Cancer is a leading case of mortality worldwide. Governments spent multibillion expenses on treatment and palliative care of diseased people. Despite these generous funding and intensive research with aim to find a cure or efficient treatment for cancer, until now there is a lack in selective cancer management strategies. Conventional treatment strategies for cancer, such as surgery, cytotoxic chemotherapy, radiation therapy, hormone therapy don’t have selectivity toward cancer – the property of discrimination of healthy organs and tissues from the diseased site. Chemotherapy is very challenging as the difference between effective and lethal doses is very minuscule in most cases. Moreover, devastating side effects dramatically changes the quality of life for cancer patients. To address these issues two main strategies are intensively utilized in chemistry: (I) the design and synthesis of novel anticancer organic compounds with higher selectivity and low toxicity profiles and the second, design and preparation of biocompatible nanocarriers for imaging and anticancer compound selective delivery nanomedicine. The following dissertation combines the above two strategies as bellows: First project is related to the design and synthetic route development toward novel nature-inspired group of heterocyclic compounds – iso-Phidianidines. The second project focused on design, preparation and evaluation of hybrid theranostics (therapeutic and diagnostic in a single entity). Chapter 1 is a general background review of the major topics that will be discussed in this dissertation. The first efficient and high-yielding synthetic route toward iso-phidianidines, containing regioisomeric form of 1,2,4-oxadiazole linked to the indole via methylene bridge is reported in Chapter 2. In vitro test of the synthesized library of iso-phidianidines revealed micromolar range of cytotoxicity toward human cervical cancer cell line. Structure activity relationship revealed the importance of presence of monosubsituted amine in 3 position of oxadiazole to maintain activity. Moreover, gradual increase of activity was detected in increasing of the length of the diamine. Polyamine (spermidine) side chain demonstrated strongest anticancer activity, identified as lead compound and may be studied further as a good candidate for cervical cancer treatment. Finally, the remaining high activity of amino-terminated iso-phidianidines demonstrated that presence of guanidine group in termini is not necessary for high cytotoxicity. The second part of this dissertation (Chapter 3) discusses the rational design, wet protocol synthesis and complete characterization of the novel hybrid material – polydopamine coated iron-cobalt nanocubes (PDFCs). This material was loaded with anticancer model drug doxorubicin in one step procedure (PDFC-DOX) and the resulting drug-delivery vehicle was found to be successfully internalized by cervical cancer cells. The cytotoxicity test demonstrated inhibition of 50% of the cells at the concentration of 30μg/ml for PDFC-DOX. Moreover, the release was highly attenuated and pH-sensitive in acidic range. PDFC was also modified with fluorescein leading to green fluorescent nanoparticles PDFC-FITC, which demonstrated excellent intracellular molecular imaging property. PDFCs with one of the highest magnetic saturation among the materials used in biomedicine (226 emu/g based on core) showed the absence of any cytotoxicity in vitro and excellent MRI contrasting property (r2=186.44 mMs-1, higher than commercial contrast agents Ferridex® and Clio®), both in vitro and in vivo on mice. They were cleared out from the mice bodies in month without affecting their health. Due to the high density of core (8.3 g/cm3) they demonstrated ability to be contrast materials also for X-Ray CT diagnostic modality, increasing the tumor detection and visualization probability in combination with MRI. In addition to it’s diagnostic and drug-delivery modalities, PDFC was evaluated also for microwave-induced cytotoxicity as a novel concept in cancer treatment. As low as 10 μg/ml concentration of PDFCs in human cervical cancer cells caused extensive death above 73% upon exposure to 2,45 GHz of microwaves for one minute. Laser irradiation (808 nm, 15 minutes) of cancer cells with internalized PDFCs caused cell death above 60%. The specific absorption rate of PDFCs at 470 MHz frequency and 20 mT of the alternating magnetic field power was 180 W/g, which is nearly 100 W higher than for commercial nanoparticles (Ferridex®).

Nanotechnology-based solutions have gained burgeoning attention in medical research, as compared with conventional therapeutic modalities, they offer advantages in efficacy, safety, and scalability. Researchers have been developing fluidic systems for nanoformulations over recent decades. Despite promising results, the clinical potential of the current nanosystems is still limited by insufficient cargo (drug and gene) loading, low production, high toxicity, low colloidal stability, unsatisfied bioavailability, and batch-to-batch variation. Flash-based self-assembly is a recently developed technology that can manufacture nanoformulations in facile, consistent, reproducible, and scalable manners. Due to the turbulent and dynamic flow generated in the mixing chamber, biomaterials self-assemble into uniform nanoparticles (NPs) through precipitation or complexation. We modified and manufactured a number of flash-based systems and evaluated their dynamic mixing profiles through simulation and empirical testing for polyplex formation and nanoparticle coating, as the dynamic fluidic control is the key for biomaterial complexation and nanoparticle coating, which provides better nanoparticle colloidal stability. In Chapter 2, we formulated polyplexes and lipid-coated NPs with controllable size and enhanced colloidal stability by exploiting the dynamic mixing of the flash-based system. Bio-inspired nanosystems with engineered functions have been advancing the field of nanomedicine. Incorporating bio-inspired components can provide nanosystems with productive ways of interacting with their surroundings by diminishing nonspecific interactions or enhancing specific targeting. Membranes from different cell types, and even organisms, can be employed and merged to meet specific goals. We derived cell membranes from distinctive mammalian cell lines to improve nanosystems with smart biological interactions, such as preserving neo-antigens or enhancing specific targeting. Another potent property of utilizing cell membranes is that they provide NPs with colloidal stability. Recent studies have reported the use of cell membrane coating onto NPs in drug delivery, imaging, phototherapies, and detoxification. The derived components from the original cell source bestow the NPs with their inherent functionality without additional complicated modulation. Cell membrane coating is a top-down technique that directly derives and harnesses the natural components, evading the technical and procedural challenges in bottom-up fabrication. However, current membrane coating techniques have problems of batch-to-batch variation and low production yield, which limits its potential for clinical translation. Taking advantage of flash-based self-assembly, we standardized and scaled up the cell membrane-coating process, which is difficult to achieve in bulk mixing approaches. The optimization of cell membrane coating was explored using various simulations. The time and cost for experimental design and optimization were reduced considerably. Cell membranes derived from tumor cells contain a rich source of tumor antigens. With the potential of cell membrane coating using flash-based self-assembly, we applied the produced cell-membrane-coated mesoporous silica nanoparticles (MSN) as a biomimetic nanovaccine for cancer immunotherapy in Chapter 3. Oral delivery of drugs and genes is a relatively convenient, patient-friendly, and safe approach. Targeted and controlled oral delivery of active pharmaceutical ingredients (API) of biomimetic nanocarriers offers significant advantages in efficacy and safety compared to conventional modalities. Besides mammalian cells, the unique functionalities of other prokaryotic and eukaryotic cell types, such as bacterium and yeasts, were exploited for macromolecule delivery. Baker’s yeast, a common yeast strain closely associated with food preparation, contains valuable polysaccharides that were reported to specifically bind to the dectin-1 receptors on the specialized intestinal epithelial cells and monocytes. Exploiting the yeast’s cell wall is a biomimetic strategy when designing an oral carrier for targeted oral drug and gene delivery. We demonstrated that the specific recognition between the microfold cells (M-cells) of the small intestine and the polysaccharides on the yeast cell wall enhances the transport of yeast-based formulations across the gut epithelium and into the lymphatic tissues in chapter 4. Utilizing the micron-sized yeast capsule or decorating a nanoparticle surface with processed yeast cell wall fragments, therapeutics were efficiently delivered to the target site through the oral path. The yeast-based formulations are biomimetic systems for targeted oral delivery of therapeutics. Taken together, the goal of this thesis is to close the gap between laboratory research and clinical translation by exploring the versatility and robustness of the developed flash technology, exploiting flash-based self-assembly for scalable production of the lipid and cell-membrane-coated nanosystems, and developing a relatively safe yeast-based drug and gene delivery platform.

Functionalized gold nanoparticles (AuNPs) provide an excellent scaffold for numerous biological applications. In these systems, the gold core imparts stability to the assembly, while the monolayer allows tuning of surface characteristics such as charge and hydrophobicity. The nano-scale size and tunable surface properties have made them an ideal candidate for manipulating protein-protein/protein-nucleic acid interactions, and delivery of therapeutics. In this thesis work, it has been demonstrated how the surface coating plays an important role in achieving a desired goal. Using organic synthesis as a tool, the monolayer was tailored to afford useful particles with biocompatibility and the ability to respond in the cellular environment. The recognition units present on the periphery of particles dictates/controls their interactions with biomolecular or cell surfaces. As described here, these engineered particles exhibited a number of bio-applications, including folding of a peptide into an α-helix, binding with DNA, and cellular delivery of genes and proteins.

The main objectives of the research presented in this thesis were to understand mechanistic aspects of the photochemistry of ferritin (Ftn) and bioconjugates that consisted of Ftn linked to gold nanoparticles (AuNPs). The photochemistry investigated in this thesis repurposed Ftn from its role in biological systems as an iron-sequestration protein to potential applications in photocatalysis and nanobiomedicine. The first phase of the thesis research developed a mechanistic understanding of the underlying mechanisms involved in the photochemistry of Ftn with relevance to photocatalysis. In particular, research was designed to determine whether the light-induced bandgap excitation of the semiconductor core of horse-spleen ferritin (HSFtn) resulted in electron transfer from the inorganic core to aqueous redox active reactant via electron transport through the 2 nm thick shell of HSFtn. To investigate this mechanistic pathway, 4-5 nm copper (hydr)oxide nanoparticles were mineralized within the internal volume of HSFtn (CuFtn). It was shown that, unlike the native iron oxyhydroxide-bearing (Ferrihydrite; Fh) Ftn, the visible light photoexcitation of the inorganic core of CuFtn (measured optical bandgap to be 3.65 eV) did not exhibit any release of redox-active metal cation from the HSFtn cage into solution. By photoexciting CuFtn in the presence of aqueous chromate (Cr(VI)) it was shown that the Cr(VI) underwent reduction to Cr(III) in solution. The research strategy eliminated the possibility that metal cations escaping from the HSFtn during photoexcitation could be responsible for Cr(VI) reduction. Hence, the research showed for the first time that electrons resulting from a photoexcited metal oxide core of Ftn could transfer through the protein shell to reduce an aqueous redox active reactant. The research also investigated the wavelength-dependent photochemistry of CuFtn to show that bandgap excitation was indeed responsible for the electrons that transfer across the protein shell. In a second project, the research investigated the bioconjugation of anisotropic AuNPs—gold nanorods (AuNRs) and gold nanostars (AuNSs)—to human H-type ferritin (HFtn). After attaching the AuNRs or AuNSs to HFtn, it was shown that the near-infrared (NIR) radiation excitation of the localized surface plasmon resonance (LSPR) of the AuNR or AuNS conjugated to HFtn led to the activation of the Fh core of the protein. This NIR photochemistry (λ = 850 nm light) resulted in the release of Fe(II) from the Ftn and also led to the reduction of Cr(VI) when it was present in the aqueous phase. The novel synthetic protocols to synthesize the bioconjugates focused on attaching the AuNRs and AuNSs to the solvent-exposed cysteines (Cys) on HFtn. The research also developed techniques for the removal of colloidal stabilizing surfactants, such as cetyltrimethyl ammonium bromide (CTAB), and TritonX-100 (TX-100), from anisotropic AuNPs (AuNR/AuNS) before their attachment to HFtn. The removal of the surfactant was not only important for attachment to the HFtn, but it also removed a cytotoxic species so that the bioconjugates could be used in research that had applications to biomedicine. Research also investigated synthetic strategies to form bioconjugates that consisted of spherical gold nanoparticles (AuNSps) attached to HSFtn. In contrast to HFtn, HSFtn contains a few solvent exposed Cys groups. Hence, a challenge that was overcome in this research was to populate the outer surface of HSFtn with thiol groups (-SH) so that AuNSps could be attached. To meet this challenge, the surface primary amine-containing amino acids (Lysine) in HSFtn were modified to active Cys using N-succinimidyl S-acetylthioacetate (SATA). After this chemical modification of HSFtn, it was shown that a relatively high density of AuNSps could be attached to HSFtn. This SATA-modified HSFtn bioconjugate system (AuNSp-HSFtn) exhibited the release of Fe(II) at wavelengths of light where λ > 475 nm. In the absence of AuNSp, HSFtn released Fe(II) during exposure to light at wavelengths of light where λ < 475 nm. The activation of the bandgap at longer wavelengths of light (λ > 475 nm) was due to the excitation of the 532 nm plasmon resonance of AuNSp and the presumed transfer of hot electrons to the inner Fh core of HSFtn. A final project investigated the use of the AuNR-HFtn bioconjugates as a photodynamic strategy utilizing NIR to suppress the growth of cancer cells with the expectation that this process will occur through the mechanism of ferroptosis. We carried out experiments that exposed prostate cancer cells (PC3) to AuNR-HFtn, and during NIR irradiation, they showed the ability to limit the growth of the cells compared to experiments where the cells were exposed to just HFtn or AuNRs. The results suggested that Fe(II) released from the HFtn led to cancer cell death through a process that might be ferroptosis. Future studies will need to investigate this possibility and whether the bioconjugates developed in this thesis will offer a novel therapeutic strategy for cancer/tumor suppression. / Chemistry

No description available.

Although great progress has been made, cancer still remains one of the most prevalent maladies plaguing mankind. New treatment methodologies using nanoparticles have come to the forefront by allowing for enhanced delivery of therapeutics to the tumor site. The design of the nanoparticle should allow for long circulation times, tumor-specific targeting and efficient release at the site of action. This requires that both the external shell and internal core of the nanoparticle be carefully selected to meet the maximal criteria of each of these steps. Poly(sialic acid) (PSA), a naturally occurring polysaccharide, meets all of the benchmarks of an effective exterior coating yet remains relatively unexplored in the field of drug delivery. Due to stealth properties, natural tumor targeting ability, and inherent pH-responsive elements, PSA has frequently been viewed as a “next-generation” surface coating. Just as important, the internal composition of the carrier should aid in effective drug loading but also rapid release. The selection of the core containing groups as well as therapeutic should be maximized in order to customize the carrier to drug. Here, we have developed PSA micelles composed of various internal groups selected to maximize drug loading and facilitate release. Loading of the chemotherapeutic doxorubicin was optimized through variations in non-covalent bonding forces between drug and carrier. Furthermore, PSA micelles composed of internal pH-responsive groups of varying hydrophobicity were also developed to tailor micelle swelling points at conditions analogous towards those found upon cellular uptake. Both of these were effective delivery platforms towards MCF-7 human breast adenocarcinoma cells. / Bioengineering

RNA nanotechnology is an emerging field that holds great promise for advancing drug delivery and materials science. Recently, RNA nanoparticles have seen increased use as an in vivo delivery system. RNA was once thought to have little potential for in vivo use due to biological and thermodynamic stability issues. However, these issues have been solved by: (1) Finding of a thermodynamically stable three-way junction (3WJ) motif; (2) Chemical modifications to RNA confer enzymatic stability in vivo; and (3) the finding that RNA nanoparticles exhibit low immunogenicity in vivo. In vivo biodistribution and pharmacokinetics are affected by the physicochemical properties, such as size, shape, stability, and surface chemistry/properties, of the nanoparticles being delivered. RNA has an inherent advantage for nanoparticle construction as each of these properties can be finely tuned. The focus of this study is as follows: (1) Construction of diverse size and shape RNA nanoparticles with tunable physicochemical properties; (2) Investigation of the effect that size, shape, and nanoparticle properties have on in vivo biodistribution; (3) Development of drug encapsulation and release mechanism utilizing RNA nanotechnology; and (4) Establishment of large-scale synthesis and purification methods of RNA nanoparticles. In (1), RNA triangle, square, and pentagon shaped nanoparticles were constructed using the phi29 pRNA-3WJ as a core motif. Square nanoparticles were constructed with sizes of 5, 10, and 20 nanometers. The RNA polygons were characterized by AFM to demonstrate formation of their predicted geometry per molecular models. Furthermore, the properties of RNA polygons were tuned both thermodynamically and chemically by substitution of nucleic acid type used during nanoparticle assembly. In (2), the biodistribution of RNA nanosquares of diverse sizes and RNA polygons of diverse shapes were investigated using tumor models in nude mice. It was found that increasing the size of the nanosquares led to prolonged circulation time in vivo and higher apparent accumulation in the tumor. However, it was observed that changing of shape had little effect on biodistribution. Furthermore, the effect of the hydrophobicity on RNA nanoparticles biodistribution was examined in mouse models. It was found that incorporation of hydrophobic ligands into RNA nanoparticles causes non-specific accumulation in healthy organs, while incorporation of hydrophilic ligands does not. Lower accumulation in vital organs of hydrophobic chemicals was observed after conjugation to RNA nanoparticles, suggesting RNA has the property to solubilize hydrophobic chemicals and reduce accumulation and toxicity in vital organs. In (3), a 3D RNA nanoprism was constructed to encapsulate a small molecule fluorophore acting as a model drug. The fluorophore was held inside the nanoprism by binding to an RNA aptamer. The ability of the stable frame of the nanoprism to protect the fragile aptamer inside was evidenced by a doubling of the fluorescent half-life in a degrading environment. In (4), a method for large-scale in vitro synthesis and purification of RNA nanoparticles was devised using rolling circle transcription (RCT). A novel method for preparing circular double stranded DNA was developed, overcoming current challenges in the RCT procedure. RCT produced more than 5 times more RNA nanoparticles than traditional run-off transcription, as monitored by gel electrophoresis and fluorescence monitoring. Finally, large-scale purification methods using rate-zonal and equilibrium density gradient ultracentrifugation, as well as gel electrophoresis column, were developed.

A major challenge of cancer treatment is successful discrimination of cancer cells from healthy cells. Nanotechnology offers multiple venues for efficient cancer targeting. Magnetoelectric nanoparticles (MENs) are a novel, multifaceted, physics-based cancer treatment platform that enables high specificity cancer targeting and externally controlled loaded drug release. The unique magnetoelectric coupling of MENs allows them to convert externally applied magnetic fields into intrinsic electric signals, which allows MENs to both be drawn magnetically towards the cancer site and to electrically interface with cancer cells. Once internalized, the MEN payload release can be externally triggered with a magnetic field. MENs uniquely allow for discrete manipulation of the drug delivery and drug release mechanisms to allow an unprecedented level of control in cancer targeting. In this study, we demonstrate the physics behind the MEN drug delivery platform, test the MEN drug delivery platform for the first time in a humanized mouse model of cancer, and characterize the biodistribution and clearance of MENs. We found that MENs were able to fully cure the model cancer, which in this case was human ovarian carcinoma treated with paclitaxel. When compared to conventional magnetic nanoparticles and FDA approved organic PLGA nanoparticles, MENs are the highest performing treatment, even in the absence of peripheral active targeting molecules. We also mapped the movement through peripheral organs and established clearance trends of the MENs. The MENs cancer treatment platform has immense potential for future medicine, as it is generalizable, personalizable, and readily traceable in the context of treating essentially any type of cancer.

The development of techniques for colloidal nanoparticle synthesis has allowed scientists to fabricate materials that can manipulate light on a scale that is small even compared to the wavelength of the light itself. This ability has led to the development of myriad and diverse applications of nanostructures in wide-ranging fields. This thesis focuses on the investigation and exploitation of nanoscale material properties in the fields of medicine and energy. The unique optical properties of nanoparticles arise from their size and their high surface area to volume ratios compared to bulk materials. As a result of this relationship, the surface characteristics of nanoparticles generally dominate their properties, whereas in bulk materials the surface atoms have very little bearing on the properties of the composite. Chapter 1 gives an introduction to nanoparticles and their optical properties, including a discussion of the plasmon resonance and the properties imbued upon nanoparticles possesing such a resonance as well as the applicability of these properties that will be explored in the subsequent chapters. Chapter 2 presents a study of the interaction of cationic, hydrophobic gold nanoparticles as probes to elucidate specific regions of interest on cell surfaces. The high imaging contrast of gold nanoparticles in electron microscopy allows for visual, macroscopic observation of the aggregation patterns formed by these nanoparticles on cell surfaces. Plasmon resonant coupling between proximal nanoparticles is exploited in order to monitor nanoprobe binding and localization over time with the use of extinction spectroscopy. The role of surface proteins in the nanoparticle-cell surface interaction is elucidated, generating composite data with relevance in pharmaceutical development and pharmacokinetics. Additionally, bacteria strain-dependent toxicity is observed and subsequently investigated for smaller gold nanoparticle probes, demonstrating a potential use for nanoparticles as strain-specific antibiotics. The development of affordable, effective antibiotic technology is one of the major scientific challenges of our time; infections from pathogen-infested drinking water alone account for millions of deaths each year worldwide. In Chapter 3, we investigate the use of titanium dioxide as an inexpensive method to harness solar energy to split water into reactive species and thereby decontamitate solutions of E. coli. Though titanium dioxide is an excellent catalyst for water splitting, it requires UV irradiation, which is fairly lacking in the solar emission spectrum. Further, recuperation of titanium dioxide nanoparticles from solution is non-trivial, and its immobilization into a film greatly limits its surface area and charge carrier efficiency, thereby limiting its activity. We treat both the poor visible light absorption capability as well as the surface area limitation in this study. CdS semiconductor nanocrystals are used to extend the absorption edge of TiO₂ further into the visible light region of the spectrum by providing for lower-energy photon absorption and charge injection into titanium dioxide. TiO₂ is also electrochemically anodized to generate TiO₂ nanotube arrays, which have greatly increased surface area as well as more efficient charge transfer properties compared to thin films of TiO₂ nanoparticles. The utility of nanoparticles in increasing the light absorption of other systems continues as a theme in the work presented in the next two chapters. Chapter 4 ex- amines the plasmonic enhancement of the solar energy conversion in a biomimetic system. In this endeavor, we enhance the photocurrent generated by a light-transducing, proton-pumping protein, bacteriorhodopsin, in a 3-dimensional wet electrochemical cell. First, we increase the overall charge carrier separation with the use of a proton- selective membrane in order to minimize ionic depolarization in the cell. We then use plasmonic nanoparticles to exploit an irregularity in the bacteriorhodopsin photocycle known as the blue light effect. This effect shortens the timescale of the photocyle by more than 99% via blue photon absorption, but it has a very low natural occurrence. Plasmonic nanoparticles tuned to the blue wavelength region increase the flux of blue photons on a local level and thereby increase the overall photocurrent generation. We first examine the importance of nanoparticle field strength to photocurrent enhancement using silver nanospheres with different capping shell thicknesses. We then consider the trade-off between (1) using a nanoparticle with a plasmon resonance tuned perfectly to the blue wavelength region and (2) using a nanoparticle with a stronger field intensity but weaker energetic presence in the blue. By minimizing ionic depolarization, minimizing shielding of the plasmon electromagnetic field, and maximizing the field strength while maintaining the plasmon frequency at the proper wavelength, we demonstrate an enhancement of 5,000-fold in the photocurrent production by bacteriorhodopsin. Chapter 5 explores a variation on the theme of Chapter 4 with an application in cancer therapeutics. Here, a photodynamic cancer drug, protoporphyrin IX (PpIX), is incorporated into complexes with silver nanospheres, gold nanospheres, and gold nanorods. Each of these nanoparticles displays a plasmon resonance in a different region of the spectrum, with consequent different overlap with the absorption or emission of the drug. Photodynamic therapeutic potential is measured in situ and in vivo, and the drug activity is shown to be strongest when drug absorption overlaps with plasmon resonance. Absorption by electronic excitations in the particle crystal lattice is shown to function as a competitive light filter and decrease drug activity. Additionally, the method of attachment of the drug to the nanoparticle is examined. Maximum enhancement of drug activity is shown to require the drug to remain bound close to the nanoparticle surface, where the electromagnetic field strength is highest. This plasmonic enhancement effect on drug activity is shown to outstrip the increase in drug activity seen when using the nanoparticle solely as a delivery platform. In Chapter 6, some synthetic techniques are presented for various nanomaterials. Included are syntheses for gold, silver, and semiconductor nanoparticles of a variety of shapes and sizes as well as for TiO₂ nanotube arrays. The relationship of the ratio of capping agent to metal salt is explored for gold nanospheres, and a method for facile tuning of the longitudinal plasmon resonance displayed by gold nanorods is presented. Synthetic techniques are also presented for the nanoparticles whose applications are explored in the preceding chapters.

This study describes a novel thermoresponsive dendritic polyethylene glycol-poly(D, L-lactide) (PEG-PDLLA) core-shell nanoparticle with potential for drug delivery and controlled release. A series of dendritic PEG-PDLLA nanoparticles were synthesized through conjugation of PEG to Starburst™ polyamidoamine (PAMAM) dendrimer G3.0 and subsequent ring-opening polymerization of DLLA, in which PEG chain length (i.e., MW=1500, 6000 or 12000 Dalton) was varied; however, the feeding molar ratio of DLLA monomers to the overall PEG repeat units on the dendrimer surface was kept at 1:1. Linear PEG-PDLLA copolymers were also syntheiszed under the same condition and used as control. According to our results, dendritic PEG-PDLLA in aqueous phase could self-assemble into spherical aggregates and the size of spherical aggregates increased with PEG chain length increase. Further, spherical aggregates made of dendritic PEG-PDLLA exhibited magnified temperature-dependence in terms of solubility change and dimension expansion as compared to linear PEG-PDLLA. The most significant size expansion was observed in particles made of dendritic PEG (12000)-PDLLA, which was twice as much as that of particles made of linear PEG (12000)-PDLLA. Water insoluble antitumor drug camptothecin (CPT) was used as a model drug for encapsulation and release studies. Spherical aggregates encapsulated more CPT when dendritic PEG-PDLLA had longer PEG-PDLLA chain and/or when temperature was elevated to body temperature. This study demonstrated that nanoscale clustering PEG-PDLLA through dendrimers magnified the thermo-sensitivity of PEG-PDLLA. Successful development of such a new particulate system made of dendritic PEG-PDLLA with an expandable dimension in response to temperature change generated a new direction for designing stimuli-responsive materials.