Rupa R Sawant

Northeastern University, Boston, Massachusetts, United States

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Publications (43)166.52 Total impact

  • Rupa Sawant, Aditi Jhaveri
    10/2014: pages 87-139; , ISBN: 978-981-4520-64-5
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    ABSTRACT: Chemoradiation-resistant cancers limit treatment efficacy and safety. We show here the cancer cell-specific, on-demand intracellular amplification of chemotherapy and chemoradiation therapy via gold nanoparticle- and laser pulse-induced mechanical intracellular impact. Cancer aggressiveness promotes the clustering of drug nanocarriers and gold nanoparticles in cancer cells. This cluster, upon exposure to a laser pulse, generates a plasmonic nanobubble, the mechanical explosion that destroys the host cancer cell or ejects the drug into its cytoplasm by disrupting the liposome and endosome. The same cluster locally amplifies external X-rays. Intracellular synergy of the mechanical impact of plasmonic nanobubble, ejected drug and amplified X-rays improves the efficacy of standard chemoradiation in resistant and aggressive head and neck cancer by 100-fold in vitro and 17-fold in vivo, reduces the effective entry doses of drugs and X-rays to 2-6% of their clinical doses and efficiently spares normal cells. The developed quadrapeutics technology combines four clinically validated components and transforms a standard macrotherapy into an intracellular on-demand theranostic microtreatment with radically amplified therapeutic efficacy and specificity.
    Nature medicine. 06/2014;
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    ABSTRACT: Chemoradiation-resistant cancer cells and unresectable micro-tumors limit treatment efficacy and lead to high nonspecific toxicity or recurrence in head and neck cancers. We show the cancer cell-specific, on-demand enhancement of the chemo- and chemoradiation therapy with mechanical intracellular impact of plasmonic nanobubbles, a laser pulseinduced explosive nano-event, not a particle. We report cellular mechanisms of cancer cell-specific detection and enhancement of the entry drug and X-ray dose and validate these mechanisms in vitro and in vivo for head and neck squamous cell carcinoma. Plasmonic nanobubble technology showed more than 10-fold enhancement of the therapeutic efficacy compared to standard chemoradiation in murine models of primary, microscopic residual and recurrent diseases. At the same time our technology efficiently spared adjacent normal tissues due to the reduction of the effective therapeutic doses of drug by 30-40 fold, X-rays by 15-fold and the treatment time to a single procedure. The developed plasmonic nanobubble technology transforms a standard macro-therapy into a cell-level on-demand theranostic treatment for primary, adjuvant and adjunct applications.
    02/2014;
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    ABSTRACT: To develop a nanostructured lipid carrier (NLC) co-loaded with doxorubicin and docosahexaenoic acid (DHA) and to evaluate its potential to overcome drug resistance and to increase antitumoral effect in MCF-7/Adr cancer cell line. The NLC was prepared by a hot homogenization method and characterized for size, zeta potential, entrapment efficiency (EE) and drug loading (DL). Drug release was evaluated by dialysis in complete DMEM, and NLC aggregation was assayed in the presence of serum. The cytotoxicity of formulations, doxorubicin uptake or penetration were evaluated in MCF-7 and MCF-7/Adr as monolayer or spheroid models. The formulation had a size of about 80 nm, negative zeta potential, EE of 99%, DL of 31 mg/g, a controlled drug release in DMEM and no particles aggregation in presence of serum. The NLC loaded with doxorubicin and DHA showed the same activity as free drugs against MCF-7 but a stronger activity against MCF-7/Adr cells. In monolayer model, the doxorubicin uptake as free and encapsulated form was similar in MCF-7 but higher for the encapsulated drug in MCF-7/Adr, suggesting a bypassing of P-glycoprotein bomb efflux. For spheroids, the NLC loaded with doxorubicin and DHA showed a prominent cytotoxicity and a greater penetration of doxorubicin. These findings suggest that the co-encapsulation of doxorubicin and DHA in NLC enhances the cytotoxicity and overcomes the doxorubicin resistance in MCF-7/Adr.
    Pharmaceutical Research 02/2014; · 4.74 Impact Factor
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    ABSTRACT: To determine the effect of different drug-loaded nanocarriers (micelles and liposomes) on delivery and treatment efficacy for radiofrequency ablation (RFA) combined with nanodrugs.
    PLoS ONE 01/2014; 9(8):e102727. · 3.53 Impact Factor
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    ABSTRACT: In this study, transferrin (Tf)-modified polyethylene glycol-phosphatidylethanolamine (mPEG-PE) micelles-loaded with the poorly water soluble drug, R547 (a potent and selective ATP-competitive cyclin-dependent kinase (CDK) inhibitor), were prepared and evaluated for their targeting efficiency, cytotoxicity in vitro and in vivo to A2780 ovarian carcinoma cells, which overexpress transferrin receptors (TfR). At 10mM lipid concentration both Tf-modified and plain micelles solubilized 800 μg of R547. Tf-modified micelles showed enhanced interaction with A2780 ovarian carcinoma cells in vitro. The involvement of TfR in endocytosis of Tf-modified micelles was confirmed by colocalization studies of micelle-treated cells with the endosomal marker Tf-Alexa488. We confirmed endocytosis of micelles in an intact form with micelles loaded with a fluorescent dye and additionally labeled with fluorescent lipid. The in vitro cytotoxicity and in vivo tumor growth inhibition studies in A2780-tumor bearing mice confirmed the enhanced efficacy of Tf-modified R547-loaded micelles compared to free drug solution and to non-modified micelles. The results of this study demonstrate the potential application of Tf-conjugated polymeric micelles in the treatment of tumors overexpressing TfR.
    Molecular Pharmaceutics 12/2013; · 4.57 Impact Factor
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    ABSTRACT: The clinical application of gene silencing mediated by small interfering RNA (siRNA) has been limited by the lack of efficient and safe carriers. Phospholipid modification of low molecular weight polyethylenimine (PEI 1.8 kDa) dramatically increased its gene down-regulation capacity while keeping cytotoxicity levels low. The silencing efficacy was highly dependent on the nature of the lipid grafted to PEI and the polymer/siRNA ratio employed. Phosphoethanolamine (DOPE and DPPE) and phosphocholine (PC) conjugation did not change the physicochemical properties and siRNA binding capacity of PEI complexes but had a large impact on their transfection and ability to down-regulate Green Fluorescent Protein (GFP) expression (60%, 30% and 5% decrease of GFP expression respectively). We found that the micelle-forming structure of DOPE and DPPE-PEI dramatically changed PEI's interaction with cell membranes and played a key role in promoting PEI 1.8 kDa transfection, completely ineffective in the absence of the lipid modification.
    Nanomedicine: nanotechnology, biology, and medicine 08/2013; · 6.93 Impact Factor
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    ABSTRACT: PURPOSE: To evaluate the effects of radiofrequency (RF) ablation without and with adjuvant intravenous (IV) liposomal doxorubicin (Doxil) on microvessel morphology and patency and intratumoral drug delivery and retention. MATERIALS AND METHODS: There were 133 tumors/animals used in this experiment. First, single subcutaneous tumors (R3230 in Fischer rats and 786-0 in nude mice) were randomly assigned to receive RF ablation alone or no treatment and sacrificed 0-72hours after treatment. Next, combined RF ablation and liposomal doxorubicin (1mg given 15min after RF ablation) was studied in R3230 tumors at 0-72hours after treatment. Histopathologic assessment, including immunohistochemical staining for cleaved caspase-3, heat-shock protein 70, and CD34, was performed to assess morphologic vessel appearance, vessel diameter, and microvascular density. Subsequently, tumors were randomly assigned to receive RF ablation alone, RF ablation and liposomal doxorubicin, or no treatment (control tumors), followed by IV fluorescent-labeled liposomes (a surrogate marker) given 0-24hours after RF ablation to permit qualitative assessment. RESULTS: RF ablation alone resulted in enlarged and dysmorphic vessels from 0-4hours, peaking at 12-24hours after RF ablation, occurring preferentially closer to the electrode. The addition of doxorubicin resulted in earlier vessel contraction (mean vessel area, 47,539μm(2)±9,544 vs 1,854μm(2)±458 for RF ablation alone at 15min; P<.05). Combined RF ablation and liposomal doxorubicin produced similar fluorescence 1hour after treatment (40.88AU/μm(2)±33.53 vs 22.1AU/μm(2)±13.19; P = .14) but significantly less fluorescence at 4 hours (24.3AU/μm(2)±3.65 vs 2.8AU/μm(2)±3.14; P<.002) compared with RF ablation alone denoting earlier reduction in microvascular patency. CONCLUSIONS: RF ablation induces morphologic changes to vessels within the ablation zone lasting 12-24hours after treatment. The addition of liposomal doxorubicin causes early vessel contraction and a reduction in periablational microvascular patency. Such changes would likely need to be considered when determining optimal drug administration and imaging paradigms.
    Journal of vascular and interventional radiology: JVIR 05/2013; · 1.81 Impact Factor
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    ABSTRACT: Abstract We prepared and evaluated transferrin (Tf) and monoclonal antibody (mAb) 2C5-modified dual ligand-targeted poly(ethylene glycol)-phosphatidylethanolamine micelles loaded with a poorly soluble drug, R547 (a selective adenosine triphosphate-competitive cyclin-dependent kinase inhibitor) for enhancement of targeting efficiency and cytotoxicity in vitro and in vivo to A2780 ovarian carcinoma compared to single ligand-targeted micelles. Micellar solubilization significantly improved the solubility of R547 from 1 to 800 μg/mL. The size of modified and non-modified micelles was 13-16 nm. Flow cytometry indicated significantly enhanced cellular association of dual ligand-targeted micelles compared to single ligand-targeted micelles. Confocal microscopy confirmed the Tf receptor-mediated endocytosis of rhodamine-labeled Tf-modified micelles after staining the micelle-treated cells with the endosomal marker Tf-Alexa488. The optimized dual-targeted micelles enhanced cytotoxicity in vitro against A2780 ovarian cancer cells compared to plain and single ligand-targeted micelles. Interestingly, in vivo anti-tumor efficacy was more pronounced for the preparation with a single-targeting ligand (Tf). The specific combination Tf and mAb 2C5 did not yield the expected increase in efficacy as was observed in vitro. This observation suggests that the relationships between targeting ligands in vivo could be more complex than in simplified in vitro systems, and the results of the optimization process should always be verified in vivo.
    Journal of Drug Targeting 04/2013; · 2.77 Impact Factor
  • Rupa R. Sawant, Vladimir P. Torchilin
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    ABSTRACT: Multifunctional nanocarriers for the delivery and targeting of therapeutic and diagnostic agents in cancer therapy have received significantly increased interest in recent years.Several multifunctional nanocarriers engineered from a wide range of materials with consolidation of various functionalities for long circulation, targetability, stimuli-sensitivity, intracellular delivery for therapy and imaging have been shown to be capable of killing the desired target diseased cells with minimal side effects to provide enhanced contrast during imaging for disease location and monitor both the fate of the nanocarrier and treatment in real time. This review highlights recent advances in the design and engineering of multifunctional nanocarriers, along with the importance of intracellular delivery.
    Current Opinion in Solid State and Materials Science 12/2012; 16(6):269–275. · 5.44 Impact Factor
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    ABSTRACT: Significant progress has been made recently in the area of immunoconjugated drugs and drug delivery systems (DDS). The immuno-modification of either the drug or DDS has proven to be a very promising approach that has significantly improved the targeted accumulation in pathological sites while decreasing its undesirable side effects in healthy tissues. The arrangement for both prolonged life in the circulation and specific target recognition represents another potent strategy in the development of immuno-targeted systems. The longevity of immuno-targeted DDS such as immunoliposomes and immunomicelles improves their targetability even in the presence of the additional passive accumulation in areas with a compromised vasculature. The added use of the immuno-targeted systems takes advantage of the specific microenvironment of pathological sites including lowered pH, increased temperature, and variation in the enzymatic activity. "Smart" stimulus-responsive systems combine different valuable functionalities including PEG-protection, targeting antibody, cell-penetration, and stimulus-sensitive functions. In this review we examined the evolution, current status and future directions in the area of therapeutical immunoconjugates and long-circulating immuno-targeted DDS.
    Advanced drug delivery reviews 09/2012; · 11.96 Impact Factor
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    ABSTRACT: In vivo photoacoustic (PA) and fluorescence flow cytometry were previously applied separately using pulsed and continuous wave lasers respectively, and positive contrast detection mode only. This paper introduces a real-time integration of both techniques with positive and negative contrast modes using only pulsed lasers. Various applications of this new tool are summarized, including detection of liposomes loaded with Alexa-660 dye, red blood cells labeled with Indocyanine Green, B16F10 melanoma cells co-expressing melanin and green fluorescent protein (GFP), C8161-GFP melanoma cells targeted by magnetic nanoparticles, MTLn3 adenocarcinoma cells expressing novel near-infrared iRFP protein, and quantum dot-carbon nanotube conjugates. Negative contrast flow cytometry provided label-free detection of low absorbing or weakly fluorescent cells in blood absorption and autofluorescence background, respectively. The use of pulsed laser for time-resolved discrimination of objects with long fluorescence lifetime (e.g., quantum dots) from shorter autofluorescence background (e.g., blood plasma) is also highlighted in this paper. The supplementary nature of PA and fluorescence detection increased the versatility of the integrated method for simultaneous detection of probes and cells having various absorbing and fluorescent properties, and provided verification of PA data using a more established fluorescence based technique. (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim).
    Journal of Biophotonics 08/2012; · 3.10 Impact Factor
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    ABSTRACT: Personalized medicine, which ultimately seeks to afford tailored therapeutic regimens for individual patients, is quickly emerging as a new paradigm in the diagnosis and treatment of diseases. The idea of casting aside generic treatments in favor of patient-centric therapies has become feasible owing to advances in nanotechnology and drug delivery coupled with an enhanced knowledge of genomics and an understanding of disease at the molecular level. This review highlights polymeric immunomicelles as a class of nanocarriers that have the potential to combine diagnosis, targeted drug therapy, as well as imaging and monitoring of therapeutic response, to render a personalized approach to the management of disease. Smart multi-functional immunomicelles, as the next generation of nanocarriers, are poised for facilitating personalized cancer treatment. This review provides an assessment of immunomicelles as tools for advancing personalized therapy of diseases, with cancer being the major focus.
    Advanced drug delivery reviews 08/2012; 64(13):1436-46. · 11.96 Impact Factor
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    Rupa R Sawant, Vladimir P Torchilin
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    ABSTRACT: Liposomes, phospholipid vesicles with a bilayered membrane structure, have been widely used as pharmaceutical carriers for drugs and genes, in particular for treatment of cancer. To enhance the efficacy of the liposomal drugs, drug-loaded liposomes are targeted to the tumors by means of passive (enhanced permeability and retention mediated) targeting, based on the longevity of liposomes in blood and its accumulation in pathological sites with compromised vasculature, and active targeting, based on the attachment of specific ligands to the liposomal surface to bind certain antigens on the target cells. Antibody-targeted liposomes loaded with anticancer drugs demonstrate high potential for clinical applications. This review highlights evolution of liposomes for both passive and active targeting and challenges in development of targeted liposomal therapeutics specifically antibody-targeted liposomes.
    The AAPS Journal 03/2012; 14(2):303-15. · 4.39 Impact Factor
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    ABSTRACT: As part of our program to develop breast cancer specific therapeutic agents, we have synthesized a conjugate agent that is a conjugate of the steroidal anti-estrogen and the potent cytotoxin doxorubicin. In this effort, we employed a modular assembly approach to prepare a novel 11β-substituted steroidal anti-estrogen functionalized with an azido-tetraethylene glycol moiety, which could be coupled to a complementary doxorubicin benzoyl hydrazone functionalized with a propargyl tetraethylene glycol moiety. Huisgen [3 + 2] cycloaddition chemistry gave the final hybrid that was evaluated for selective uptake and cytotoxicity in ER(+)-MCF-7 and ER(-)-MDA-MB-231 breast cancer cell lines. The results demonstrated that the presence of the anti-estrogenic component in the hybrid compound was critical for selectivity and cytotoxicity in ER(+)-MCF-7 human breast cancer cells as the hybrid was ~70-fold more potent than doxorubicin in inhibition of cell proliferation and promoting cell death.
    Bioconjugate Chemistry 03/2012; 23(4):785-95. · 4.58 Impact Factor
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    ABSTRACT: Nanotechnology is playing an increasing role in targeted drug delivery into pathological tissues. Drug-loaded pharmaceutical nanocarriers can be delivered into diseased sites by passive targeting (spontaneous accumulation of nanocarriers in the areas with affected vasculature) or by active targeting (via site-specific ligands attached to the surface of drug-loaded nanocarriers). Subsequent level of targeting requires cellular internalization of nanocarriers and their specific association with certain individual cell organelles. The control over intracellular distribution of pharmaceutical nanocarriers requires effective and noninvasive methods of their visualization inside cells. In an attempt to enhance cellular internalization of pharmaceutical nanocarriers and their association with mitochondria specifically, we have prepared three types of cationic liposomes and investigated their intracellular distribution. The analysis was performed using Raman microspectroscopy in order to provide morphological information as well as biochemical signatures of the sample. It was demonstrated that Raman microscopy allows evaluation of the extent of mitochondrial association depending on the liposome composition.
    Molecular Pharmaceutics 02/2012; 9(4):930-6. · 4.57 Impact Factor
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    ABSTRACT: A low molecular weight polyethyleneimine (PEI 1.8 kDa) was modified with dioleoylphosphatidylethanolamine (PE) to form the PEI-PE conjugate investigated as a transfection vector. The optimized PEI-PE/pDNA complexes at an N/P ratio of 16 had a particle size of 225 nm, a surface charge of +31 mV, and protected the pDNA from the action of DNase I. The PEI-PE conjugate had a critical micelle concentration (CMC) of about 34 μg/ml and exhibited no toxicity compared to a high molecular weight PEI (PEI 25 kDa) as tested with B16-F10 melanoma cells. The B16-F10 cells transfected with PEI-PE/pEGFP complexes showed protein expression levels higher than with PEI-1.8 or PEI-25 vectors. Complexes prepared with YOYO 1-labeled pEGFP confirmed the enhanced delivery of the plasmid with PEI-PE compared to PEI-1.8 and PEI-25. The PEI-PE/pDNA complexes were also mixed with various amounts of micelle-forming material, polyethylene glycol (PEG)-PE to improve biocompatibility. The resulting particles exhibited a neutral surface charge, resistance to salt-induced aggregation, and good transfection activity in the presence of serum in complete media. The use of the low-pH-degradable PEG-hydrazone-PE produced particles with transfection activity sensitive to changes in pH consistent with the relatively acidic tumor environment.
    Biomaterials 02/2012; 33(15):3942-51. · 8.31 Impact Factor
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    ABSTRACT: Multidrug resistance (MDR) mediated by overexpression of drug efflux transporters such as P-glycoprotein (P-gp), is a major problem, limiting successful chemotherapy of breast cancer. The use of siRNA to inhibit P-gp expression in MDR tumors is an attractive strategy to improve the effectiveness of anticancer drugs. We have synthesized a novel conjugate between a phospholipid (dioleoylphosphatidylethanolamine) and polyethylenimine (PEI) for siRNA delivery, for the purpose of silencing P-gp to overcome doxorubicin resistance in MCF-7 human breast cancer cells. The dioleoylphosphatidylethanolamine-PEI conjugate enhanced the transfection efficacy of low-molecular-weight PEI, which was otherwise totally ineffective. In addition, the polyethylene glycol/lipid coating of the new complexes gave rise to small micelle-like nanoparticles with improved biocompatibility properties. Both coated and noncoated formulations delivered P-gp-specific siRNA to MDR cells. The combination of doxorubicin and P-gp silencing formulations led to a twofold increase of doxorubicin uptake and a significant improvement of the therapeutic effect of doxorubicin in resistant cells.
    Nanomedicine 01/2012; 7(1):65-78. · 5.26 Impact Factor
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    ABSTRACT: To investigate the effect of IV liposomal quercetin (a known down-regulator of heat shock proteins) alone and with liposomal doxorubicin on tumor growth and end-point survival when combined with radiofrequency (RF) tumor ablation in a rat tumor model. Solitary subcutaneous R3230 mammary adenocarcinoma tumors (1.3-1.5 cm) were implanted in 48 female Fischer rats. Initially, 32 tumors (n=8, each group) were randomized into four experimental groups: (a) conventional monopolar RF alone (70°C for 5 min), (b) IV liposomal quercetin alone (1 mg/kg), (c) IV liposomal quercetin followed 24hr later with RF, and (d) no treatment. Next, 16 additional tumors were randomized into two groups (n=8, each) that received a combined RF and liposomal doxorubicin (15 min post-RF, 8 mg/kg) either with or without liposomal quercetin. Kaplan-Meier survival analysis was performed using a tumor diameter of 3.0 cm as the defined survival endpoint. Differences in endpoint survival and tumor doubling time among the groups were highly significant (P<0.001). Endpoint survivals were 12.5±2.2 days for the control group, 16.6±2.9 days for tumors treated with RF alone, 15.5±2.1 days for tumors treated with liposomal quercetin alone, and 22.0±3.9 days with combined RF and quercetin. Additionally, combination quercetin/RF/doxorubicin therapy resulted in the longest survival (48.3±20.4 days), followed by RF/doxorubicin (29.9±3.8 days). IV liposomal quercetin in combination with RF ablation reduces tumor growth rates and improves animal endpoint survival. Further increases in endpoint survival can be seen by adding an additional anti-tumor adjuvant agent liposomal doxorubicin. This suggests that targeting several post-ablation processes with multi-drug nanotherapies can increase overall ablation efficacy.
    Journal of Controlled Release 12/2011; 160(2):239-44. · 7.63 Impact Factor
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    ABSTRACT: siRNA therapeutics are currently regarded as promising candidates to make a leap forward in the search for treatments of various hard to cure diseases. In order to exploit the full potential of siRNA based therapeutics, development of delivery systems that can efficiently guide the siRNA molecules to their target without major side effects will be the key to success. Lipid based delivery systems, originating from earlier research in the fields of gene delivery, are the most studied candidates for siRNA delivery. Here we discuss the requirements that need to be met by these siRNA delivery systems to ensure adequate stability after systemic application and subsequent deposition in the target tissue. The encountered hurdles in the blood stream and the solutions proposed in literature are discussed.
    Journal of Controlled Release 10/2011; 158(3):362-70. · 7.63 Impact Factor

Publication Stats

392 Citations
166.52 Total Impact Points

Institutions

  • 2008–2014
    • Northeastern University
      • • Center for Pharmaceutical Biotechnology and Nanomedicine
      • • Department of Pharmaceutical Sciences
      Boston, Massachusetts, United States
  • 2010–2011
    • Beth Israel Deaconess Medical Center
      • Department of Radiology
      Boston, MA, United States