressed. The author then states the hypotheses mentioned above, stating the three components present in the NP and hence listing the various potential advantages that this system has to offer. The introduction of the article is very well written- it proceeds by mentioning present solutions to the research problem, highlights the limitations of these solutions, and ultimately concludes by presenting a viable and attractive alternative solution.
One of the most important highlights of this article is the material selection and system design. The materials selected are PLGA core, DSPE-PEG shell and a soybean lecithin lipid monolayer at the interface. A schematic of the system is given below.
Reproduced from 
The materials selected are appropriate, logical and justified. Ester-terminated PLGA is a very popular and widely used biodegradable polymer in the field of drug delivery   . The ester linkage in the backbone of these polymers renders them degradable in-vivo via hydrolysis. Since both the L and D chiral forms of PLA have been incorporated, the resulting PLGA is amorphous in nature. Due to this there is homogeneous dispersion of the active drug in the carrier core . PLGA is approved by FDA and is hydrophobic in nature due to which it can readily encapsulate poorly water-soluble drugs. . PEG is highly hydrophilic in nature due to the presence of ether bonds as well as terminal hydroxyl molecules that can hydrogen bond with water. The use of a long chain hydrophilic molecule like PEG as the shell of the nanoparticle will prevent protein adsorption due to two reasons: steric repulsion towards hydrophobic proteins and “water barrier theory”, i.e. presence of a tightly bound water layer around the particle which thermodynamically prevents protein adsorption due to solvent entropy loss . Prevention of protein adsorption will enable the particles to be undetected by innate immunity system, thereby preventing phagocytic uptake. Moreover, the “Steric Stabilization” of the NP will prolong their circulation time  . The third component- soybean lecithin is a naturally occurring lipid extracted from soybean whereas the DSPE covalently conjugated to PEG is an FDA approved phospholipid. These lipids are water insoluble surfactants because of the presence of very long hydrocarbon chains that make them highly hydrophobic. . When these lipids are hence present at the interface between the core and the shell, they can effectively prevent the free diffusion of small drug molecules from the core. Furthermore, since these lipids can reduce the penetration of water molecules to the core, they can reduce the rate of degradation of PLGA by decreasing the rate of hydrolysis, hence providing sustained drug release instead of “Terminal Drug Dumping” . The hypothesis of the article hence seems correct and logical on the basis of material selection.
The two synthesis techniques used in this article for the design of lipid-polymer hybrid NP system are nanoprecipitation and self-assembly. To briefly summarize, a mixture of soy lecithin and DSPE-PEG was dissolved in aqueous-ethanol solution by heating the solution to 65°C. The concentration of soy lecithin was kept below its critical micelle concentration to prevent the formation of liposomes. A solution of PLGA with or without DTXL in acetonitrile is added dropwise to the lipid solution under gentle stirring followed by vortexing for 3 min. Finally, the solution is stirred gently for 2 hours at room temperature to allow self-assembly. Nanoprecipitation or solvent displacement method is a very widely used technique in the synthesis of colloidal nanocarriers . This method is based on the displacement of a semi-polar, water miscible solvent by interfacial deposition of the polymer . This technique is simple to execute and easy for scale up. Self-assembly is the process in which disordered components align themselves into controlled nanostructures via physical or chemical means . This technique overcomes various limitations of conventional methods such as batch-to-batch variation, difficulty in controlling the surface properties of the NPs, unwanted drug release and so on . It allows one to engineer NPs with desired physicochemical properties while maintaining the scalability of the process. Another critical factor in the synthesis is heating the lipid solution to ensure that all the lipids are in liquid phase. As lipids are insoluble in water, a heated ethanol-aqueous solution will enable the lipids to dissolve in the organic ethanol phase (lipids are soluble in alcohols ). Since the primary hypothesis of the article is to overcome the limitations of conventional systems such as their complex two step formulations and limited scalability, the use of nanoprecipitation and self-assembly as a one step synthesis technique is a very good choice for the article.
The characterization methods used in this article are Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), High Performance Liquid Chromatography (HPLC), and Fluorescence Microscopy (FM). The characterization methods employed in the article are appropriate. For instance, TEM was used to image the NP by using uranyl acetate negative staining to stain the lipid monolayer. TEM is a widely used technique for analysing the morphology of colloidal nanocarriers as it provides information about the size, shape and integrity of the nanoparticles . The NP size and surface charge was obtained via DLS. Particle sizing and measurement of zeta potential using DLS is appropriate as DLS is less time consuming and not subjective as compared to microscopic sizing techniques . HPLC coupled with a UV-detector was used for evaluating drug encapsulation and drug release. Calculation of encapsulation yield requires that the drug is extracted from the system using a suitable solvent, whereas determination of drug release is widely done by using dialysis techniques . Since the solvent used in HPLC is acetonitrile/water it allows for the extraction of drug from the system. PBS buffer which was used in the article is a suitable dialysis medium for in-vitro drug release studies. Furthermore, using particle size change as a function time is a suitable parameter to evaluate the physicochemical stability of the NP . However, it would have been better if the size distribution of NPs was also evaluated as it is a parameter as important as particle size for colloidal drug delivery nanocarriers .
With regards to reproducibility, it can be said that sufficient number of experiments have been performed. Particle size and zeta potential was reported on the basis of three repeat measurements. Drug encapsulation and release was evaluated using 30 slide A-lyzer MINI dialysis micro tubes. Similarly, in-vitro serum stability experiments were performed in triplicates. The two controls used throughout this article are PLGA-PEG NPs and PLGA NPs. It would have been better if the authors had also used a conventionally used liposomal drug delivery system or a lipo-particle drug carrier to better demonstrate the advantages that their system has over these alternatives.
The results and discussions section of the article is well written. The hypotheses of the article are tested and proven with correct supporting data and logical explanations. For instance, to test the hypothesis that the incorporation of a lipid monolayer at the interface of the polymer core and polymer shell would act as “molecular fence” that limits drug diffusion from core and enables sustained drug release by reducing the rate of hydrolysis of the core; the drug encapsulation and drug release in the hybrid NP was measured along with the two controls. The results demonstrated clearly that the controls in which a lipid monolayer was absent had poor encapsulation efficiency and faster drug release as compared to the hybrid NPs thereby validating the hypothesis. Similarly, to test the hypothesis that these particles can be used for targeted drug delivery, EDC-NHS activation chemistry was used to couple A10 aptamer to carboxy functionalized lipid-PEG and then made hybrid NPs using these. A10 aptamer has a high binding affinity towards prostate specific membrane antigen (PSMA) which is expressed by prostate cancer cells. The results of FM (figure given below) clearly demonstrated that PSMA-targeted drug carrying hybrid NPs were differentially taken up by the cancer cells as opposed to the cells that did not express PSMA.
It can be said that the research question addressed by this article is important. This is because one of the biggest obstructions in the translation of targeted NPs to clinical trials is the
FM results demonstrate that the aptamer-targeting NPs bind selectively to cells expressing PSMA in figure (A) and do not bind to cells that do not express PSMA. (Green fluorescence indicates binding) Images Reproduced from 
difficulty in controlling the biophysiochemical properties of such NPs while trying to come up with processes that are scalable, simple and robust . Although the author does address the problems this system might encounter during preparation of protein-based targeting systems , the overall synthesis technique and the advantages offered by this system can provide a possible solution to the present difficulties. With regards to originality, it can be concluded that this work is original. The impact factor of ACS Nano is 13.709 and this article has been cited 575 times till date. Furthermore, after the publication of this article, many articles were published that utilized similar system design .
The conclusion of the article is precise and recapitulates the system design, the hypothesis and the results. The conclusions drawn are very well supported by the data and the corresponding explanations.
3. Relating to Course:
Colloid Science plays a pivotal role in drug delivery applications. The use of sub-micron sized materials refers to Colloidal drug delivery. This method of drug delivery provides routes towards enhanced solubility of drugs, controlling drug release, modifying pharmacokinetics and so on . Nanospheres – a class of nanoparticle employed in this article, are essentially colloidal particles which have drug encapsulated within the polymer matrix. These particles range in size from 25-200 nm  which is exactly the size range of the particles in this study. Although many aspects of this article such as self-assembly, characterization of colloidal properties like zeta potential, morphology, particle size etc can be directly related to what we have learnt in class, I will discuss about one of these aspects – Nanoprecipitation.
Nanoprecipitation involves the solution of a hydrophobic solute in a polar organic solvent, which is then poured into a non-solvent (water) of the solute. The polar organic solvent is miscible with the non-solvent. This spontaneous emulsification process in the absence of surfactant is called as the “Ouzo” effect and results in the instantaneous formation of a dispersion of nanoparticles. The “Ouzo” domain lies between the binodal and the spinodal regions of the phase diagram of this ternary system. .
When the solute solution is mixed with the non-solvent, the concentration of solute in the final solution is above the thermodynamic solubility limit. If we consider the ternary phase diagram of a solute, solvent and non-solvent system, we are essentially in the metastable region due to which we get nucleation of the solute particles. The process described above is nothing but homogeneous nucleation in the metastable stage when critical supersaturation is achieved. The classical nucleation theory can be used to explain this. The Gibbs free energy associated with the process of nuclei formation is given as -
is the surface tension and
is the difference in Gibbs free energy of the two phases per unit volume. Since we lose energy in making the particle, and gain energy by putting particles into the precipitate, this
goes through a maximum. Analogous to what we have learned in class, we can hence define a critical radius or Kelvin radius r* as follows. Only if the particle size is above r*, they are stable and can grow.
We know that if supersaturation is low, we get very few stable nuclei . Hence in nanoprecipitation where we need homogeneous supersaturation, it is essential that the organic and aqueous phases are mixed rapidly and the diffusion of components is faster than the rate of nanoparticle nucleation. The particles now continue to grow until the concentration of the solute is lowered to its equilibrium concentration. When this happens, the growth of particles mainly depends on the diffusion coefficient of the solute molecules. If the time scale of nanoprecipitation is long, Ostwald Ripening  can also result in further growth of the particles. Another mechanism that is responsible for the nucleation and growth of particles during nanoprecipitation at high supersaturation is “Diffusion Limited Cluster-Cluster Aggregation” (DLCA), that mainly revolves around random collisions of particles .
Ultimately, the different factors that affect the particle size, concentration and dispersity of the nanoparticles synthesized via nanoprecipitation are surface tension, supersaturation, diffusion coefficients and Ostwald Ripening (time scale).
It can be concluded that the research question addressed by this article is important and the article is original. The hypotheses of the article are logical and well stated. The materials selected and the system design strategy employed in order to address the research question and to test the hypotheses is original, innovative, scientifically sound and well explained. The characterization methods used in the article are justified and suitable. Controls utilized in the article are proper and sufficient number of replicate experiments have been conducted to guarantee reproducibility of the results. This being said, some improvements with regards to the characterization techniques and controls have been suggested. The hypotheses of the article are tested and proven with correct supporting data and logical explanations. The conclusions drawn are supported by the results. The article is written in a clear and succinct manner with good pictorial representation of data. Overall it can be concluded that this article has very good scientific quality of work.
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